Advance drug delivery and combinational drug approaches for hepatoprotective action of berberine: a progressive overview with underlying mechanism
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
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,*,
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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.com2 Satish Sardana et al.
Graphical Abstract
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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 pigment having strong fluorescent characteristics under ul-
chemically as quaternary ammonium salt of cationic traviolet light. Due to its stronger yellow colour, berbe-
isoquinoline alkaloids group (2,3-methylenedioxy-9,10- rine and berberine-containing plants were widely utilized
dimethoxyprotoberberine chloride; C20H18NO4+) with a in the past for the purpose of dye in textile, wool, leather
molecular mass of 336.36122 g/mol. The compound was and wood industries.[5] The multifunctional nature of berbe-
isolated first time from Hydrastis canadensis (goldenseal) rine as a health-promoting agent was established therapeu-
in 1917.[1, 2] Subsequently, many of rhizomes, roots and tically due to diversified effects on several enzymes, many
barks of various plants are explored including Arcangelisia receptors and pathways related to cell signalling that have
flava, Argemone mexicana, Berberis aquifolium, B. aristata, been widely explored and reviewed in subsequent time inter-
B. vulgaris, B. darwinii, B. petiolaris, Coptis chinensis, vals.[6–22] Further, hepatoprotective activity of berberine have
C. japonica, C. teeta, Cortex rhellodendri, Eschscholzia been explored experimentally using various models including
californica, Hydrastis canadensis, Mahonia aquifolium, in vitro, in vivo, ex vivo and clinical trial with underlying
Phellodendron amurense, Rhizoma coptidis, Tinospora molecular mechanism reviewed in various time interval.[23–25]
cordifolia and Xanthorhiza simplicissima as a possible In brief, many of the review articles are focussed spe-
source for identification and separation of berberine majorly cially NAFLD,[26–32] liver fibrosis,[33] obesity and liver func-
from Berberideae, Panaveraceae, Ranunculaceae, Rutaceae tions.[34] Despite many therapeutic advances including
and Menispermaceae families.[3, 4] hepatoprotection berberine is also categorized under BCS IIIAdvance drug delivery and combinational drug approaches 3
drugs due to its poor oral bioavailability and intestinal ab- for the most part of studies. However, the potential risk of
sorption.[4] This poor bioavailability and intestinal absorp- clinically relevant pharmacological interaction is mainly lim-
tion issues limit the effective clinical application of berberine ited to cyclosporine and warfarin.[52, 53] Additionally, in a very
to translate therapeutic and health-promoting outcome.[14] In recent article biodistribution and pharmacokinetic profile of
this connection, several attempts have been made to the im- both berberine and its metabolites were discussed on liver
provement of oral bioavailability and intestinal absorption hepatocytes.[54]
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- Biodistribution, Pharmacokinetics and BCS
bination therapy, complexation, structure modification and Class of Berberine
recent advance drug delivery system for the improvement of As per the biopharmaceutical classification system (BCS), ber-
hepatoprotective action of berberine is present in the litera- berine has been placed as a class III drug.[55–57] As per reports,
ture. Therefore, the current study was designed to deliver the it was found to be sparingly soluble in water with poor intes-
recent progress of work established towards making berbe- tinal absorption and oral bioavailability. In fact, during the
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
rine as suitable drug candidates for prevention and treatment study, the absolute bioavailability of berberine was found to
of liver-related disorder by incorporating several approaches. be4 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
μM liver. integrity.[65]
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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]
MethotrexateAdvance 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]
Rapamycin
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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 hepatocytes6 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]
200 mg oral
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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
0, 5, 10 and 15 Tumour-induced angiogenesis using HCC Prevents secretion of VEGF and down-regulates VEGF mRNA expres-
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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 assays8 Satish Sardana et al.
Table 1 Continued
Dose (kg/body Model Mechanism
weight/day)
0, 1, 5, 10, 20, Human hepatoma cells harboring hepatitis C Autophagy inhibition irrespective of the HCV genome presence.[145]
40, 80, 100, 200 virus RNA
and 400 μM
ISCHEMIA/REPERFUSION (I/R)
100 mg oral IR hepatic injury after orthotopic liver trans- Promotes liver transplantation during I/R injury partly via Sirt1/
plantation (OLT) on rats FoxO3α-mediated autophagy activation.[146]
18.6 mM Preservation solution for rat model of ex vivo Preserves mitochondrial function and bioenergetics by protecting liver
liver transplant from toxic effects caused by I/R.[147]
100 mg oral Hepatic cold ischemia rat model Reducing apoptosis, possibly via PI3K/Akt/mTOR signalling pathway
modulation.[148]
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
or multiple[95–97] were studied for hepatoprotective action of • ER stress improvement in hepatocytes and gut microbi-
berberine. Among these carbon, tetra chlorides induce liver ota regulation.
toxicity is one of the most studied model. Based on the data
the major postulated mechanism for hepatoprotection of ber-
berine are: Parasite/microorganism
In this model very few studies were conducted. One of the
• NLRP3 inflammasome pathway activation interference study in this context was conducted by inducing hepatic in-
(associated with the P2X7 activation), inflammatory cell jury in mice by using Schistosoma mansoni (a water-borne
infiltration and inflammation suppression via IL-10, IL- parasite). During this study berberine (12 mg/kg oral) was
6, LPS, TNF-α and ET involvement. found to ameliorate both liver damage and oxidative stress
• Inhibition of oxidative stress through ROS generation conditions produced due to schistosomiasis.[98]
and also participate by regulating antioxidant-responsive
element-related proteins and genes, that is Nrf2-Keap1- Obesity/fatty liver
expression. High-fat diet causing NAFLD,[99–117] obesity[118–121] and
• Inhibition of hepatocyte necrosis via p53 pathway- NASH[115, 122–125] were major protocol adopted for testing the
mediated hepatocyte apoptosis. effect of berberine through various mechanism. The minimum
• Improvement in fibrogenic potential via involvement of and maximum selected dose was found to be 30 to 300 mg/kg
MMP-2 responsible for stimulation of collagen deposits for oral administration and 5 to 10 mg/kg for intraperitoneal
degradation. administration, respectively. Additionally, the dose upto 50
• AMPK activation and blocking of expression of Nox4 µg/ml was tested for in vitro model studied. Animal such as
and Akt. rats, mice, black sea bream and blunt snout bream are ma-
• Reducing lipid peroxidation via TLR4 gene expression jorly used. Based on the data the major postulated mechanism
regulation. for hepatoprotection of berberine are:
• Attenuated vascular congestion, lipid synthesis (FASN,
THRSP, ACC, AMPK-α, ACLY), regulating uptake of • Reduced hepatic fat content by reversing HFD-elicited
fatty acids (CD36) and lipid oxidation (CPT1α, PPARα, dysregulation of MTTP.
ACOX1). • Protein and mRNA levels of IRS-2 upregulation leading
• Low to moderate cytochrome modulatory po- to improvement in insulin resistance.
tentials (Normalization of both flavin-containing • Down-regulation of both UCP2 proteins and UCP2
monooxygenases and cytochromes P450). mRNA expression levels in hepatic tissue.
• Restoring hepatocyte nuclear factor 4α/microsomal • Improvement in mitochondrial SirT3 activity followed
triglyceride transfer protein pathways, peroxisome by mitochondrial function normalization and energetic
proliferator-activated receptor, that is α/peroxisome deficit caused by impaired OXPHOS.
proliferator-activated receptor-gamma Co-activator- • Completely reverse the reduced Nrf2 and MRAK052686
1α. expression.
• Ability to chelate iron and Nrf2/HO-1 pathway • Restore the expression of L-PK via demethylation and
upregulation. the increase in histone H3 and H4 acetylation levels.
• Keap-1, P38MAPK and NF-κB inhibition. • Suppression of inflammation without involving AMPK.
• Reduced expression of apoptotic protein caspase-3 and • Inhibition of the ERK/mTOR pathway.
pro-apoptotic protein Bax followed by increased anti- • Involvement of ATF6/SREBP-1c pathway for reversing
apoptotic protein Bcl-2 expression. ER stress-activated lipogenesis.
• Significant decrease in LDH release. Inhibits cellular glu- • Ameliorating intestinal barrier function.
tathione depletion inhibiting the mTOR signalling path- • Restore liver function by mitochondria protection and
way mediated through CD147. normalization of gut microbiota.
• Up-regulation of P-TEFb expression. • Inhibit BSH, elevate TCA and activate FXR majorly in-
• PPARalpha/delta/gamma protein expression modulation volved in the uptake of long-chain fatty acids inhibition
in liver responsible for metabolism. in the liver.Advance drug delivery and combinational drug approaches 9
• Progression of hepatic steatosis to steatohepatitis was • Hepatic stellate cell proliferation inhibition for liver fi-
downregulated via reduction of oxidative stress. brosis prevention.
• CXCR4 signalling pathways inhibition via restoration of • Induction of p53 and Fas apoptotic system activity.
the balance of α1-AT and NE levels. • Effective for high-concentration leptin-induced NAFLD
• Inhibiting glucogenesis via regulating lipid metabolism. via up-regulation of the mRNA expression of leptin re-
• Liver protection under cholesterol overloading via ceptor.
autophagic flux regulation including cholesterol metab- • Prevents secretion of VEGF and down-regulates VEGF
olism and COX2-prostaglandin synthesis inhibition. mRNA expression.
• Mediating autophagy and FGF21 activation. • Transcription regulation on hepatic genes responsible for
• Ameliorate lipid accumulation and inflammation via re- fatty acid and glucose metabolism.
duction in LPS production and release of inflammatory • Both ROS-triggered caspase-dependent induction and
cytokines by hepatic macrophages. caspase-independent apoptosis pathways.
• Activation of the Nrf2/ARE signalling pathway. • AMPK activation in HepG2 cells followed by both apop-
• Involvement of p38MAPK/ERK-COX2 pathway for in- totic and autophagic death induction.
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
flammation and angiogenesis genes regulation. • Lipid-lowering effects by improvement in low-density
• Caused phosphorylation of SREBP-1c and AMPK. Further, lipoprotein receptor expression.
attenuates hepatic steatosis and reduces liver TG synthesis • Arachidonic acid metabolic pathway suppression.
via AMPK-SREBP-1c-SCD1 pathway activation. • Retarded cancer cell growth by regulating SP1 and miR-
• Fatty acid β-OX partly inhibition via SIRT3-mediated 22-3p and its downstream targets, that is BCL2 and
LCAD deacetylation caused by HFD. CCND1, in HCC.
• SIRT3/AMPK/ACC pathway activation to ameliorates, • HCC cell invasion and migration via uPA receptor inac-
HFD-induced hepatic steatosis. tivation by up-regulation of PAI-1 and down-regulation
• Regulate Angptl2 pathway. of uPA.
• Inhibit nuclear translocation of NF-κB via involvement • Involvement of NF-κB p65 pathway for apoptosis pro-
of TLR4/MyD88/NF-κB pathway. motion.
• Reverse the abnormal expression of LDLR and MTTP • Improvement on lipid metabolism disorder via FXR/
followed by lipid synthesis inhibition. SREBP-1c/FAS pathway regulation.
• Restoration of Treg/Th17 ratio and regulation of chemerin/ • Suppression of TNF-α expression and mitochondrial bi-
CMKLR1 signalling pathway responsible for overall in- ogenesis induction to decreased cellular ROS.
flammation and lipid deposition reduction in liver. • Early Growth Response 1 level upregulation responsible
• Improves lipid disorder, reduced aortic plaque formation for miR-373 expression transactivation.
and alleviated hepatic lipid accumulation, mainly asso- • Promotes CDKIs p21Cip1 and p27Kip1 expression via
ciated with PCSK9 down-regulation through ERK1/2 Akt/FoxO3a/Skp2 axis regulation. Further induces G0/
pathway. G1 phase cell cycle arrest.
• Multiple genes expression modulation responsible for • Upregulation of ABCA1 protein levels via involvement of
hepatic stellate cell activation and cholangiocyte prolif- PKCδ to reduce the phosphorylation of serine residues in
eration. ABCA1.
• Reduced hepatic lipid accumulation by lipolysis gene ex- • Antiproliferative effect of berberine was due Akt,
pression upregulation and lipogenesis gene expression PHLPP2 and Mst1 involvement (an autoinhibitory trian-
downregulation followed by improvement in muscle gle).
lipid contents. • Inhibits inflammation and mitochondria-dependent ap-
• Repressed complex I in the liver and gut, mainly respon- optosis.
sible for lipid metabolism inhibition (Alleviates from • Induced AMPK activation responsible for hepatic FGF21
both obesity and fatty liver). expression via NUR77.
• Transcriptional regulation of SETD2 activity for • Strengthens radiosensitivity through Nrf2 signalling
hepatoprotection via steatosis. pathway suppression.
• Elevated HIF-2 expression, insulin resistance and disor- • Radiosensitizer towards treating liver cancer by blocking
der of lipid metabolism. autophagy and cell cycle arrest resulting in senescence.
• Activate SIRT1-FoxO1-SREBP2 signal pathway.
• Antagonizes β-catenin pathway via β-catenin translation
Hepatocellular carcinoma and mTOR activity inhibition.
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] Hepatitis c virus
Hep3B and HEK293[138] cells line was used to investigate the A study included cell culture-derived HCV viral
hepatoprotective action of berberine through various mech- pseudoparticles bearing HCV glycoproteins for hepatitis C
anism. Upto 96 mM dose of berberine was found to be tested. virus entry-related assays of berberine (0, 2, 5, 10, 20, 50
The various postulated mechanism for hepatoprotective ac- and 100 μM) via targeting the viral E2 glycoprotein was es-
tion of berberine are: tablished.[144] In another studies, effect of berberine (0, 1, 5,
10, 20, 40, 80, 100, 200 and 400 μM) was investigated on
• Calcium and potassium channels inhibitory actions in i- human hepatoma cells nurturing hepatitis C virus RNA via
solated rat hepatocytes. autophagy inhibition.[145]10 Satish Sardana et al.
Table 2 Drug delivery system associated with improvement of bioavailability of berberine
Drug delivery approaches/methods Outcome
Dendrimer
Dendrimer of G4 PAMAM via conjugation and encapsulation ap- Conjugated dendrimers was found to be more prominent.[149]
proaches was developed
Erythrocyte-hemoglobin self-assembly system
Interaction with erythrocyte and the combination with Hb Low plasma and high tissue concentration was achieved.[150]
Hydrogel/beads
Self-assembled beads developed by shaking alpha-cyclodextrin with Bioavailability improvement of poorly water soluble or lipophilic
soybean oil drug.[151]
A novel composite pH-responsive hydrogel beads using carboxy- Improvement in efficacy and stability.[152]
methyl starch-g-poly (acrylic acid)/palygorskite/starch/sodium algi-
nate (CMS-g-PAA/PGS/ST/SA)
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
Silk sericin-derived hydrogel by thiol-ene click chemistry Eco-friendly way for biomedical industries.[153]
Liposomes
Liposomes was developed through co-precipitation method from Improve the absorption by 4-fold compared with free drug.[154]
berberine bisulfate and polyvinyl pyrrolidone (PVP) with the ratio of
1: 5.
Liposomes was developed by thin-film hydration/extrusion method. Exhibits tumour growth inhibition in HepG2 tumour-bearing mice.[155]
Memory fibers
Programme release through shape memory fibres by core-sheath wet- Smart drug delivery-based vehicles of targeted drug with highly adjust-
spinning technology able doses.[156]
Microparticles
Microparticles in hollow capsular devices (in house 3D printed) via Improve sustained and prolonged absorption with oral bioavailability
emulsion crosslinking method enhancement.[157]
Microemulsion
Oleic acid, Tween 80 and PEG400 was incorporate to get the Promising for oral drug delivery system.[158]
microemulsion
Microemulsion technique was developed via pseudo tertiary phase Improvement of absorption in the intestinal tract.[159]
diagrams
Zuojin Wan microemulsion-based gel and hydrogel delivery system Improvement in relative bioavailability for transdermal route.[160]
Nanoparticles/nano-crystals/nanocarriers
Biogenic gold nanoparticles using Trapa bispinosa was developed Active against folic acid expressing HeLa cells.[161]
Chitosan-coating based nano-liposomal carrier Promising for the oral delivery and improve in bioavailability.[162]
Chitosan/fucoidan-taurine based conjugated nanoparticles Effective for treatment of defective intestinal epithelial tight junction’s
barrier.[163]
Polymeric nanoparticles via nanoprecipitation technique Improvement in entrapment efficiency.[164]
Solid lipid nanoparticles Effective against hepatosteatosis via lipogenesis inhibition and lipolysis
induction.[165]
Janus magnetic mesoporous silica nanoparticles based on Fe3O4 head Safe and effective against hepatocellular carcinoma.[166]
for magnetic targeting and a mesoporous SiO2 body for delivery of
berberine.
PEG-lipid-PLGA hybrid nanoparticles by solvent evaporation method Improvement in relative oral bioavailability, affinity, liposolubility, drug-
loading efficiency and sustained/controlled release action.[167]
Spherical shaped sliver based nano-particles was synthesized by the Improves acetaminophen-induced liver and kidney damage probably via
biofabrication technique proinflammatory factor & NF-kB factors inhibition.[168]
Brij-S20-modified nanocrystals Improvement in the oral bioavailability having poor water solubility
and Pgp-mediated efflux.[169]
Janus gold mesoporous silica nanocarriers using folic acid Triple-therapies strategies for liver cancer.[170]
Sonication, coating and extrusion based on red blood cell membrane- RBGPs hold the potential to achieve sustained-release and long circula-
camouflaged BH-loaded gelatin nanoparticles (RBGPs) tion to avoid side effects associated by high plasma concentration.[171]
PLGA nanoparticles by nanoprecipitation and encapsulation Liver protection is higher as compare to normal drug.[172]
Natural polysaccharide (chitosan-alginate)-based nanoparticles by Effective for oral delivery of poorly soluble and permeable drugs.[173]
ionic gelation method
Nanoparticles developed by anti-solvent precipitation methods Improved in liver protection and high blood concentration.[174]
Nanostructured lipid carriers using modified solvent injection method Mitigate hepatic I/R-induced lesion via modulation of HMGB1/TLR4/
NF-κB signaling and autophagy.[175]Advance drug delivery and combinational drug approaches 11
Table 2 Continued
Drug delivery approaches/methods Outcome
Self-emulsifying or micro-emulsifying microsphere/drug
Membrane emulsification technology Suitable for poorly water soluble drug.[176]
Efficient self-micro-emulsification region was identified by pseudo Bioavailability improvement.[177]
ternary phase diagrams
The optimal self-microemulsion formula was composed of OP, To get small particle size and stable formulation.[178]
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 Promising strategies for oral bioavailability improvements.[179]
ASD with hydrogenated phosphatidylcholine Improvement in intestinal absorption, permeability and bioavailabil-
ity.[180]
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
Taste-masked microcapsules containing disintegrating tablets
Orally disintegrating tablets containing microcapsule and coated Taste masking to improve patient compliance.[181]
with Eudragit E100.
Ischemia/reperfusion injuries Cynara scolymus, Cichorium intybus and Taraxacum
Berberine (100 mg/kg/ oral) was investigated on ischemia/ officinalis,[189] evodiamine,[190–192] ferulic acid,[193] insulin sensi-
reperfusion (IR) hepatic injury after orthotopic liver trans- tizer,[194] lysergol,[195] metformin,[196] plant stanols,[197] puerarin
plantation on rats and found to promote liver transplant is- and baicalin,[198] red yeast rice and policosanols,[199] red yeast
chemia/reperfusion injury partly via Sirt1/FoxO3α mediated rice and Morus alba leaves extract,[200] red yeast rice and
autophagy activation.[146] Moreover, berberine (18.6 mM) was chitosan,[201] red rice, liposomal berberine and curcumin,[202]
found to preserve mitochondrial function and bioenergetics, resveratrol,[203, 204] resveratrol and glibenclamide,[205] Rhizoma
protecting the liver from the damaging effects caused by I/R, Coptidis with Cortex Cinnamomi,[206] S allyl cysteine,[207]
when tested as a part of preservation solution for rat model silymarin,[208, 209] simvastatin,[210] sitagliptin,[211] and sodium
of ex vivo liver transplant.[147] Similarly, berberine (100 mg/ caprate.[212–214] Among advance drug delivery including com-
kg/oral) in another study was investigated on hepatic cold is- binational approach such as baicalin complex,[215] baicalin
chemia rat model via reducing apoptosis, possibly involving and gardenia fruit complex,[216] baicalin nanocrystals,[217]
PI3K/Akt/mTOR signalling pathway modulation.[148] carboxymethylcellulose and hyaluronic acid hydrogel,[218]
carboxymethyl hexanoyl chitosan/hyaluronic acid pol-
ymer gel,[219] cellulose nanofiber based hydrogel,[220] citric
Berberine-Based Advance Drug Delivery acid based salt cocrystal,[221] Coptidis rhizoma extract based
System nano-drug delivery,[222] cucurbitacin B based phospho-
In Table 2 details on berberine-based advance drug delivery lipid complex,[223] doxorubicin based liposomes,[224] fumaric
system was discussed. Various drug delivery approaches acid based co-crystal,[225] 2-hydroxypropyl-β-cyclodextrin
such as dendrimer,[149] erythrocyte-hemoglobin self-as- (HPβCD) complex,[226] magnolol based complex,[227] modi-
sembly system,[150] hydrogel/beads,[151–153] liposomes,[154, 155] fied β-cyclodextrin encapsulation,[228] modified sodium algi-
memory fibers,[156] microparticles,[157] microemulsion,[158–160] nate and NIPAM based nanogels,[229] O-hexadecyl-dextran
nanoparticles/nano-crystals/nanocarriers,[161–175] self- based nanoparticles,[230] ibuprofen-based co-crystal,[231]
emulsifying or micro-emulsifying microsphere/drug,[176–178] mangiferin salt,[232] polylactide-poly (ethylene glycol)
solid dispersion[179, 180] and taste-masked microcapsules con- diblock copolymers based self-assembled filomicelles,[233]
taining disintegrating tablets[181] were investigated to improve sodium N-[8-(2-hydroxybenzoyl) amino] caprylate based
the solubility, bioavailability and permeability related issues. microsphere,[234] sulfonato-β-cyclodextrin based supra-
The major outcome of these delivery systems is to overcome molecular nanoparticle,[235] vanillin-cross-linked chitosan
the solubility issue, bioavailability hurdle and permeability microcarriers,[236] and wogonoside based complex.[215]
followed by improvement in efficacy and safety. Similarly, structure modification using a core molecules of
berberine such as berberrubine,[237] demethyleneberberine,[238,
239]
demethylenetetrahydroberberine,[240] oxyberberine[241] and
Berberine-Based Combinational Drug 9-O-benzoyl- substitution.[242]
Approaches
Novel combination, structure modifications and advance
drug delivery system using berberine for improvement of sol- Clinical Trial for Hepatoprotection
ubility, bioavailability and permeability was shown in Table 3. Table 4 describes the various clinical trial conducted on ber-
Berberine was investigated by combination with bicyclol,[182] berine in terms of investigations of hepatoprotective action
chitosan and chitosan hydrochloride,[55] chlorogenic acid on human beings. In brief, berberine was tested for liver func-
and tocotrienols,[183] coptisine, palmatine, epiberberine and tions,[47, 210, 243] hepatitis B and hepatitis C,[244] hypercholester-
jatrorrhizine,[184] Coptis chinensis,[185] Coptidis rhizoma ex- olemia,[245] NASH,[183, 246, 247] and NALFD.[248–254] The major
tract,[186] curcumin,[187] curcumin with dextran coating,[188] mechanisms included are12 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]
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
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]
deliveryAdvance drug delivery and combinational drug approaches 13
Table 3 Continued
Combinations/structure modifications and drug delivery approaches Outcome
Cucurbitacin B based phospholipid complex Improve therapeutic effectiveness associated with bile duct-drug target
delivery system.[223]
Doxorubicin based liposomes Enables superior therapeutic index than Doxil.[224]
Fumaric acid based co-crystal Solubility and Stability improvements.[225]
2-Hydroxypropyl-β-cyclodextrin (HPβCD) complex Supports to develop oral solution dosage.[226]
Magnolol based complex Improves absorption and metabolism time.[227]
Modified β-cyclodextrin encapsulation Shows a higher affinity for binding to kit22.[228]
Modified sodium alginate and NIPAM based nanogels Improves drug loading and release.[229]
O-hexadecyl-dextran based nanoparticles Improved high glucose stress induced apoptosis.[230]
Ibuprofen-based co-crystal Improves obesity via protein kinases TBK1 and IKKɛ inhibition.[231]
Downloaded from https://academic.oup.com/rpsppr/article/2/1/rqad002/6991356 by guest on 31 May 2023
Mangiferin salt Improved lipid modulation and metabolisms of glucose in HepG2
cells.[232]
Polylactide-poly (ethylene glycol) diblock copolymers-based Sustained delivery.[233]
self-assembled filomicelles
Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate based microsphere Improve oral delivery.[234]
Sulfonato-β-cyclodextrin-based supramolecular nanoparticle Improvement in both controlled and sustained release action.[235]
Vanillin-cross-linked chitosan microcarriers. Carriers for both drugs and cells with improved therapeutic matrix.[236]
Wogonoside based complex Improves bioavailability.[215]
Structure modifications
Berberrubine Alleviates NAFLD via glucose modulation glucose and metabolism of
lipid and also restoring gut microbiota.[237]
Demethyleneberberine Exhibit antioxidant action, inhibits mitochondrial dysfunction and stea-
tosis caused by alcoholic liver disease mouse model.[238]
Demethyleneberberine Attenuates NAFLD via AMPK activation and oxidative stress inhibi-
tion.[239]
Demethylenetetrahydroberberine Alleviates NAFLD via NLRP3 inflammasome inhibition and oxidative
stress in mice.[240]
Oxyberberine Attenuating adipocyte inflammation and hepatic insulin pathway via
AMPK activation.[241]
9-O-benzoyl- substitution Exerts triglyceride-lowering action via AMPK pathway.[242]
• Enzymes like CYP3A4 are inhibited in liver by Ber. But • Decreasing serum levels of both ceramide and ceramide-
no significant effect was observed. 1-phosphate, respectively. Levels of Spingomyelin (with
• No significant effect on Liver/ Liver transaminases was C39 chains) were reduced, while that of Sphinomyelines
observed during the study. (with C35 chains) was enhanced.
• Combination therapy proved efficacious and safe, in • No safety concerns were reported related to liver.
hypercholesteraemic patients. • Significant improvement in lipid fat content, liver-related
• Reduced FBG and triglyceride levels in patients effected enzymes (ALT, GGT) and weight less.
by T2DM and IFG levels. Found to be safe in patients • Sex-dependent effects on NAFLD patients.
with hyperglycaemic patients with liver damage. • The effect of berberine was less significant on fasting
• Enhanced levels of serum adiponectin, in patients of blood glucose, lipid profile or liver enzymes in NAFLD
NAFLD effected with insulin. patients.
• 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 Patents
combination was efficacious in type 2 diabetes effected Table 5 describes the patents on berberine in terms of
by NAFLD. hepatoprotective and related action. Among patients where
• Liver and metabolic parameters improved significantly hepatoprotection using berberine includes hepatitis B virus
after administration of dosage. infection treatment formula, synthetic analogues for fatty
• 25% more effectiveness was observed in the treatment liver and hepatic steatosis, glycyrrhetinate enantiomeric salt,
group with berberine. polyherbal medicinal pill, sigma 1 receptor binding com-
• Reduced in HFC and body weight. Enhancement in lipid pound, treatment of hepatic oxidative stress, cirrhosis, chronic
profiles, glucose and serum triglycerides while reduced liver disease and chronic hepatitis,[255] weight-loss formula,[256]
ALT and AST. and remedies for hepatic glycogenesis and lipid metabolismYou can also read
