RPS Pharmacy and Pharmacology Reports, 2023, 2, 1–23

https://doi.org/10.1093/rpsppr/rqad002
Advance access publication 18 January 2023
Review

Advance drug delivery and combinational drug approaches

for hepatoprotective action of berberine: a progressive
overview with underlying mechanism
Satish Sardana1, Rupa Gupta1, Kumud Madan2, , Dheeraj Bisht3, , Vijay Singh Rana4, ,
Samir Bhargava4, and Neeraj Kumar Sethiya4,*,

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1
Amity Institute of Pharmacy, Amity University Haryana, Gurugram, India
2
School of Pharmacy, Sharda University, Greater Noida, India
3
Department of Pharmaceutical Sciences, Sir J. C. Bose Technical Campus Bhimtal, Kumaun University, Nainital, India
4
Faculty of Pharmacy, DIT University, Dehradun, India
*
Correspondence: Neeraj Kumar Sethiya, Faculty of Pharmacy, DIT University, Mussoorie Diversion Road, Dehradun, Uttarakhand-248009, India.
Email: neeraj.sethiya@dituniversity.edu.in

Abstract
Objectives Berberine has attracted prominent interest recently due to its wide pharmacological actions in the management and treatment
of several diseases including the liver. However, restricted bioavailability and permeability make this drug as a better choice to develop sev-
eral value-added products for the improvement of both safety and efficacy. Much of researches has already been conducted in this direction
using several approaches to fix this issue. Therefore, the current article was designed to summarize all approaches taking together to enhance
hepatoprotection by berberine including molecular mechanism.
Methods Online scientific databases from PubMed were assessed for collecting information on berberine. All the collected information were
classified and incorporated into different sections such as recent progress of research on advance drug delivery systems and combinational ap-
proaches addressing the above issue for improvement of hepatoprotective action of berberine.
Key findings The electronically PubMed database search yielded 7454 articles from different countries in several languages. Out of them 270
articles published between 1932 and 2022 were included, corresponding to all detailed overviews on berberine including research pertaining to
toxicity and safety, biodistribution, pharmacokinetics, biopharmaceutics classification system, hepatoprotection against various hepatotoxicant
agent, advance drug delivery system, combinational drug approaches, clinical trial for hepatoprotection and patents. The review of the literature
reveals that berberine exhibits a potent hepatoprotective action with several molecular action mechanisms. Additionally, current trends of formu-
lation technology for enhancement of hepatoprotective action of berberine in terms of safety and efficacy are well co-related in present work.
Conclusion It was well established and concluded from the present work that both advance drug delivery system and combinational drug ap-
proaches may serve for enhancement of restricted hepatoprotective action of berberine due to poor bioavailability, solubility and permeability.
Additionally, berberine-based advanced delivery system including in combination with bioavailability and permeability enhancers may provide an
added advantage in the near future to meet the objectives.

Received: November 19, 2022. Editorial Acceptance: January 17, 2023

© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact journals.permissions@oup.com
2 Satish Sardana et al.

Graphical Abstract

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Keywords: Berberine; liver; hepatoprotection; advanced drug delivery; drug combinations
Abbreviations: ACC, 1-aminocyclopropane-1-carboxylic acid; ACCα, acetyl-CoA carboxylase alpha; ACLY, ATP-citrate lyase; ACOX1, Acyl-CoA oxidase; Akt/
FoxO3a/Skp2, Akt kinase/Forkhead box O transcription factor/S-phase kinase-associated protein; ALT/AST, alanine and aspartate aminotransferase; AMPK,
activated protein kinase; AMPK-α, activated protein kinase catalytic α-subunit; AST, aspartate transaminase; ATF6/SREBP, activating transcription factor
6/ sterol regulatory element-binding proteins; Bcl-2, B-cell leukemia/lymphoma 2 protein; BCL2, B-cell lymphomagenesis; Ber, berberine; CCl4, carbon tetra
chloride; CCND1, cyclin D1 protein; CD147, cluster of differentiation 147; CD36, cluster of differentiation 36; CDKIs p21Cip1, cyclin-dependent kinase inhibitors;
CPT1α, carnitine palmitoyltransferase 1α; CXCR4, chemokine receptor type 4; ERK1/2, extracellular signal-regulated kinase ½; FASN, fatty acid synthase;
FBG, fasting blood glucose; FXR/SREBP-1c/FAS, farnesoid X-receptor/sterol regulatory element-binding protein-1c/ fatty acid synthetase; G4 PAMAM, poly-
amidoamine; G6P, glucose-6-phosphate dehydrogenase; GGT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; HeLa cells, henrietta lacks cell line;
HepG2, human hepatoma cell line; HHL-5, human hepatocyte line 5; HMGB1/TLR4/NF-κB, high mobility group box 1/ toll-like receptor 4/ nuclear factor kappa
B; HNF4α, hepatocyte nuclear factor 4α; Huh7, human hepatoma-derived; HUVECs, human umbilical vein endothelial cells; IFG, impaired fasting glucose; IL,
interleukin; LDR, low-density lipoprotein; L-PK, L-type pyruvate kinase; LPS, lipopolysaccharide; LSI, lifestyle intervention; MCD, methionine–choline-deficient;
MMP-2, matrix metallopeptidase-2; mTOR, mammalian target of rapamycin; MTTP, microsomal triglyceride transfer protein; NAFLD, non-alcoholic fatty liver
disease; NASH, non-alcoholic steatohepatitis; NF-κB, nuclear factor kappa B; NLRP3, NLR family pyrin domains-containing protein-3; Nrf2/HO-1, Nuclear factor
erythroid 2-related factor/ heme oxygenase-1; Nrf2-Keap1, nuclear factor erythroid 2–related factor 2- Kelch-like ECH-associated protein 1; NUR77, nuclear
receptor 77; P2X7, purinergic type 2 receptor family (the second signal to inflammasome activation); P38MAPK, p38 mitogen-activated protein kinases; PANSS,
positive and negative syndrome scale; PCSK9, proprotein convertase subtilisin/kexin type 9 serine protease; PEPCK, phosphoenolpyruvate carboxykinase;
Pio, pioglitazone; PPAR, peroxisome proliferator-activated receptors; PPARα, peroxisome proliferator-activated receptor α; PPARγ, peroxisome proliferator-
activated receptor gamma; P-TEFb, positive transcription elongation factor b; RCT, randomised clinical trial; ROS, reactive oxygen species; SirT3, Sirtuin T3
gene; SREBP-1c, sterol regulatory element-binding protein-1c; T2DM, Type 2 diabetes mellitus; TBK1 and IKKɛ, TANK-binding kinase 1 & IκB kinases; THRSP,
thyroid hormone responsive protein; TLR4, toll-like receptor 4; TNF-α, tumour necrosis factor alpha; UCP2, uncoupling protein 2; VEGF, vascular endothelial
growth factor

Introduction Physically berberine (berberis species) is a yellow-coloured

Berberine is a plant-based compound characterized
chemically as quaternary ammonium salt of cationic
isoquinoline alkaloids group (2,3-methylenedioxy-9,10-
dimethoxyprotoberberine chloride; C20H18NO4+) with a
molecular mass of 336.36122  g/mol. The compound was
isolated first time from Hydrastis canadensis (goldenseal)
in 1917.[1, 2] Subsequently, many of rhizomes, roots and
barks of various plants are explored including Arcangelisia
flava, Argemone mexicana, Berberis aquifolium, B. aristata,
B. vulgaris, B. darwinii, B. petiolaris, Coptis chinensis,
C. japonica, C. teeta, Cortex rhellodendri, Eschscholzia
californica, Hydrastis canadensis, Mahonia aquifolium,
Phellodendron amurense, Rhizoma coptidis, Tinospora
cordifolia and Xanthorhiza simplicissima as a possible
source for identification and separation of berberine majorly
from Berberideae, Panaveraceae, Ranunculaceae, Rutaceae
and Menispermaceae families.[3, 4]
pigment having strong fluorescent characteristics under ul-
traviolet light. Due to its stronger yellow colour, berbe-
rine and berberine-containing plants were widely utilized
in the past for the purpose of dye in textile, wool, leather
and wood industries.[5] The multifunctional nature of berbe-
rine as a health-promoting agent was established therapeu-
tically due to diversified effects on several enzymes, many
receptors and pathways related to cell signalling that have
been widely explored and reviewed in subsequent time inter-
vals.[6–22] Further, hepatoprotective activity of berberine have
been explored experimentally using various models including
in vitro, in vivo, ex vivo and clinical trial with underlying
molecular mechanism reviewed in various time interval.[23–25]
In brief, many of the review articles are focussed spe-
cially NAFLD,[26–32] liver fibrosis,[33] obesity and liver func-
tions.[34] Despite many therapeutic advances including
hepatoprotection berberine is also categorized under BCS III
Advance drug delivery and combinational drug approaches
drugs due to its poor oral bioavailability and intestinal ab-
sorption.[4] This poor bioavailability and intestinal absorp-
tion issues limit the effective clinical application of berberine
to translate therapeutic and health-promoting outcome.[14] In
this connection, several attempts have been made to the im-
provement of oral bioavailability and intestinal absorption
via advance drug delivery system have been discussed and
reviewed by several authors.[20, 35–40] However, still there is no
any work pertaining to summarizes approaches such as com-
bination therapy, complexation, structure modification and
recent advance drug delivery system for the improvement of
hepatoprotective action of berberine is present in the litera-
ture. Therefore, the current study was designed to deliver the
recent progress of work established towards making berbe-
rine as suitable drug candidates for prevention and treatment
of liver-related disorder by incorporating several approaches.
Additionally, data related to toxicity profile, pharmacoki-
netics, molecular mechanism of hepatoprotection on various
liver diseases, drug delivery system, clinical trial and recent
status of intellectual property right protection are summar-
ized for better understanding.
Methods
The exhaustive search of the literature was accomplished
with the information retrieved by using online electronic
search on PubMed database, google and Indian Patent search
using Berberine as the searching keyword. Publications does
not fall under toxicity and safety, biodistribution, pharma-
cokinetics, biopharmaceutics classification system (BCS),
hepatoprotection against various hepatotoxicant agent
focussing mechanism of action, advance drug delivery
system, combinational drug approaches and clinical trial for
hepatoprotection were excluded from the study. The elec-
tronic PubMed database search yielded 7454 articles from
different countries in several languages. Out of the 270 ar-
ticles published between 1932 and 2022 were included. The
major limitation of the present work is several studies are
published in other than the English language. Further, the
present study was designed in such a way to accomplish our
objective and should be not similar to the earlier published
review
Toxicity and Safety Profile
LD50 of pure berberine was reported to be 25 mg/kg in mice
and considered to be safe with rare to mild adverse effects.[41]
However, some studies also claim the development of gastric
lesions as associated side effects of berberine and its deriva-
tives.[42, 43] Such, gastrointestinal side effects including diar-
rhoea and constipation may be associated with the delays of
small intestinal transit time from experimental evidence.[44]
Some of the notable interaction warrants the safety of the
berberine including berberine displaces bilirubin from al-
bumin,[45] thiopental, tolbutamide and warfarin, from their
protein binding sites to increase plasma levels[46] and increase
the level of cyclosporine A.[47, 48] Some of the clinical studies
also indicated adverse effects such as transient elevation of
bilirubin level in serum,[49] distribution of sex-hormone syn-
thesis pathway,[50] and suppression of both immune func-
tions, that is cellular and humoral.[51] Overall, the safe use
of berberine including a dosage ranges of 500–1000 mg/day
3
for the most part of studies. However, the potential risk of
clinically relevant pharmacological interaction is mainly lim-
ited to cyclosporine and warfarin.[52, 53] Additionally, in a very
recent article biodistribution and pharmacokinetic profile of
both berberine and its metabolites were discussed on liver
hepatocytes.[54]
Biodistribution, Pharmacokinetics and BCS
Class of Berberine
As per the biopharmaceutical classification system (BCS), ber-
berine has been placed as a class III drug.[55–57] As per reports,
it was found to be sparingly soluble in water with poor intes-
tinal absorption and oral bioavailability. In fact, during the
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study, the absolute bioavailability of berberine was found to
be <1%, and even absorbed berberine excreted back to the in-
testinal lumen via P-glycoprotein involvement from the gut.[10,
58]
In brief, a study shown on a rat using noncompartmental
model, where unbound berberine was transported to bile via
active transportation and which was further metabolized in
liver by action of P450 enzyme system through demethylation
in phase I and glucuronidation in the phase II, respectively.[59]
Additionally, four main glucuronide conjugates based berbe-
rine metabolites were identified in rats, that is berberrubine,
demethyleneberberine, jatrorrhizine and thalifendine.[60]
Subsequently, intestinal bacterial flora was found to play role
in enterohepatic circulation of both berberine and its con-
jugated metabolites.[58] On the contrary, only a very small
amount of unchanged form of berberine was found to be
eliminated by urines.[61] Further, berberine was found to be
distributed into all major organs with the highest amount
obtained in the liver and readily excreted via the urine after
absorption.[62]
Berberine as Hepatoprotective Agent
Evidence on berberine exhibited hepatoprotective actions
on various liver toxicity models by both in vitro and in vivo
along with postulated mechanism of action were summarized
in Table 1. In brief liver protection by berberine on various
models including chemical/metal/drug-induced hepatotox-
icity, parasite/microorganism infected liver damage, obesity/
fatty liver damage, hepatocellular carcinoma, hepatitis c virus
and ischemia/reperfusion injuries were incorporated. Among
these chemical/metal/drug-induced hepatotoxicity and
NAFLD were found to be the most studied models. Several
dose by several routes of administration has been incorpo-
rated to get the effect as depicted in Table 1. In this context,
5 mg/kg/b.w. was the minimum oral dose and 324 mg/kg/b.w.
was found to be the maximum dose of berberine to translate
hepatoprotective effects. However, for intraperitoneal admin-
istration minimum dosage was 0.4 mg/kg/b.w and the max-
imum dose was 10 mg/kg/b.w, respectively. The brief details
of the studies are summarized herewith:
Chemical/metal/drug-induced hepatotoxicity
Hepato-toxicants such as acetaminophen,[63, 64] arsenic,[65]
carbon tetra chloride,[66–72] cisplatin,[73] cyclophosphamide,[74]
diethylnitrosamine,[75] doxorubicin,[76–78] ethanol,[79–81] ferrous
sulfate,[82] lead acetate,[83] methotrexate,[84–86] paraquat,[87] ra-
pamycin,[88] tert-butyl hydroperoxide,[89] streptozotocin,[90,
91]
thioacetamide,[92, 93] tunicamycin[94] and more than two
4 Satish Sardana et al.

Table 1 Hepatoprotective action of berberine and postulated molecular mechanism

Dose (kg/body Model Mechanism

weight/day)

CHEMICAL/METALS/DRUG INDUCED
Acetaminophen
5 mg i.p. Steatohepatitis and acute acetaminophen tox- Interferes with activation of the NLRP3 inflammasome pathway
icity via interference with P2X7 (a purinergic receptor responsible for
inflammasome activation). [63]
5 mg i.p. Acetaminophen-induced toxicity in mice Inhibition of hepatocyte necrosis, inflammatory response and oxidative
stress.[64]
Arsenic
10, 25 and 50 Arsenic-induced mitochondria toxicity on rat Reduced ROS generation, without restoring mitochondrial membrane

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μM liver. integrity.[65]
Carbon tetra chloride (CCl4)
120 mg oral CCl4-induced toxicity in rats Antioxidant action.[66]
80–120 mg oral CCl4-induced acute toxicity in rats Effective for both prevention and treatment of liver toxicity.[67]
5 and 10 mg i.p. CCl4-intoxicated mice Attenuate oxidative or nitrosative stress along with inflammatory re-
sponse inhibition.[68]
3 and 9 mg i.p. CCl4-intoxicated mice Liver fibrosis amelioration via suppression of hepatic oxidative stress
and fibrogenic potential followed by degradation stimulation of colla-
gen deposits by MMP-2.[69]
25 and 50 mg CCl4-induced liver fibrosis in mice AMPK activation and blocking of expression of Nox4 and Akt.[70]
oral
50 mg oral CCl4-induced NASH rats Ameliorated hyperlipidemia, oxidative stress, observed neurotoxicity,
inflammation, hyperglycemia and hyperinsulinemia.[71]
5, 10 and 15 mg CCl4-induced liver injury in rats Effectively regulating Nrf2-Keap1-antioxidant-responsive element-
oral related proteins and genes expression and p53 pathway-mediated hepa-
tocyte apoptosis inhibition.[72]
Cisplatin
0.4 mg i.p. Cisplatin-induced nephro- and hepato-toxicity Intensified enzymatic oxidant status and downregulate lipid
in rats peroxidation by decrease in TLR4 gene expression.[73]
Cyclophosphamide
50 mg oral Cyclophosphamide-induced hepato-toxicity in Exhibit anti-inflammatory and antioxidant action by alleviating ele-
rats vated serum marker enzymes.[74]
Diethylnitrosamine
200 mg oral Diethylnitrosamine-induced cirrhosis in rats Improve intestinal dysbacteriosis, responsible to reduce liver toxicity
induced by pharmacological or pathological intervention.[75]
Doxorubicin
60 mg/kg oral Doxorubicin-induced hepatotoxicity in mice Attenuated inflammatory cell infiltration, vascular congestion,
hepatocellular degeneration, necrosis and fibrosis.[76]
5–20 mg oral Doxorubicin-induced acute hepatorenal toxicity Liver protective effects.[77]
in rats
Various dose Doxorubicin-induced hepatotoxicity Exhibit antioxidant and immune response with low to moderate cyto-
chrome modulation.[78]
Ethanol
200 mg oral Ethyl alcohol-induced inflammation and lipid Attenuated vascular congestion, lipid synthesis (FASN, THRSP, ACC,
deposition in rats AMPK-α, ACLY), regulating uptake of fatty acids (CD36) and lipid
oxidation (CPT1α, PPARα, ACOX1).[79]
10, 50 and Ethanol induce liver disease in male mice Exhibit immunosuppressive response.[80]
100 mg oral (C57BL/6J)
200 and 300 mg Ethanol-induced oxidative stress and steatosis Restoring hepatocyte nuclear factor 4α/microsomal triglyceride trans-
oral in mice fer protein pathways, peroxisome proliferator-activated receptor, that
is α/peroxisome proliferator-activated receptor-gamma Co-activator-
1α.[81]
Ferrous sulfate (FeSO4)
10 mg oral FeSO4-induced hepatic and renal damages in Reduction in lipid peroxidation and ability to chelate iron.[82]
rats.
Lead acetate
50 mg oral Lead acetate induce toxicity in rats Inhibiting lipid peroxidation and enhancing antioxidant defenses.[83]
Methotrexate
Advance drug delivery and combinational drug approaches 5

Table 1 Continued

Dose (kg/body Model Mechanism

weight/day)

25 and 50 mg Methotrexate-induced liver injury Attenuated both oxidative stress and apoptosis, possibly via Nrf2/
oral HO-1 pathway and PPARγ upregulation.[84]
100 mg oral Methotrexate-induced liver toxicity in rats Ameliorative both oxidative stress and any of biochemical changes.[85]
50 mg oral Methotrexate induced liver toxicity in rats P38MAPK, Keap-1 and NF-κB inhibition. Further, reduced expression
of pro-apoptotic protein Bax and apoptotic protein caspase-3 with
increase in the expression of anti-apoptotic protein Bcl-2.[86]
Paraquat
5 mg oral Paraquat-induced toxicity in rat Significant decrease in ROS formation, cell death and LDH release.
Also inhibits cellular glutathione depletion and over all improve in liver
function enzyme level.[87]

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Rapamycin
62.5 µM Rapamycin-mediated human hepatoma cell Synergistically inhibiting the mTOR signalling pathway mediated
(HCC cells SMMC7721 and HepG2) death through CD147 with at least in part.[88]
Tert-butyl hydroperoxide
0.5 and 5 mg Tert-butyl hydroperoxide-induced oxidative Exhibit chemopreventive role via reducing oxidative stress in living
i.p. damage in liver of rat systems.[89]
Streptozotocin
75, 150 and Streptozotocin-type 2 diabetic rats liver Up-regulation of P-TEFb expression, antilipid peroxidation and antiox-
300 mg oral idant status.[90]
75, 150 and Streptozotocin-type 2 diabetic rats liver Metabolic-related PPARalpha/delta/gamma protein expression modu-
300 mg oral lation in liver.[91]
Thioacetamide
50 mg oral Thioacetamide injection in rats Treat liver fibrosis via antioxidant and anti-inflammatory action.[92]
10 mg i.p. Rat liver xenobiotic-metabolizing enzymes after Normalization of both cytochromes P450-dependent and flavin-
partial hepatectomy containing monooxygenases.[93]
Tunicamycin
75, 150 and Tunicamycin induced ER-stress liver injury mice Improves ER stress in hepatocytes and regulate gut microbiota in
300 mg oral (C57BL/6) mice.[94]
More than one
4 mg oral Acetaminophen or CCl4-induced toxicity in Selective therapeutic effect against acetaminophen.[95]
rodents
200 mg oral Thioacetamide (TAA) and carbon tetrachloride Inducing ferrous redox reaction to activate ROS-mediated HSC
(CCl4)-induced liver fibrogenesis in mouse ferroptosis.[96]
50, 100 or Rat liver fibrosis-induced by multiple hepato- Regulation of the both anti-oxidant system and lipid peroxidation.[97]
200 mg oral toxic factors.
PARASITE/MICROORGANISM
12 mg/kg oral Schistosoma mansoni-induced hepatic injury Ameliorate liver damage and oxidative stress conditions caused by
in mice schistosomiasis.[98]
HFD/OBESITY/FATTY LIVER
200 mg oral HFD-feds rats Partially counteract dysregulation of MTTP by reversing the methyla-
tion state, leading to reduce in hepatic fat content.[118]
187.5 mg oral HFD-fed NAFLD rats Improve insulin resistance by up-regulating both mRNA and protein
levels of IRS-2 (key molecule identified for insulin signaling path-
way).[99]
162 and 324 mg HFF-fed NAFLD rats Downregulate the expression of UCP2 proteins and UCP2 mRNA
oral levels in hepatic tissue.[100]
100 mg oral HFD-fed rats Improve mitochondrial SirT3 activity, normalizing mitochondrial func-
tion and energetic deficit state caused by impaired OXPHOS.[119]
200 mg oral HFD-fed steatotic animal Completely reversed the MRAK052686 and Nrf2 reduced expres-
sion.[122]
200 mg oral HFD-fed NAFLD rats Restore the expression of L-PK via demethylation and the increase in
histone H3 and H4 acetylation levels.[101]
200 mg oral HFD-feds mice Alleviates NASH and its predisposing factors. Normalization of gut
microbiota might underlie its effect.[120]
100 mg oral Obesity-associated NAFLD on mice Suppression of inflammation without involving AMPK.[102]
50 mg oral HFD-fed mice and oleate-palmitate-induced Inhibition of the ERK/mTOR pathway.[258]
lipotoxicity hepatocytes
6 Satish Sardana et al.

Table 1 Continued

Dose (kg/body Model Mechanism

weight/day)

200 mg oral MCD-fed NAFLD male mice (C57BL/6J) Involvement of ATF6/SREBP-1c pathway for reversing ER stress-
activated lipogenesis.[103]
150 mg oral HFD-fed NAFLD rats Restore the liver function and provide significant protection via ameli-
orating barrier function of intestine.[104]
50 or 100 mg HFD-fed blunt snout bream Megalobrama Attenuated liver damage via the protection for mitochondria.[259]
oral amblycephala
150 mg oral Wild type (WT) and intestine-specific FXR Inhibit BSH, elevate TCA and activate FXR, majorly involve in uptake
knockout (FXRint–/–) mice for Hepatic Lipid of long-chain fatty acids inhibition in the liver.[105]
Metabolism
10 µM and HFD-induced NAFLD rats and Huh7 cells Improve damage caused by oxidative stress.[260]

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200 mg oral
0.2 g oral HFDC-fed NASH mice CXCR4 signalling pathways inhibition via restoration of the balance of
α1-AT and NE levels.[123]
150 mg oral HFD-induced NAFLD rats Inhibiting glucogenesis via regulating lipid metabolism.[106]
100 mg oral C57BL/6 mice with AD (containing 1.25% cho- Liver protection under cholesterol overloading via autophagic flux
and 20 µg/ml lesterol and 0.5% cholic acid) and HCD (con- regulation including cholesterol metabolism and COX2-prostaglandin
taining 1.25% cholesterol) and HepG2 cells synthesis inhibition.[261]
5 mg i.p. HFHS-fed liver-specific SIRT1 knockout mice Mediating autophagy and FGF21 activation.[262]
and their wild-type littermates for hepatic ste-
atosis
200 mg oral HFD-fed NAFLD mice Ameliorate lipid accumulation and inflammation via reduction in LPS
production and release of inflammatory cytokines by hepatic macro-
phages.[107]
100 mg oral HFD-fed NAFLD rats Activation of the Nrf2/ARE signalling pathway.[108]
250 mg/kg oral STZ injection + HFHC for NASH-HCC mice Involvement of p38MAPK/ERK-COX2 pathway for inflammation and
model angiogenesis genes regulation.[124]
30 mg/ml HFD-fed NAFLD mice and patients Caused phosphorylation of SREBP-1c and AMPK. Further, attenuates
hepatic steatosis and reduces liver TG synthesis via AMPK-SREBP-1c-
SCD1 pathway activation.[109]
300 mg oral HFD-fed NAFLD mice Fatty acid β-OX partly inhibition via SIRT3-mediated LCAD
deacetylation caused by HFD.[110]
100 mg oral HFD-fed NAFLD rodents SIRT3/AMPK/ACC pathway activation to ameliorates, HFD-induced
hepatic steatosis.[111]
300 mg oral HFD-fed NAFLD rats Angptl2 pathway regulation.[112]
200 mg oral HFD-fed NAFLD rats Inhibit nuclear translocation of NF-κB via involvement of TLR4/
MyD88/NF-κB pathway.[113]
100 mg oral HFD-fed NAFLD rats Reverse the abnormal expression of LDLR and MTTP followed by
lipid synthesis inhibition.[114]
300 mg oral A rat model of NASH was established by a Restoration of Treg/Th17 ratio and regulation of chemerin/CMKLR1
high-fat diet in rats signalling pathway responsible for overall inflammation and lipid dep-
osition reduction in liver.[125]
0, 5, 25 and HFD-fed ApoE-/- for therosclerotic lesions and Improves lipid disorder, reduced aortic plaque formation and alleviated
50 µg/ml and hepatic steatosis hepatic lipid accumulation, mainly associated with PCSK9 down-
50–100 mg oral regulation through ERK1/2 pathway.[263]
50 mg oral HFD-fed NAFLD and NASH mouse Multiple genes expression modulation responsible for hepatic stellate
cell activation and cholangiocyte proliferation.[31]
50 mg/kg oral HFD-fed black sea bream (Acanthopagrus Reduced hepatic lipid accumulation by lipolysis gene expression
schlegelii) upregulation and lipogenesis gene expression downregulation followed
by improvement in muscle lipid contents.[115]
1.4 and 0.075 g HFD-fed NALFD male mice Repressed complex I in liver and gut, mainly responsible for lipid
oral metabolism inhibition (alleviates from both obesity and fatty
liver).[116]
5–10 mg i.p. HFHS-fed NAFLD mouse and a palmitate- Transcriptional regulation of SETD2 activity for hepatoprotection via
treated hepatocyte steatosis model were gener- steatosis.[117]
ated
300 mg oral HFD-fed mice Elevated HIF-2 expression, insulin resistance and disorder of lipid me-
tabolism.[121]
Advance drug delivery and combinational drug approaches 7

Table 1 Continued

Dose (kg/body Model Mechanism

weight/day)

HEPATOCELLULAR CARCINOMA (HCC)/OTHER CELL LINES

1–300 μM Tight-seal whole-cell patch-clamp techniques in Calcium and potassium channels inhibitory actions in isolated rat hep-
enzymatically isolated rat hepatocytes. atocytes.[264]
0–20 μg/ml Activated rat hepatic stellate cells (CFSCs) Hepatic stellate cell proliferation inhibition for liver fibrosis preven-
tion.[126]
0–96 mM and HCC- HepG2 cells and HepG2 human HCC Induction of p53 and Fas apoptotic system activity.[127]
40 or 80 mg i.p. xenograft mice
0.1, 5, 10, 15, HepG2 cells treated with high concentrations Effective against high-concentration leptin-induced NAFLD via up-
20, 25 and 30 of leptin. regulation of the mRNA expression of leptin receptor.[128]
μM/l

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0, 5, 10 and 15 Tumour-induced angiogenesis using HCC Prevents secretion of VEGF and down-regulates VEGF mRNA expres-
mM HUVECs sion.[139]
1–100 μM Primary hepatocytes were isolated from non- Transcription regulation on hepatic genes responsible for fatty acid and
fasted male SD glucose metabolism.[265]
0.8–50 μM HCC and SMMC-7721 cells. Both ROS-triggered caspase-dependent induction and caspase-
independent apoptosis pathways.[140]
10, 50 and 100 Human HCC-HepG2 AMPK activation in HepG2 cells followed by both apoptotic and
μM autophagic death induction.[129]
15 μM Human HCC-HepG2 Lipid-lowering effects by improvement in low-density lipoprotein re-
ceptor expression.[130]
200 µM and H22, HepG2 and Bel-7404 cells and H22 trans- Arachidonic acid metabolic pathway suppression.[131]
12.5, 25 and planted tumour model in mice HCC
50 mg oral
100 μM HCC HepG2 cell line Retarded cancer cell growth by regulating SP1 and miR-22-3p and its
downstream targets, that is BCL2 and CCND1, in HCC.[132]
25, 50, 100 and HCC cell lines Bel-7402 and SMMC-7721 HCC cell invasion and migration via uPA receptor inactivation by up-
200 μM regulation of PAI-1 and down-regulation of uPA.[141]
0, 10, 50 and HepG2 Involvement of NF-κB p65 pathway for apoptosis promotion.[133]
100 μM
0.01, 0.1 and NAFLD based on HepG2 cells induced by oleic Improvement on lipid metabolism disorder via FXR/SREBP-1c/FAS
1 μM acid pathway regulation.[134]
1–10 μM Steatosis using HepG2 hepatocytes Suppression of TNF-α expression and mitochondrial biogenesis induc-
tion to decreased cellular ROS.[135]
10 mM Immortalized MIHA hepatocyte cell line for Early Growth Response 1 (EGR1) level upregulation responsible for
hepatic steatosis miR-373 expression transactivation.[266]
0, 30, 60 and Cell cycle arrest in HCC Promotes CDKIs p21Cip1 and p27Kip1 expression via Akt/FoxO3a/
120 μM Skp2 axis regulation. Further induces G0/G1 phase cell cycle ar-
rest.[142]
200 mg oral ABCA1 in QSG-7701 hepatocytes and in Upregulation of ABCA1 protein levels via involvement of PKCδ to re-
NASH-induced mice duce the phosphorylation of serine residues in ABCA1.[267]
50 and 100 μM HepG2 cell lines Antiproliferative effect of berberine was due Akt, PHLPP2 and Mst1
involvement (an autoinhibitory triangle).[268]
5, 10 and 20μM L02 hepatocytes injury induced by D-GalN Inhibits inflammation and mitochondria-dependent apoptosis.[269]
(5mM)/TNF-α (100 ng/ml)
2.5 mmol/l FGF21 expression in primary mouse hepato- Induced AMPK activation responsible for hepatic FGF21 expression
cytes. via NUR77.[270]
0, 10, 20 and Radiation-induced oxidative stress and apopto- Strengthens radiosensitivity through Nrf2 signalling pathway suppres-
40 μM sis in Huh7, HHL-5 and HepG2 cells sion.[143]
2.68 mM HCC-HepG2 cells. Radiosensitizer towards treating liver cancer by blocking autophagy
and cell cycle arrest resulting in senescence.[136]
1, 5 and 25 μg/ FFA-induced steatosis on HepG2 cells Activate SIRT1-FoxO1-SREBP2 signal pathway.[137]
ml
50 µM HCC cells (Hep3B, HepG2), HEK293 and Antagonizes β-catenin pathway via β-catenin translation and mTOR
Huh7 cells activity inhibition.[138]
HEPATITIS C VIRUS
0, 2, 5, 10, 20, Cell culture-derived HCV viral pseudoparticles Targets viral E2 glycoprotein.[144]
50 and 100 μM bearing HCV glycoproteins for hepatitis C virus
entry-related assays
8 Satish Sardana et al.
Table 1 Continued
Dose (kg/body Model
weight/day)
0, 1, 5, 10, 20, Human hepatoma cells harboring hepatitis C
40, 80, 100, 200 virus RNA
and 400 μM
ISCHEMIA/REPERFUSION (I/R)
100 mg oral IR hepatic injury after orthotopic liver trans-
plantation (OLT) on rats
18.6 mM Preservation solution for rat model of ex vivo
liver transplant
100 mg oral Hepatic cold ischemia rat model
or multiple[95–97] were studied for hepatoprotective action of
berberine. Among these carbon, tetra chlorides induce liver
toxicity is one of the most studied model. Based on the data
the major postulated mechanism for hepatoprotection of ber-
berine are:
• NLRP3 inflammasome pathway activation interference
(associated with the P2X7 activation), inflammatory cell
infiltration and inflammation suppression via IL-10, IL-
6, LPS, TNF-α and ET involvement.
• Inhibition of oxidative stress through ROS generation
and also participate by regulating antioxidant-responsive
element-related proteins and genes, that is Nrf2-Keap1-
expression.
• Inhibition of hepatocyte necrosis via p53 pathway-
mediated hepatocyte apoptosis.
• Improvement in fibrogenic potential via involvement of
MMP-2 responsible for stimulation of collagen deposits
degradation.
• AMPK activation and blocking of expression of Nox4
and Akt.
• Reducing lipid peroxidation via TLR4 gene expression
regulation.
• Attenuated vascular congestion, lipid synthesis (FASN,
THRSP, ACC, AMPK-α, ACLY), regulating uptake of
fatty acids (CD36) and lipid oxidation (CPT1α, PPARα,
ACOX1).
• Low to moderate cytochrome modulatory po-
tentials (Normalization of both flavin-containing
monooxygenases and cytochromes P450).
• Restoring hepatocyte nuclear factor 4α/microsomal
triglyceride transfer protein pathways, peroxisome
proliferator-activated receptor, that is α/peroxisome
proliferator-activated receptor-gamma Co-activator-
1α.
• Ability to chelate iron and Nrf2/HO-1 pathway
upregulation.
• Keap-1, P38MAPK and NF-κB inhibition.
• Reduced expression of apoptotic protein caspase-3 and
pro-apoptotic protein Bax followed by increased anti-
apoptotic protein Bcl-2 expression.
• Significant decrease in LDH release. Inhibits cellular glu-
tathione depletion inhibiting the mTOR signalling path-
way mediated through CD147.
• Up-regulation of P-TEFb expression.
• PPARalpha/delta/gamma protein expression modulation
in liver responsible for metabolism.
Mechanism
Autophagy inhibition irrespective of the HCV genome presence.[145]
Promotes liver transplantation during I/R injury partly via Sirt1/
FoxO3α-mediated autophagy activation.[146]
Preserves mitochondrial function and bioenergetics by protecting liver
from toxic effects caused by I/R.[147]
Reducing apoptosis, possibly via PI3K/Akt/mTOR signalling pathway
modulation.[148]
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• ER stress improvement in hepatocytes and gut microbi-
ota regulation.
Parasite/microorganism
In this model very few studies were conducted. One of the
study in this context was conducted by inducing hepatic in-
jury in mice by using Schistosoma mansoni (a water-borne
parasite). During this study berberine (12  mg/kg oral) was
found to ameliorate both liver damage and oxidative stress
conditions produced due to schistosomiasis.[98]
Obesity/fatty liver
High-fat diet causing NAFLD,[99–117] obesity[118–121] and
NASH[115, 122–125] were major protocol adopted for testing the
effect of berberine through various mechanism. The minimum
and maximum selected dose was found to be 30 to 300 mg/kg
for oral administration and 5 to 10 mg/kg for intraperitoneal
administration, respectively. Additionally, the dose upto 50
µg/ml was tested for in vitro model studied. Animal such as
rats, mice, black sea bream and blunt snout bream are ma-
jorly used. Based on the data the major postulated mechanism
for hepatoprotection of berberine are:
• Reduced hepatic fat content by reversing HFD-elicited
dysregulation of MTTP.
• Protein and mRNA levels of IRS-2 upregulation leading
to improvement in insulin resistance.
• Down-regulation of both UCP2 proteins and UCP2
mRNA expression levels in hepatic tissue.
• Improvement in mitochondrial SirT3 activity followed
by mitochondrial function normalization and energetic
deficit caused by impaired OXPHOS.
• Completely reverse the reduced Nrf2 and MRAK052686
expression.
• Restore the expression of L-PK via demethylation and
the increase in histone H3 and H4 acetylation levels.
• Suppression of inflammation without involving AMPK.
• Inhibition of the ERK/mTOR pathway.
• Involvement of ATF6/SREBP-1c pathway for reversing
ER stress-activated lipogenesis.
• Ameliorating intestinal barrier function.
• Restore liver function by mitochondria protection and
normalization of gut microbiota.
• Inhibit BSH, elevate TCA and activate FXR majorly in-
volved in the uptake of long-chain fatty acids inhibition
in the liver.
Advance drug delivery and combinational drug approaches
• Progression of hepatic steatosis to steatohepatitis was
downregulated via reduction of oxidative stress.
• CXCR4 signalling pathways inhibition via restoration of
the balance of α1-AT and NE levels.
• Inhibiting glucogenesis via regulating lipid metabolism.
• Liver protection under cholesterol overloading via
autophagic flux regulation including cholesterol metab-
olism and COX2-prostaglandin synthesis inhibition.
• Mediating autophagy and FGF21 activation.
• Ameliorate lipid accumulation and inflammation via re-
duction in LPS production and release of inflammatory
cytokines by hepatic macrophages.
• Activation of the Nrf2/ARE signalling pathway.
• Involvement of p38MAPK/ERK-COX2 pathway for in-
flammation and angiogenesis genes regulation.
• Caused phosphorylation of SREBP-1c and AMPK. Further,
attenuates hepatic steatosis and reduces liver TG synthesis
via AMPK-SREBP-1c-SCD1 pathway activation.
• Fatty acid β-OX partly inhibition via SIRT3-mediated
LCAD deacetylation caused by HFD.
• SIRT3/AMPK/ACC pathway activation to ameliorates,
HFD-induced hepatic steatosis.
• Regulate Angptl2 pathway.
• Inhibit nuclear translocation of NF-κB via involvement
of TLR4/MyD88/NF-κB pathway.
• Reverse the abnormal expression of LDLR and MTTP
followed by lipid synthesis inhibition.
• Restoration of Treg/Th17 ratio and regulation of chemerin/
CMKLR1 signalling pathway responsible for overall in-
flammation and lipid deposition reduction in liver.
• Improves lipid disorder, reduced aortic plaque formation
and alleviated hepatic lipid accumulation, mainly asso-
ciated with PCSK9 down-regulation through ERK1/2
pathway.
• Multiple genes expression modulation responsible for
hepatic stellate cell activation and cholangiocyte prolif-
eration.
• Reduced hepatic lipid accumulation by lipolysis gene ex-
pression upregulation and lipogenesis gene expression
downregulation followed by improvement in muscle
lipid contents.
• Repressed complex I in the liver and gut, mainly respon-
sible for lipid metabolism inhibition (Alleviates from
both obesity and fatty liver).
• Transcriptional regulation of SETD2 activity for
hepatoprotection via steatosis.
• Elevated HIF-2 expression, insulin resistance and disor-
der of lipid metabolism.
Hepatocellular carcinoma
Hepatic stellate,[126] HCC (hepatocellular carcinoma)
HepG2,[127–138] HUVECs,[139] SMMC-7721,[140, 141] H22,[131] Bel
7404,[131, 141] MIHA,[133] QSG-7701,[142] Huh7,[138] HHL-5,[143]
Hep3B and HEK293[138] cells line was used to investigate the
hepatoprotective action of berberine through various mech-
anism. Upto 96 mM dose of berberine was found to be tested.
The various postulated mechanism for hepatoprotective ac-
tion of berberine are:
• Calcium and potassium channels inhibitory actions in i-
solated rat hepatocytes.
9
• Hepatic stellate cell proliferation inhibition for liver fi-
brosis prevention.
• Induction of p53 and Fas apoptotic system activity.
• Effective for high-concentration leptin-induced NAFLD
via up-regulation of the mRNA expression of leptin re-
ceptor.
• Prevents secretion of VEGF and down-regulates VEGF
mRNA expression.
• Transcription regulation on hepatic genes responsible for
fatty acid and glucose metabolism.
• Both ROS-triggered caspase-dependent induction and
caspase-independent apoptosis pathways.
• AMPK activation in HepG2 cells followed by both apop-
totic and autophagic death induction.
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• Lipid-lowering effects by improvement in low-density
lipoprotein receptor expression.
• Arachidonic acid metabolic pathway suppression.
• Retarded cancer cell growth by regulating SP1 and miR-
22-3p and its downstream targets, that is BCL2 and
CCND1, in HCC.
• HCC cell invasion and migration via uPA receptor inac-
tivation by up-regulation of PAI-1 and down-regulation
of uPA.
• Involvement of NF-κB p65 pathway for apoptosis pro-
motion.
• Improvement on lipid metabolism disorder via FXR/
SREBP-1c/FAS pathway regulation.
• Suppression of TNF-α expression and mitochondrial bi-
ogenesis induction to decreased cellular ROS.
• Early Growth Response 1 level upregulation responsible
for miR-373 expression transactivation.
• Promotes CDKIs p21Cip1 and p27Kip1 expression via
Akt/FoxO3a/Skp2 axis regulation. Further induces G0/
G1 phase cell cycle arrest.
• Upregulation of ABCA1 protein levels via involvement of
PKCδ to reduce the phosphorylation of serine residues in
ABCA1.
• Antiproliferative effect of berberine was due Akt,
PHLPP2 and Mst1 involvement (an autoinhibitory trian-
gle).
• Inhibits inflammation and mitochondria-dependent ap-
optosis.
• Induced AMPK activation responsible for hepatic FGF21
expression via NUR77.
• Strengthens radiosensitivity through Nrf2 signalling
pathway suppression.
• Radiosensitizer towards treating liver cancer by blocking
autophagy and cell cycle arrest resulting in senescence.
• Activate SIRT1-FoxO1-SREBP2 signal pathway.
• Antagonizes β-catenin pathway via β-catenin translation
and mTOR activity inhibition.
Hepatitis c virus
A study included cell culture-derived HCV viral
pseudoparticles bearing HCV glycoproteins for hepatitis C
virus entry-related assays of berberine (0, 2, 5, 10, 20, 50
and 100 μM) via targeting the viral E2 glycoprotein was es-
tablished.[144] In another studies, effect of berberine (0, 1, 5,
10, 20, 40, 80, 100, 200 and 400 μM) was investigated on
human hepatoma cells nurturing hepatitis C virus RNA via
autophagy inhibition.[145]
10
Table 2 Drug delivery system associated with improvement of bioavailability of berberine
Drug delivery approaches/methods
Dendrimer
Dendrimer of G4 PAMAM via conjugation and encapsulation ap-
proaches was developed
Erythrocyte-hemoglobin self-assembly system
Interaction with erythrocyte and the combination with Hb
Hydrogel/beads
Self-assembled beads developed by shaking alpha-cyclodextrin with
soybean oil
A novel composite pH-responsive hydrogel beads using carboxy-
methyl starch-g-poly (acrylic acid)/palygorskite/starch/sodium algi-
nate (CMS-g-PAA/PGS/ST/SA)
Silk sericin-derived hydrogel by thiol-ene click chemistry
Liposomes
Liposomes was developed through co-precipitation method from
berberine bisulfate and polyvinyl pyrrolidone (PVP) with the ratio of
1: 5.
Liposomes was developed by thin-film hydration/extrusion method.
Memory fibers
Programme release through shape memory fibres by core-sheath wet-
spinning technology
Microparticles
Microparticles in hollow capsular devices (in house 3D printed) via
emulsion crosslinking method
Microemulsion
Oleic acid, Tween 80 and PEG400 was incorporate to get the
microemulsion
Microemulsion technique was developed via pseudo tertiary phase
diagrams
Zuojin Wan microemulsion-based gel and hydrogel delivery system
Nanoparticles/nano-crystals/nanocarriers
Biogenic gold nanoparticles using Trapa bispinosa was developed
Chitosan-coating based nano-liposomal carrier
Chitosan/fucoidan-taurine based conjugated nanoparticles
Polymeric nanoparticles via nanoprecipitation technique
Solid lipid nanoparticles
Janus magnetic mesoporous silica nanoparticles based on Fe3O4 head
for magnetic targeting and a mesoporous SiO2 body for delivery of
berberine.
PEG-lipid-PLGA hybrid nanoparticles by solvent evaporation method
Spherical shaped sliver based nano-particles was synthesized by the
biofabrication technique
Brij-S20-modified nanocrystals
Janus gold mesoporous silica nanocarriers using folic acid
Sonication, coating and extrusion based on red blood cell membrane-
camouflaged BH-loaded gelatin nanoparticles (RBGPs)
PLGA nanoparticles by nanoprecipitation and encapsulation
Natural polysaccharide (chitosan-alginate)-based nanoparticles by
ionic gelation method
Nanoparticles developed by anti-solvent precipitation methods
Nanostructured lipid carriers using modified solvent injection method
Satish Sardana et al.
Outcome
Conjugated dendrimers was found to be more prominent.[149]
Low plasma and high tissue concentration was achieved.[150]
Bioavailability improvement of poorly water soluble or lipophilic
drug.[151]
Improvement in efficacy and stability.[152]
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Eco-friendly way for biomedical industries.[153]
Improve the absorption by 4-fold compared with free drug.[154]
Exhibits tumour growth inhibition in HepG2 tumour-bearing mice.[155]
Smart drug delivery-based vehicles of targeted drug with highly adjust-
able doses.[156]
Improve sustained and prolonged absorption with oral bioavailability
enhancement.[157]
Promising for oral drug delivery system.[158]
Improvement of absorption in the intestinal tract.[159]
Improvement in relative bioavailability for transdermal route.[160]
Active against folic acid expressing HeLa cells.[161]
Promising for the oral delivery and improve in bioavailability.[162]
Effective for treatment of defective intestinal epithelial tight junction’s
barrier.[163]
Improvement in entrapment efficiency.[164]
Effective against hepatosteatosis via lipogenesis inhibition and lipolysis
induction.[165]
Safe and effective against hepatocellular carcinoma.[166]
Improvement in relative oral bioavailability, affinity, liposolubility, drug-
loading efficiency and sustained/controlled release action.[167]
Improves acetaminophen-induced liver and kidney damage probably via
proinflammatory factor & NF-kB factors inhibition.[168]
Improvement in the oral bioavailability having poor water solubility
and Pgp-mediated efflux.[169]
Triple-therapies strategies for liver cancer.[170]
RBGPs hold the potential to achieve sustained-release and long circula-
tion to avoid side effects associated by high plasma concentration.[171]
Liver protection is higher as compare to normal drug.[172]
Effective for oral delivery of poorly soluble and permeable drugs.[173]
Improved in liver protection and high blood concentration.[174]
Mitigate hepatic I/R-induced lesion via modulation of HMGB1/TLR4/
NF-κB signaling and autophagy.[175]
Advance drug delivery and combinational drug approaches
Table 2 Continued
Drug delivery approaches/methods
Self-emulsifying or micro-emulsifying microsphere/drug
Membrane emulsification technology
Efficient self-micro-emulsification region was identified by pseudo
ternary phase diagrams
The optimal self-microemulsion formula was composed of OP,
propanediol, cinnamon oil and total alkaloid from Rhizoma Coptidis
with the ratio of 4:8:3:6.
Solid dispersion
Solid dispersion by solvent evaporation technique
ASD with hydrogenated phosphatidylcholine
Taste-masked microcapsules containing disintegrating tablets
Orally disintegrating tablets containing microcapsule and coated
with Eudragit E100.
Ischemia/reperfusion injuries
Berberine (100  mg/kg/ oral) was investigated on ischemia/
reperfusion (IR) hepatic injury after orthotopic liver trans-
plantation on rats and found to promote liver transplant is-
chemia/reperfusion injury partly via Sirt1/FoxO3α mediated
autophagy activation.[146] Moreover, berberine (18.6 mM) was
found to preserve mitochondrial function and bioenergetics,
protecting the liver from the damaging effects caused by I/R,
when tested as a part of preservation solution for rat model
of ex vivo liver transplant.[147] Similarly, berberine (100 mg/
kg/oral) in another study was investigated on hepatic cold is-
chemia rat model via reducing apoptosis, possibly involving
PI3K/Akt/mTOR signalling pathway modulation.[148]
Berberine-Based Advance Drug Delivery
System
In Table 2 details on berberine-based advance drug delivery
system was discussed. Various drug delivery approaches
such as dendrimer,[149] erythrocyte-hemoglobin self-as-
sembly system,[150] hydrogel/beads,[151–153] liposomes,[154, 155]
memory fibers,[156] microparticles,[157] microemulsion,[158–160]
nanoparticles/nano-crystals/nanocarriers,[161–175] self-
emulsifying or micro-emulsifying microsphere/drug,[176–178]
solid dispersion[179, 180] and taste-masked microcapsules con-
taining disintegrating tablets[181] were investigated to improve
the solubility, bioavailability and permeability related issues.
The major outcome of these delivery systems is to overcome
the solubility issue, bioavailability hurdle and permeability
followed by improvement in efficacy and safety.
Berberine-Based Combinational Drug
Approaches
Novel combination, structure modifications and advance
drug delivery system using berberine for improvement of sol-
ubility, bioavailability and permeability was shown in Table 3.
Berberine was investigated by combination with bicyclol,[182]
chitosan and chitosan hydrochloride,[55] chlorogenic acid
and tocotrienols,[183] coptisine, palmatine, epiberberine and
jatrorrhizine,[184] Coptis chinensis,[185] Coptidis rhizoma ex-
tract,[186] curcumin,[187] curcumin with dextran coating,[188]
11
Outcome
Suitable for poorly water soluble drug.[176]
Bioavailability improvement.[177]
To get small particle size and stable formulation.[178]
Promising strategies for oral bioavailability improvements.[179]
Improvement in intestinal absorption, permeability and bioavailabil-
ity.[180]
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Taste masking to improve patient compliance.[181]
Cynara scolymus, Cichorium intybus and Taraxacum
officinalis,[189] evodiamine,[190–192] ferulic acid,[193] insulin sensi-
tizer,[194] lysergol,[195] metformin,[196] plant stanols,[197] puerarin
and baicalin,[198] red yeast rice and policosanols,[199] red yeast
rice and Morus alba leaves extract,[200] red yeast rice and
chitosan,[201] red rice, liposomal berberine and curcumin,[202]
resveratrol,[203, 204] resveratrol and glibenclamide,[205] Rhizoma
Coptidis with Cortex Cinnamomi,[206] S allyl cysteine,[207]
silymarin,[208, 209] simvastatin,[210] sitagliptin,[211] and sodium
caprate.[212–214] Among advance drug delivery including com-
binational approach such as baicalin complex,[215] baicalin
and gardenia fruit complex,[216] baicalin nanocrystals,[217]
carboxymethylcellulose and hyaluronic acid hydrogel,[218]
carboxymethyl hexanoyl chitosan/hyaluronic acid pol-
ymer gel,[219] cellulose nanofiber based hydrogel,[220] citric
acid based salt cocrystal,[221] Coptidis rhizoma extract based
nano-drug delivery,[222] cucurbitacin B based phospho-
lipid complex,[223] doxorubicin based liposomes,[224] fumaric
acid based co-crystal,[225] 2-hydroxypropyl-β-cyclodextrin
(HPβCD) complex,[226] magnolol based complex,[227] modi-
fied β-cyclodextrin encapsulation,[228] modified sodium algi-
nate and NIPAM based nanogels,[229] O-hexadecyl-dextran
based nanoparticles,[230] ibuprofen-based co-crystal,[231]
mangiferin salt,[232] polylactide-poly (ethylene glycol)
diblock copolymers based self-assembled filomicelles,[233]
sodium N-[8-(2-hydroxybenzoyl) amino] caprylate based
microsphere,[234] sulfonato-β-cyclodextrin based supra-
molecular nanoparticle,[235] vanillin-cross-linked chitosan
microcarriers,[236] and wogonoside based complex.[215]
Similarly, structure modification using a core molecules of
berberine such as berberrubine,[237] demethyleneberberine,[238,
239]
demethylenetetrahydroberberine,[240] oxyberberine[241] and
9-O-benzoyl- substitution.[242]
Clinical Trial for Hepatoprotection
Table 4 describes the various clinical trial conducted on ber-
berine in terms of investigations of hepatoprotective action
on human beings. In brief, berberine was tested for liver func-
tions,[47, 210, 243] hepatitis B and hepatitis C,[244] hypercholester-
olemia,[245] NASH,[183, 246, 247] and NALFD.[248–254] The major
mechanisms included are
12 Satish Sardana et al.

Table 3 Combinations/structure modifications and drug delivery approaches including berberine for improving hepatoprotective action

Combinations/structure modifications and drug delivery approaches Outcome

Combinations
Bicyclol Alleviates NAFLD.[182]
Chitosan and chitosan hydrochloride Improvement in intestinal absorption.[55]
Chlorogenic acid and tocotrienols Improve metabolic system and liver parameters on overweight
subjects.[183]
Coptisine, palmatine, epiberberine and jatrorrhizine Synergetic action for lowering efficacy on cholesterol.[184]
Coptis chinensis Improvement in detoxification.[185]
Coptidis rhizoma extract (metabolites) Improvement in pharmacokinetics.[186]
Curcumin Exhibited improved ameliorative action on rats with NAFLD than
lovastatin.[187]

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Curcumin with dextran coating Promote oral absorptions with prolonged circulation and synchro-
nized biodistribution with improved ameliorative effects on NAFLD
in mice.[188]
Cynara scolymus, Cichorium intybus and Taraxacum officinalis Normalize CCl4-induced rat liver toxicity.[189]
Evodiamine Improved apoptosis on HHC.[190]
Evodiamine Cholesterol absorption inhibition in intestine during HFD.[191]
Evodiamine NAFLD via gut microbiota and intestinal barrier safety.[192]
Ferulic acid Cleansing promoters for detoxification.[193]
Insulin sensitizer NAFLD with significant influence on oxidative stress.[194]
Lysergol Bioavailability enhancement.[195]
Metformin Improvement in NAFLD with type 2 diabetes mellitus.[196]
Plant stanols Reduces plasma cholesterol synergistically in rats.[197]
Puerarin and baicalin Protects from NAFLD via upregulation of hepatic IR expression and
PPAR-γ levels.[198]
Red yeast rice and policosanols Reduces cholesterol levels via improved endothelial function and insu-
lin sensitivity.[199]
Red yeast rice and Morus alba leaves extract (LopiGLIK) Significantly reduced levels of serum CLC (−11.4%) without changing
PCSK9 plasma levels.[200]
Red yeast rice and chitosan Primary prevention by improving Non-HDL cholesterol levels on
dyslipidemia individuals.[201]
Red rice (fermented), liposomal berberine and curcumin Improve lipid profiles and reduces inflammatory markers.[202]
Resveratrol Improves the lipid-lowering efficacy.[203]
Resveratrol Exhibit chemotherapeutic effect in transglutaminase 2 and
hepatocarcinoma.[204]
Resveratrol and glibenclamide Modifies activities of xenobiotic-metabolizing enzyme.[205]
Rhizoma Coptidis with Cortex Cinnamomi Improvement in tissue distribution pattern of berberine in rats.[206]
S allyl cysteine Ameliorated hepatocarcinoma induced by DEN+CCl4.[207]
Silymarin (Berberol) Effective in reducing glycosylated hemoglobin.[208]
Silymarin Supplement for improving liver function.[209]
Simvastatin Improves the lipid-lowering efficacy.[210]
Sitagliptin Improving insulin resistance in NAFLD.[211]
Sodium caprate Improvement in intestine absorption.[212]
Sodium caprate Intestine absorption improvement in rats.[213]
Sodium caprate Inhibiting hepatic gluconeogenesis via AMPK pathway.[214]
Drug delivery approaches
Baicalin complex Improves bioavailability.[215]
Baicalin and Gardenia fruit complex Solubility enhancement.[216]
Baicalin nanocrystals Orally promote co-absorption of both the components.[217]
Carboxymethylcellulose and hyaluronic acid hydrogel Improvement in anti-inflammatory release system.[218]
Carboxymethyl hexanoyl chitosan/ hyaluronic acid polymer gel Sustained release.[219]
Cellulose nanofiber based hydrogel Controlled drug delivery.[220]
Citric acid based salt cocrystal Improving solid-state properties of berberine chloride.[221]
Coptidis rhizoma extract based nano-drug Improving pharmacokinetics.[222]
delivery
Advance drug delivery and combinational drug approaches
Table 3 Continued
Combinations/structure modifications and drug delivery approaches
Cucurbitacin B based phospholipid complex
Doxorubicin based liposomes
Fumaric acid based co-crystal
2-Hydroxypropyl-β-cyclodextrin (HPβCD) complex
Magnolol based complex
Modified β-cyclodextrin encapsulation
Modified sodium alginate and NIPAM based nanogels
O-hexadecyl-dextran based nanoparticles
Ibuprofen-based co-crystal
Mangiferin salt
Polylactide-poly (ethylene glycol) diblock copolymers-based
self-assembled filomicelles
Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate based microsphere
Sulfonato-β-cyclodextrin-based supramolecular nanoparticle
Vanillin-cross-linked chitosan microcarriers.
Wogonoside based complex
Structure modifications
Berberrubine
Demethyleneberberine
Demethyleneberberine
Demethylenetetrahydroberberine
Oxyberberine
9-O-benzoyl- substitution
• Enzymes like CYP3A4 are inhibited in liver by Ber. But
no significant effect was observed.
• No significant effect on Liver/ Liver transaminases was
observed during the study.
• Combination therapy proved efficacious and safe, in
hypercholesteraemic patients.
• Reduced FBG and triglyceride levels in patients effected
by T2DM and IFG levels. Found to be safe in patients
with hyperglycaemic patients with liver damage.
• Enhanced levels of serum adiponectin, in patients of
NAFLD effected with insulin.
• Berberine enhanced the conditions in patients. The ad-
ministration of berberine lowered liver enzymes.
• Better insulin sensitivity, liver functions and lipid treat-
ment of treatment groups enhanced significantly. The
combination was efficacious in type 2 diabetes effected
by NAFLD.
• Liver and metabolic parameters improved significantly
after administration of dosage.
• 25% more effectiveness was observed in the treatment
group with berberine.
• Reduced in HFC and body weight. Enhancement in lipid
profiles, glucose and serum triglycerides while reduced
ALT and AST.
13
Outcome
Improve therapeutic effectiveness associated with bile duct-drug target
delivery system.[223]
Enables superior therapeutic index than Doxil.[224]
Solubility and Stability improvements.[225]
Supports to develop oral solution dosage.[226]
Improves absorption and metabolism time.[227]
Shows a higher affinity for binding to kit22.[228]
Improves drug loading and release.[229]
Improved high glucose stress induced apoptosis.[230]
Improves obesity via protein kinases TBK1 and IKKɛ inhibition.[231]
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Improved lipid modulation and metabolisms of glucose in HepG2
cells.[232]
Sustained delivery.[233]
Improve oral delivery.[234]
Improvement in both controlled and sustained release action.[235]
Carriers for both drugs and cells with improved therapeutic matrix.[236]
Improves bioavailability.[215]
Alleviates NAFLD via glucose modulation glucose and metabolism of
lipid and also restoring gut microbiota.[237]
Exhibit antioxidant action, inhibits mitochondrial dysfunction and stea-
tosis caused by alcoholic liver disease mouse model.[238]
Attenuates NAFLD via AMPK activation and oxidative stress inhibi-
tion.[239]
Alleviates NAFLD via NLRP3 inflammasome inhibition and oxidative
stress in mice.[240]
Attenuating adipocyte inflammation and hepatic insulin pathway via
AMPK activation.[241]
Exerts triglyceride-lowering action via AMPK pathway.[242]
• Decreasing serum levels of both ceramide and ceramide-
1-phosphate, respectively. Levels of Spingomyelin (with
C39 chains) were reduced, while that of Sphinomyelines
(with C35 chains) was enhanced.
• No safety concerns were reported related to liver.
• Significant improvement in lipid fat content, liver-related
enzymes (ALT, GGT) and weight less.
• Sex-dependent effects on NAFLD patients.
• The effect of berberine was less significant on fasting
blood glucose, lipid profile or liver enzymes in NAFLD
patients.
Patents
Table 5 describes the patents on berberine in terms of
hepatoprotective and related action. Among patients where
hepatoprotection using berberine includes hepatitis B virus
infection treatment formula, synthetic analogues for fatty
liver and hepatic steatosis, glycyrrhetinate enantiomeric salt,
polyherbal medicinal pill, sigma 1 receptor binding com-
pound, treatment of hepatic oxidative stress, cirrhosis, chronic
liver disease and chronic hepatitis,[255] weight-loss formula,[256]
and remedies for hepatic glycogenesis and lipid metabolism
14 Satish Sardana et al.

Table 4 Clinical investigation of berberine on human for hepatoprotection

Model Number of patient Study Dosage/duration Outcome

design

Liver functions dur- 104 patients (52: Ber- Random- All treated after transplant with Cyclosporine Enzymes like CYP3A4 inhibition
ing renal-transplant berine treatment and ized, Con- + Azathioprine (25–50 mg/day) + Prednisone in liver without any significant
recipients treatment 52: without berberine trolled (5–15 mg/day). For Cyclosporine [0–6 months effect.[47]
treatment Clinical – 6–8 mg/kg/day, 6–12 months – 4–6 mg/kg/
Trial day, over 1 year – 2–5 mg/kg/day and berberine
dose – 0.2 gm (3 times/day) – Tablets orally
Risk of berberine on 40 patients (Berberine Random Berberine: 500 mg tablets, Combination – No significant effect on Liver/
liver with moder- group: 8 Males + 12 Assign- Tablets contained Ber – 500 mg + Policosanol Liver transaminases was observed
ate mixed hyper- Females) Combination ment – 10 mg + 200 mg Red yeast Extract rice (3 mg during study.[243]
lipidemia groups: 8 males + 12 Monacolin) + Folic Acid – 2mg + Coenzyme
Females Q10 – 2 mg + Astaxanthin – 0.5 mg

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Safety in liver and 63 patients hypercho- RCT Dose Berberine: 1gm/day for 2 months; Combination therapy proved
kidney functions on lesterolemia (Ber- Simvastatin: 20 mg/day- for or 2 months. efficacious and safe, in
hypercholesteraemic berine: 20 patients; In combination – Berberine (2 times/day) = hypercholesteraemic patients.[209]
patients simvastatin: 20 Simvastatin (Once) – for 2 months
patients and berberine
+ simvastatin: 20)
Hepatitis B and 35 Patients with IFG RCT Berberine: 2 g/day for 1 months Reduced FBG and triglyceride
hepatitis C (18 Patients: Hepatitis levels in patients effected by
B – (6 with T2DM, 12 T2DM and IFG levels. Found to
with IFG); 17 Patients: be safe in patients with hyper-
Hepatitis C – (7 with glycaemic patients with liver
T2DM, 10 with IFG). damage.[244]
NAFLD 68 Patients (Treatment Clinical Berberine: 500 mg/day for 3 months Enhanced levels of serum
group: 38 and control trial adiponectin, in patients of
group: 30) NAFLD effected with insulin.[248]
Type 2 Diabetes 60 Patients in 2 RCT Berberine (500 mg/day: for 12 weeks) and Berberine enhanced the conditions
with NAFLD groups Xuezhikang for 12 weeks. in patients. The administration
of berberine lowered liver en-
zymes.[249]
NAFLD due to 78 Patients (Treatment Clinical Metformin: control group and metformin + Better insulin sensitivity, liver
type-2 diabetes group: 38 and control trial berberine: treatment group (Berberine: 500 mg/ functions and lipid treatment of
group: 40) day for 16 Weeks) treatment groups enhanced signif-
icantly. The combination was effi-
cacious in type 2 diabetes effected
by NAFLD.[250]
Liver steatosis 40 patients – Sub- Double Berberine and chlorogenic acid (Trixy®) Liver and Metabolic parameters
jected to placebo blind, improved significantly after ad-
for 8 weeks-Wash cross-over ministration of dosage.[182]
Out Period 2 weeks designed
– Resubjected to RCT
alternative therapy of
8 Weeks
NASH based com- 96 patients (Selected Random Treatment group: Ber (500 mg/day) + Yi-Gan- 25% more effectiveness was ob-
plicated metabolize randomly between trial Ling (3 months) and Control group – Acarbose served in treatment group with
syndrome treatment and control) + Yi-Gan-Ling (3 months) berberine.[246]
NAFLD LSI – 53/62; LSI + Pio Parallel- Pioglitazone-15 mg/day and Berberine-0.5 g Reduced in HFC and body
(NCT00633282) – 55/60 and LSI + Ber controlled, tid: 16 weeks (Administered 30 min before weight. Enhancement in lipid
– 47/62. Male-98 and open-label meals) profiles, glucose and serum trigly-
Female-86 RCT cerides while reduced ALT and
AST.[251]
NAFLD 41 – (LSI + Berberine) Parallel- 500 mg tid: 16 weeks (Administered 30 min Decreasing serum levels of
(NCT00633282). and 39-LSI. Male-46 controlled, before meals) both ceramide and ceramide-1-
and Female-34 open-label phosphate. Levels of Spingomyelin
RCT (with C39 chains) reduced, while
that of Sphinomyelines (With C35
chains) was enhanced.[252]
Hypercholester- 30 Patients Ran- Nutraceutical combination NC in Red Rice No Safety concerns were reported
olemia in HIV- domized extract 200 mg - (Having 3 mg Monacolin); related to liver.[245]
infected patients (2-Arm) Policosanol - 10 mg; Ber – 500 mg;
(NCT03470376) Cross- Astaxanthin – 0.5 mg; Folic Acid – 0.2 mg and
Over trial Coenzyme Q10 – 2 mg. Therapy for 3 months
(Once daily)
Advance drug delivery and combinational drug approaches 15

Table 4 Continued

Model Number of patient Study Dosage/duration Outcome

design

NASH with diabe- Placebo-32/33, Dou- Berberine ursodeoxycholate (BUDCA) – 500 Significant improvement in lipid
tes (NCT03656744) BUDCA 500 and ble-blind, and 1000 mg: 2 times/day-18 Weeks fat content, liver related enzymes
1000 mg. Male-28 placebo- (ALT, GGT) and weight less.[247]
and Female-72 controlled
RCT
NAFLD with LSI - 53; LSI + Pio- Parallel- Pioglitazone – 15 mg/day and Berberine 0.5 g Sex-dependent effects on NAFLD
or without 47; LSI + Ber - 55. controlled, tid: for 16 weeks patients.[253]
type 2 diabetes Male – 85 and Female open-label
(NCT00633282) - 70 RCT
NAFLD 50 patients with Open- Berberine group-6.25 gm/day orally: for 45 The effect of berberine was less
confirmed fatty liver label days (5L water including 100 g dried berberine significant on lipid profile, fasting

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(Intervention: 25 and double- boiled at 167 °F until 4L) blood glucose or liver enzymes in
control: 25) blinded NAFLD patients.[254]
RCT

Table 5 Patents on hepatoprotective potential of berberine

Patent number Objective Outcome

CN101642454 Hepatitis B virus infection Inhibit replication of intracellular DNA.[255]

treatment formula
CN102370930, Synthesis of berberine analogs Able to reduces lipid levels by increasing hepatic expression via AMPK
CN102327426 and and medication for fatty liver activation to improve the oxidation of fatty acid and reducing accu-
CN101579340 and hepatic steatosis mulation of hepatic triglyceride to release in the form of VLDL.[255]
CN101367800 Glycyrrhetinate enantiomeric Useful for chronic inflammation and hepatitis.[255]
salt
CN101347525 Polyherbal medicinal pill Useful for inflammation and cancer.[255]
WO2010101649 Sigma 1 receptor binding Protect uninfected human cells from Hepatitis C virus infection by
compound reducing susceptibility followed by inhibition of viral spread among
cellular population.[255]
WO2010040058 Treatment of hepatic oxidative Retard the liver fibrosis progression, chronic liver disease, cirrhosis
stress, cirrhosis, chronic liver and chronic hepatitis.[255]
disease and chronic hepatitis.
N103393679A Weight-loss formula Downregulated lipidated LC3-II (an autophagy marker, in a time and
dose-dependent manner). Further, reduce LC3-II accumulation via in-
hibition of autophagic flux in C3H10T1/2 adipocytes.[256]
CN109224071A Improving the development of Reduced HNF4α, miR-122, (FAS1), SREBP-1, ACCα, G6P, PEPCK
hepatic glycogenesis and lipid and CPT-1 expression levels in type 2 diabetes or palmitic acid incu-
metabolism disorders bated in HepG2 cells.[257]
CN112138007A 8-oxoberberine Protect hepatocytes by fat accumulation reduction, also able to signifi-
cantly decreased ALT, TG and AST levels in cells.[257]
CN105693805A Bile acids and berberine for Improves liver functions.[257]
treatment of liver diseases and
cholestatic disorders
CN105693813A Combination of berberine Reduce cholesterol content, promotes obvious phospholipid reduction
with glycyrrhetinic acid and inhibition of the inflammatory reaction.[257]

disorders, 8-oxoberberine based synthetic compound, treat-
ment of liver diseases and cholestatic disorders including bile
acids and combination with glycyrrhetinic acid.[257]
Conclusion and Future Direction
Berberine was found to be safe and effective natural product
for long-term treatment and management of various dis-
eases and pathological conditions including liver protection.
However, the poor bioavailability of berberine (less than 1%)
limits clinical use and therefore several strategies have been
recently tested to improve the bioavailability of berberine.
In this article, evidence collected from various sources is
scrutinized to accomplish hepatoprotective action of berbe-
rine and its mechanisms, recent drug delivery system, com-
bination approaches, clinical trial and patent redirecting
towards the improvement of safety and efficacy of berberine
on liver protections to meet the objective. Taken all together,
berberine herewith represents a very promising therapeutic
molecules for the protection of liver injuries through several
damages via regulation of lipid and glucose metabolism, in-
flammatory response and oxidative stress. The promising ap-
plications of berberine can be found to be further enhanced
due to poor pharmacokinetics by advance drug delivery
16
approaches, combined treatment and structure modifications.
In addition to clinical efficacy, the safety of berberine is also
a key factor that affects its potential application using all
the approaches as applied for improving solubility, bioavail-
ability and permeability. Therefore, in conclusion, restricted
bioavailability and permeability can be improved by both
advance drug delivery system and combinational drug ap-
proaches as evidenced from the present work. Additionally,
berberine-based advance delivery system including in combi-
nation with bioavailability and permeability enhancer may
provide an added advantage in the near future to meet the
objectives. Further, well-designed, large-scale, long-term and
high-quality multicenter clinical trials are necessary to eval-
uate the efficacy and safety of modified berberine to get sev-
eral value-added products.
Supplementary Material
Supplementary data are available at RPS Pharmacy and
Pharmacology Reports online.
Conflict of interest
The author(s) declare that there are no conflicts of interest.
Acknowledgments
All authors acknowledge the administrative and technical sup-
port provided by Amity University Haryana, Gurugram and
DIT University, Dehradun, India for writing the current article.
Funding
This work was not funded by any of the agencies.
Authors contributions:
Satish Sardana: Supervision; Rupa Gupta: Data curation
and writing the original draft; Kumud Madan: Supervision
and visualization; Dheeraj Bisht: Resources and meth-
odology; Vijay Singh Rana: Formal analysis; Samir
Bhargava: Resources and methodology; Neeraj K. Sethiya:
Conceptualization, methodology, visualization and revi-
sion.
Data availability statement
Data sharing is not applicable to this article as no datasets
were generated or analysed during the current study.
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