Berberis Vulgaris and Berberine: An Update Review · perlipidemia, inflammation, bacterial and viral infections, cerebral ischemia trauma, mental disease, Alzheimer disease, osteoporosis,

REVIEW

Berberis Vulgaris and Berberine: An UpdateReview

Mohsen Imenshahidi and Hossein Hosseinzadeh*Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Berberine is an isoquinoline alkaloid present in several plants, including Coptis sp. and Berberis sp. Berberine isa customary component in Chinese medicine, and is characterized by a diversity of pharmacological effects. Anextensive search in electronic databases (PubMed, Scopus, Ovid, Wiley, ProQuest, ISI, and Science Direct) wereused to identify the pharmacological and clinical studies on Berberis vulgaris and berberine, during 2008 to 2015,using ‘berberine’ and ‘Berberis vulgaris’ as search words. We found more than 1200 new article studying theproperties and clinical uses of berberine and B. vulgaris, for treating tumor, diabetes, cardiovascular disease, hy-perlipidemia, inflammation, bacterial and viral infections, cerebral ischemia trauma, mental disease, Alzheimerdisease, osteoporosis, and so on. In this article, we have updated the pharmacological effects of B. vulgarisand its active constituent, berberine. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: Berberis vulgaris; berberine; barberry; pharmacokinetic.

INTRODUCTION

Barberry (Berberis vulgarisL.) is a well knownmedicinalplant in Iran and is also used as food additive(Khosrokhavar et al., 2010). Berberine is an isoquinolinealkaloid belongs to the structural class of protoberberinesand present in many plants including B. vulgaris.Previously, we reviewed the pharmacological and

therapeutic effects of B. vulgaris and its active constitu-ent, berberine (Derosa et al., 2012). But during theseyears, a large body of papers published about differentpharmacological and therapeutic effects of berberineand B. vulgaris. Here, we have updated the last reviewarticle using most of researches during 2008–2015 aboutthe pharmacological properties and clinical uses of ber-berine and B. vulgaris.In our previous review article about B. vulgaris and its

most active constituent, berberine, we presented a tablethat lists the applications of different parts of barberry(root, bark, leaf, and fruit) in folk medicine of Iranand other countries (Derosa et al., 2012) (Table 1).

RESEARCH METHOD

An extensive search in electronic databases (PubMed,Scopus, Ovid, Wiley, ProQuest, ISI, and Science Direct)were used to identify the pharmacological and clinicalstudies on Berberis vulgaris and berberine, during2008–2015, using ‘berberine’ and ‘Berberis vulgaris’ assearch words.

PHARMACOKINETIC

Bioavailability

Berberine has poor intestinal absorption and oral bio-availability. In two studies in rats, oral bioavailabilityof berberine has reported less than 1% (0.68% (Chenet al., 2011), and 0.36% (Liu et al., 2010)). Intestinalfirst-pass elimination of berberine, interaction withP-glycoprotein (Pg-P) pumps and high extractionand distribution in the liver are the major barriersof berberine oral bioavailability (Liu et al., 2010;Fratter, De Servi, 2015).

This poor bioavailability limits clinical use of berber-ine, and several strategies have been tested to improvethe bioavailability of berberine. D-α-tocopherylpolyethylene glycol 1000 succinate at a concentrationof 2.5% could improve area under the curve (AUC)(0–36) of berberine by 1.9 time probably via inhibitionthe activity of P-glycoproteins (Chen et al., 2011).Chitosan-N-AcetylCystein (Fratter, De Servi, 2015)and beta-cyclodextrin have increased the intestinal ab-sorption of berberine because of its solubilizing effectand P-glycoprotein (P-gp) modulatory activity (Zhanget al., 2013). Lysergol (Patil et al., 2013) and sodiumcaprate (Lv et al., 2010; Du et al., 2011) are othercompounds that have improved the oral bioavailabilityof berberine.

A spray dried mucoadhesive microparticle formula-tion of berberine has been prepared and increased theAUC of berberine by 6.98 fold (Godugu et al., 2014).Anoralmicroemulsion formulationof berberine resulted6.47 times greater oral bioavailability (Gui et al., 2008).Another study has used an anhydrous reversemicelle de-livery system provided via lyophilization of water-in-oilemulsion which 2.4-fold increase in oral bioavailabilityof berberine was demonstrated (Wang et al., 2011c).

* Correspondence to: Hossein Hosseinzadeh, Department of Pharmaco-dynamics and Toxicology, Pharmaceutical Research Center, School ofPharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.E-mail: [email protected]

PHYTOTHERAPY RESEARCHPhytother. Res. 30: 1745–1764 (2016)Published online 16 August 2016 in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/ptr.5693

Copyright © 2016 John Wiley & Sons, Ltd.

Received 02 April 2016Revised 04 July 2016

Accepted 16 July 2016

Distribution

Although berberine’s bioavailability and plasma levelare very low and cannot explain its pharmacologicaleffects, in vivo studies show that tissue distribution ofberberine and its active metabolites are higher thanthose concentrations in the blood after oral administra-tion (Yan et al., 2009; Tan et al., 2013). For example, ina study, oral administration of berberine (200mg/kg)

to rats has shown that berberine quickly distributesin the liver, kidneys, muscle, lungs, brain, heart,pancreas, and fat in a descending order of its amountand berberine’s level in most of studied tissues is higher(or much higher) than that in plasma 4h afteradministration. Organ distribution of berberine’s majormetabolites [berberrubine (M1), thalifendine (M2),and jatrorrhizine (M4)] was also higher than thoseconcentrations in the blood (Tan et al., 2013).

Table 1. The traditional uses of B. vulgaris (NAPALERT Database)

System Effect Part of plant Preparation Country

Cardiovascular Antihypertensive Stem bark Decoction FranceIn varicose veins Decoction Iran

Blood Blood rectifier Dried root Decoction IranGastrointestinal Choleretic Dried entire Infusion Iran

Cholagogue Root Fluid extract FranceLaxative Dried root Decoction Iran

Dried entire Infusion IranDried root – Decoction Iranroot barkFruit Turkey

Stomachic Fruit Infusion TurkeyBeverage in severe Dried fruit – H2O extract- IranDiarrhea Root Root IndiaHepatic Dried fruit H2O extract Irandisorders associated + stem barkwith hepaticGall bladder and liver Dried root root BulgariaHepatitis Dried root Decoction IranIntestinal ulcers Root Root IndiaIndigestion associated Dried root Decoction Iranwith hepatic disordersor loss of appetite.In hemorrhoids Decoction Iran

Endocrine Painful menstruation Fruit Hot H2O ArgentinInhibit Root Root Hot H2O Afghani

Immune system Antiinflammatory Dried root Root BulgariaRheumatoid arthritis Dried root Decoction Iran

+ stem barkAntirheumatic Flowers Decoction ChinaGout Decoction Iran

Organisms Antimicrobial Dried root Root BulgariaBeverage in typhus Dried root H2O extract IranIn malaria Decoction Iran

Central nervous system Beverage to Dried fruit H2O extract IranSedative Dried root Root Bulgaria

Respiratory Whooping cough Fruit Decoction TurkeyGargle to reduce Dried leaf Infusion Turkeycold symptomsBlood vomiting due Root Root Indiato lung disorders

Skin Irrigate wounds or Dried leaf Infusion IranIn scorbutic patients Dried leaf Infusion IranChewed by scorbutic Leaf External Iranto harden gumsDisinfectant Dried root Decoction

Renal Renal or urinary Dried part Hot H2O IndiaDiuretic Dried root Root IranKidney inflammation Dried root Root BulgariaNephritis Dried root Decoction Iran

Other Astringent Dried fruit H2O Italy

NAPALERT, Natural Products Alert.

1746 M. IMENSHAHIDI AND H. HOSSEINZADEH

Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 1745–1764 (2016)

Metabolism

Some studies show that oxidative demethylationand glucuronidation are the major metabolic pathwaysof berberine in rats. The major circulating metabolitesof berberine are M1 and M2 (via demethylation),M3 (via demethylenation) (Fig. 1), and their corre-sponding glucuronides, with M2-glucuronide approxi-mately 24-fold higher than M1-glucuronide. SeveralCYP enzymes are involved in formation of M1 andM2. The glucuronidation of M2 is much faster thanM1. Both M1 and M2 can be glucuronidated byUGT2B1and UGT1A1 while M2 glucuronidation isfavored by UGT1A1 (Liu et al., 2009).In vivo studies about the CYPs mediate metabolism

of berberine shows that CYP2D6 is the primary humanCYP producing berberine’s metabolites, followed byCYP1A2, 3A4, 2E1, and CYP2C19 (Guo et al., 2011a;Li et al., 2011b). Chen et al. have shown that CYP2D6and CYP1A2 were responsible for 75.253 9% and23.323 6% of the berberine metabolite M1, and respon-sible for 46.893 8% and 8.679 5% of M2 (thalifendine orberberrubine) (Chen et al., 2013b). Therefore, CYP2Dsubfamily plays a major role in berberine metabolism,and CYP2D6 pharmacogenetics and drug-drug interac-tions should be considered when berberine is used.

Excretion

In a study in rat, the excretion profiles of berberine andits metabolites after oral administration of administra-tion 200mg/kg has been evaluated. The results indicatethat total recovered rate of berberine is 22.83% andmajor route of excretion of berberine is fecal [9.2 ×10-6% in bile (24 h), 0.0939% in urine (48h) and 22.74%in feces (48h)]. The major metabolites of berberine[thalifendine (M1) and berberrubine (M2)], mostlyexert via bile and urine (Fig. 2) (Ma et al., 2013b).

Effect of berberine on cytochromes P450 andP-glycoproteins

Many in vitro and animal studies have reported interac-tions between berberine and cytochromes P450 (CYPs)

or P-gp, but little is known about whether berberinealters CYP activities in humans, especially afterrepeated regular doses and are this possible alternationsclinically important or not?

One study shows that Berberine has no influence onthe activities of CYP3A4, CYP1A2, and CYP2C19 butcan inhibit the activity of CYP2E1 and CYP2D6 (Chenet al., 2013a). On the other hand, a study has demon-strated the activity of CYP3A4 and CYP1A2 could be

Figure 1. Chemical structures of berberine and its metabolites.

Figure 2. Pharmacokinetic of berberine. Colour figure can beviewed at wileyonlinelibrary.com

1747BERBERIS VULGARIS AND BERBERINE


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induced by berberine in HepG2 cell, which wasconfirmed by the increase of its mRNA and proteinexpression (Cui et al., 2014). Totally, it seems that theeffect of berberine on CYPs activity is dose-dependent.Lower doses of berberine appear to have a low risk ofdrug-drug interactions related to change in CYP enzymeactivity. However, high doses of berberine may suppressCYPs activity and cause drug–drug interactions. Forexample, repeated administration of the three low dosesof oral berberine for 14days (10, 30, 100mg/kg, i.g.,daily) to C57BL/6 mice did not affect the expression of20 dominant CYPs in mice livers. However, highest doseof berberine (300mg/kg), caused 67.6% and 87.4%,decrease in mRNA of CYP3A11 and CYP3A25, respec-tively, whereas the mRNA of CYP1A2 increased43.2%, and activities of CYP2D22 and CYP3A11decreased 32.4% and 67.9%, respectively. CYP 2B10,CYP2A4, and CYP2C29 were not altered at mRNAand enzyme activity levels (Guo et al., 2011b). Inhumans, A two-phase randomized-crossover clinicalstudy in healthy male subjects showed that repeatedadministration of berberine (300mg, three times a day,p.o.) decreases the activities of CYP2D6, 2C9, andCYP3A4 (Guo et al., 2012). The inhibition of intestinalP-gp is another drug–drug interaction that should beconsidered in administration of berberine. In animalstudies; berberine caused a dose-dependent increase inbioavailability of digoxin and cyclosporine A by inhibi-tion of intestinal P-gp (Qiu et al., 2009).

INTERACTION WITH OTHER DRUGS

Metformin. Co-administration of 10mg/kg berberineand 2mg/kg metformin at a single intravenous dose inrats, have increased the initial plasma concentrationand AUC of metformin and have decreased volume ofdistribution and systemic clearance of metformin in rats,suggesting that berberine inhibits disposition of metfor-min through OCT1 and OCT2. Berberine inhibits thetransport activity of OCT1 and OCT2 and has a signifi-cant potential of drug–drug interactions with metformin(Kwon et al., 2015). Regarding common use of berber-ine in diabetic patients, this drug–drug interaction isvery important.Ketoconazole.Oral co-administration of 60mg/kg ber-

berine with 10mg/kg Ketoconazole increased the AUCfor Ketoconazole to 215% compared with those adminis-tered Ketoconazole alone in male rats. AUC for berber-ine enhanced to 173%comparedwith those administeredberberine alone. These pharmacokinetic interactionsmay have some role in the synergism reported for berber-ine and ketoconazole (Zhou et al., 2012).

Digoxin. Berberine increases bioavailability of Digoxinprobably via its inhibitory effect on intestinal P-gp.Administration of berberine (30,100mg/kg) to ratsincreases the AUC of Digoxin by 33% and 70%, respec-tively (Ju et al., 2011).Cyclosporine A. CYP3A4 and CYP3A5 and P-gp are

involved in cyclosporine A bioavailability. Berberine isa CYP3A4 inhibitor and a P-gp transporter substrate(Colombo et al., 2014). Interaction studies have shownthat coadministration of cyclosporine A with berberine

significantly increases the blood concentration of cyclo-sporine A (Wu et al., 2005; Xin et al., 2006; Qiu et al.,2009). For example, in a clinical trial, on 52 renal-transplant recipients, co-administration of cyclosporineA and 0.2 g berberine three times daily for 3months,has increased the trough blood concentrations of cyclo-sporine A by 88.9%. (Wu et al., 2005). Berberine alsoincreases the emptying time of stomach and small intes-tine which might be another reason for the increase incyclosporine A bioavailability. (Xin et al., 2006). In viewof these findings, concomitant administration of berber-ine is not reasonable during cyclosporine A treatment.

Toxicology

Generally, berberine shows very low toxicity and sideeffects (Pang et al., 2015). The administration methodis a significant factor which can affect acute toxicity ofberberine. In mice, the LD50 of intravenous injectionand intraperitoneal injection are, respectively, 9.0 and57.6 g/kg, and intragastric administration caused noLD50. (Kheir et al., 2010). In human, some clinical stud-ies that evaluated the safety of berberine, reported onlymild gastrointestinal reactions, including diarrhea andconstipation (Zhang et al., 2008c; Zhang et al., 2010;Pang et al., 2015). But some other clinical studiesindicated different adverse effects including transient el-evation in serum bilirubin level (Linn et al., 2012), distri-bution of sex-hormone synthesis pathway (Lao-Onget al., 2013), suppression of both cellular and humoralimmune functions (Mahmoudi et al., 2016), andprothrombotic effects (Holy et al., 2009).

CENTRAL NERVOUS SYSTEM EFFECTS

Autoimmune encephalomyelitis and multiple sclerosis

Berberine has been proposed as a potential therapeuticagent for multiple sclerosis (MS). In experimental auto-immune encephalomyelitis (EAE), an established modelof MS, berberine has ameliorated clinical severity andpathological parameters of EAE. It has reduced thepermeability of blood–brain barrier and has inhibitedthe activity of MMP-9 in the CSF and brain of EAEmice(Ma et al., 2010). Inhibition of differentiation of Th17cells through direct actions on the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription(STAT) pathway is a mechanism that has been proposedfor this effect (Qin et al., 2010). Berberine also inhibitsgelatinase activity and reduces laminin degradationwhich provides further support that berberine can be apotential therapeutic agent for MS (Jiang et al., 2013).

Anticonvulsant

Temporal lobe epilepsy is a long lasting neurological dis-order that is resistant to available drugs. A study hasshown that berberine pretreatment can attenuate spon-taneous recurrent seizures in intrahippocampal kainate(4μg)-induced temporal lobe epilepsy in rats. Regardingthat in this study, berberine has also reduced the nitritelevel and lipid peroxidation, it has been suggested that



berberine’s effect is due to its effectiveness in lesseningof oxidative stress (Mojarad and Roghani, 2014). Inanother study, we showed that B. integerrima, whichcontains berberine as main constituent, has anticonvul-sant activity in pentylenetetrazole-induced seizures andtherefore, may be useful in petit mal epilepsy(Hosseinzadeh et al., 2013).

Antidepressant

Berberine inhibits the immobility period in mice in bothtail-suspension and forced swim tests and following itsacute administration has resulted in increased levels ofdopamine (31%), norepinephrine (31%), and serotonin(47%) in the whole brain of mice. The antidepressant-like effect of berberine in forced swim test has beeninhibited by pretreatment with l-arginine or sildenafil.Therefore, it can be concluded that berberine exertsantidepressant-like effect in mice probably via modulat-ing brain biogenic amines (serotonin, norepinephrine,and dopamine) and nitric oxide pathway (Kulkarniand Dhir, 2008). In another study, it has been shownthat berberine is a substrate and also an inhibitor ofOCT2 and OCT3, and its inhibition on OCT2-mediatedand OCT3-mediated NE and 5-HT uptake may contrib-ute to the increased monoamine concentration in mousebrain (Sun et al., 2014).

Neuroprotective

Berberine has shown neuroprotective effects in severalbrain injury models (Zhou et al., 2008; Benaissa et al.,2009; Abdel Moneim, 2015). In a chronic brain injurymodel of rats (administration of aluminum trichloride),berberine administration 4h following the aluminumadministration significantly prevents rats from theimpairment of learning and memory function and hip-pocampal neuron injury, while significantly inhibits thedecreasing of ChAT and SOD activities, the increasingof AchE activities, MDA contents, and MAO-Bactivities, as well as the expression of MAO-B mRNAand protein.(Liu et al., 2008a; Zhang et al., 2009).In a middle cerebral artery occlusion model of ische-

mic injury, berberine has improved neurological out-come and reduced ischemia/reperfusion (I/R)-inducedcerebral infarction 48h after occlusion of middlecerebral artery via inhibition of reactive oxygen speciesgeneration, and subsequent release of pro-apoptoticfactor cytochrome c and apoptosis-inducing factors inmitochondria (Zhou et al., 2008).Berberine shows anti-apoptotic effects against ische-

mia by decreasing HIF-1α, caspase 9, caspase 3, and in-creasing Bcl-2/Bax ratio (Zhang et al., 2012a) and by theincreased phosphor-activation of Akt (higher p-Akt tototal Akt), (Hu et al., 2012a; Kim et al., 2014b; SimoesPires et al., 2014; Zhang et al., 2014d). Berberine can in-hibit the degradation of retinoblastoma mRNA throughits function on the poly (A) tail which avoids cells enter-ing in the apoptotic process (Chai et al., 2014). However,pro-apoptosis by berberine under hypoxia also has beenreported (Cui et al., 2009), and it seems that berberineregulates neuronal apoptosis in cerebral ischemia, whichmight be dependent on the degree of cell injury (Zhanget al., 2012a).

Berberine activates neurons by blocking K+ currentand lowering the threshold of the action potential. In aneonatal rat model of degenerating brain disease in-duced by MK-801, berberine has shown neuroprotectiveeffects on damaged neurons probably via blocking K+

current and lowering the threshold of the action poten-tial (Lee et al., 2010a) adenosine monophosphate(AMP)-activated protein kinase (AMPK) activation inBV-2 microglia (Lu et al., 2010), reducing the productionof tumor necrosis factor-α, interleukin-1β, and prosta-glandin E2 from activated microglia (Nam et al., 2010;Chen et al., 2014a), inhibition of the excessive produc-tion of glutamate (Campisi et al., 2011; Lin et al., 2013),reducing matrix metalloproteinase-9 activity (Honget al., 2012), decreasing nitric oxide (NO) productionin oligodendroglial cells (Nadjafi et al., 2014a),increasing heme oxygenase-1 mRNA and proteinexpression (Chen et al., 2012), and attenuation ofintracellular Ca2+ overload (Nadjafi et al., 2014b) areother mechanisms proposed for neuroprotective andanti-neuroinflammatory effects of berberine.

Parkinson

There is controversy about the effect of berberine onParkinson, and it seems to be related to the model ofParkinson and type of cells used in different studies. In6-hydroxydopamine-lesioned model of Parkinson’sdisease in rat, treated with l-DOPA (10mg/kg) and/orberberine (5 and 15mg/kg) once daily for 21days,berberine leads to the degeneration of dopaminergicneurons in the substantia nigra (Shin et al., 2013).Berberine also, aggravates 6-hydroxydopamine-inducedcytotoxicity in PC12 cells and enhances the degenera-tion of dopaminergic cell death. It also decreaseddopamine levels in substantia nigra (Kwon et al., 2009).

On the other hand, pretreatment of SH-SY5Y cellswith berberine significantly reduces 6-hydroxy-dopamine-induced generation of reactive oxygenspecies, caspase-3 activation, and subsequent cell death.Furthermore, berberine induces p38 and PI3K/Aktactivation, which are involved in Nrf2 expression andneuroprotection (Bae, Lee, Kim, et al., 2013).

In a model of Parkinson’s disease in mice, induced by1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine/probe-necid treatment, berberine enhanced coordination andmotor balance by preventing dopaminergic neuronaldamage. Berberine also improved short-term memoryby reducing apoptosis in the hippocampus. Berberineshowed maximal potency at 50mg/kg. Based on thesedata, berberine may serve as a potential therapeuticagent for the alleviation of motor dysfunction andmemory impairment in patients with Parkinson’sdisease (Kim et al., 2014a).

Drug dependence

Berberine inhibits the rewarding effects of drugs of abusesuch as cocaine, morphine, and nicotine (Bhutada,Mundhada, Bansod, et al., 2011).

Cocaine. Berberine can be effective for inhibiting thebehavioral and reinforcing effects of cocaine possiblyvia modulating the central dopaminergic system. Astudy in male Sprague-Dawley rats shows that



administration of berberine (200mg/kg, p.o.) 30minbefore the daily injections of cocaine significantly re-duces the cocaine-induced dopamine biosynthesis andlocomotor activity via inhibition of tyrosine hydroxylaseexpression (Lee et al., 2009).Ethanol. Administration of berberine (2.5, 5, and

10mg/kg, i.p.) reduces locomotor stimulant effect ofacute ethanol and reduces ethanol-induced rewardingeffects in mice (Pa et al., 2010). In another study, usingthe ethanol withdrawal-induced hyperexcitabilitymethod in mice, administration of berberine in higherdoses (10 and 20mg/kg, i.p.) dose-dependently attenu-ated ethanol withdrawal-induced hyperexcitability signs(Bhutada et al., 2011).Morphine. Recently, we reported that aqueous

extract of B. vulgaris can reduce morphine withdrawalsyndrome, using conditioned place preference method.In our study, administration of aqueous extract ofbarberry (200mg/kg) inhibited the acquisition andreinstatement of morphine-induced conditioned placepreference (Imenshahidi et al., 2014). Berberine alsosignificantly reduces morphine withdrawal behaviorsfollowing discontinuation of repeated morphineadministration in rats, possibly through decreasinghippocampal brain-derived neurotrophic factor mRNAexpression and blocking the increase in hypothalamicCRF expression and TH expression in the locuscoeruleus (Lee et al., 2012).

Huntington disease

Using transgenic mouse model expressing theHuntington disease (HD) protein, berberine canalleviate motor dysfunction and prolong the survival oftransgenic N171-82Q HD mice and promote the degra-dation of mutant huntingtin by increasing autophagicfunction. Berberine can also reduce the accumulationof mutant huntingtin in cultured cells. It seems that ber-berine can be tested on HD patients to further evaluateits effects in treatment of HD patients (Jiang et al., 2015).

Analgesic effects

B. vulgaris hydroethanolic extract has shownantinociceptive effects in different animal models ofpain such as, acetic acid-induced writhing test (forchronic pain) and tail-flick test (for acute pain) but isless effective than morphine. Berberine in dose of20mg/kg, has also shown antiallodynic effect compara-ble with that of amitriptyline 10mg/kg in allodynia in-duced by chronic constriction injury of the sciaticnerve in rats, a neuropathic pain model, probably viaits antioxidative and anti-inflammatory properties(Kim, 2015).

CARDIOVASCULAR EFFECTS

Cardiovascular effects of berberine have been studiedextensively during recent years and many new proper-ties have been attributed to this active ingredient of B.vulgaris including antiatherosclerosis, antihypercho-lesterolemia, cardiotonic, and antiarythmia effects.

Atherosclerosis

Many studies have reported anti-atherosclerosis effectof berberine and several mechanisms have suggestedexplaining this property of berberine. Lee et al. havesuggested that berberine inhibits the formation of foamcells by macrophages via enhancing LXRalpha-ABCA1-dependent cholesterol efflux (Lee et al.,2010b). Berberine can also effectively reduce intracellu-lar superoxide levels in lipopolysaccharide-stimulatedmacrophages via selective inhibition of gp91 super(phox) expression and enhancement of SOD activity.The intracellular superoxide level is an important sourceof oxidative stress in the developing atheroma (Sarnaet al., 2010).

The induction of human serum paraoxonase 1(PON1) by berberine explains another mechanism ofprotection against atherosclerosis (Cheng et al., 2011).PON1 is associated with high-density lipoprotein(HDL) and can inhibit the oxidative modification oflow-density lipoprotein (LDL), implying thatPON1 may prevent atherosclerosis (Cheng et al.,2011). Berberine reduces matrix metalloproteinase-9(MMP-9) and extracellular matrix metalloproteinase in-ducer expression by inhibiting the activation of p38pathway in PMA-induced macrophages (Huang et al.,2011) and reducing the activity of NF-kappaB inoxLDL-induced macrophages (Wang et al., 2009a;Huang et al., 2012). This suggests a potential role forberberine as a therapeutic agent for stabilizingatherosclerotic plaque because overproduction ofMMPs by monocytes/macrophages leads to degradationof extracellular matrix and atheroscleroticplaque rupture (Huang et al., 2011). Berberine also in-hibits human aortic smooth muscle cell, possibly bydown-regulating urokinase-type plasminogen activatorMMP-2 and MMP-9; and interrupting activatorprotein-1 and NF-kappa B mediated signaling pathways(Liu et al., 2014). Berberine can also inhibit the expres-sion of LOX-1 through ET-1 receptors (Guan et al.,2010; Chi et al., 2014a) and promote the expression ofscavenger receptor class B type I in macrophage-derived foam cells (Guan et al., 2010). Inducing autoph-agy through activation of the AMPK/mTOR signalingpathway (Fan et al., 2015), inhibition of the expressionand production of TNF-alpha, MCP-1, and IL-6, viaPPAR receptors (Chen et al., 2008; Pham et al., 2011;Chi et al., 2014b) and inhibition of cholesterol accumula-tion in human macrophages by impairment ofmacropinocytosis (Zimetti et al., 2015) are othermechanisms proposed for anti-atherosclerotic effects ofberberine (Table 2).

On the other hand, there is one report that indicatesberberine can promote the development of atheroscle-rosis and foam cell formation. The foam cell formationis mediated through induction of scavenger receptor Aexpression in macrophages, and increasing the uptakeof modified LDL (Li et al., 2009b).

Endothelial dysfunction

Berberine has a beneficial effect on endothelial functionby increasing NO. NO plays a pivotal role in the regula-tion of endothelial progenitor cells (EPC) function andmobilization (Xu et al., 2009a) which contribute in



improvement of endothelial function (Xu et al., 2008). Aclinical study has demonstrated that Berberine-inducedup-regulation of the number and function of circulatingEPCs in healthy subjects is related to NO production(Xu et al., 2009a). Mechanistically, it has been shownthat improvement of the proliferative activity of EPCsby berberine is via the PI3K/AKT/eNOS signaling path-way (Xiao et al., 2014).Elevated circulating endothelial microparticles are

associated with endothelial dysfunction (Wang et al.,2009b). Berberine therapy (1.2 g/d) in healthy subjectsfor 1month has reduced circulating CD31+/CD42�microparticles and upregulated endothelial function(Wang et al., 2009b). Another clinical study in healthysubjects also showed that berberine treatment signifi-cantly reduces circulating CD31+/CD42� MPs throughreducing oxidative stress (Cheng et al., 2013).Berberine has shown anti-inflammatory effects in vas-

cular endothelial cells. These anti-inflammatory effectsexert by inhibition of the TNF-alpha-induced expressionof ICAM1, and the activation of NFkappaB in culturedhuman aortic endothelial cells (Liu et al., 2015b).

Anti-arrhythmic effect

Berberine has shown anti-arrhythmic effect in stretch-induced arrhythmias after myocardial infarction in ratsby reducing the incidence of premature ventricularbeats and inhibiting the occurrence of ventriculartachycardia (Cao et al., 2012). In diabetic rats, alsoberberine produces anti-arrhythmic effects. The effectsof berberine on IK1/Kir2.1 may be an importantmechanism for this anti-arrhythmic effect (Yu et al.,2009; Wang et al., 2011b). Whole-cell patch-clamp instreptozotocin-induced diabetic rats were subjected toheart ischemia by the occlusion of left anteriordescending coronary artery has shown that oraladministration of berberine (100mg/kg), recoversdepressed I(to) and I(Ca) currents and significantlyshortens the prolonged QTc interval (Cao et al.,2012). In addition, berberine also suppresses the cur-rent of hyperpolarization-activated cyclic nucleotide-gated four channels that may contribute to pacemakercurrents (Ifs) and its antiarrhythmic action (Chen et al.,2014b).

Table 2. Different mechanisms of berberine and related pharmacological or therapeutic potentials

Mechanism Pharmacologic effect Therapeutic potential Reference

Inhibits gelatinase activity Treatment of MS (Jiang et al., 2013)Reduces laminin degradation Treatment of MS (Jiang et al., 2013)Inhibition of organic cationtransporter 2 (OCT2)and 3 (OCT3),

Inhibition of 5-HTand NE uptake

Antidepressant (Sun et al., 2014)

Decreasing caspase 9,caspase 3 and increasingBcl-2/Bax ratio

Anti-apoptotic effectsin brain

Neuroprotective effects (Zhang et al., 2012a)

Reduction of tyrosinehydroxylase expression

Inhibition of dopamine biosynthesis Inhibition of cocaine dependence (Lee et al., 2009)

Decrease in hippocampalBDNF mRNA expression

Ameliorating depression-likeand anxiety-like behaviors

Inhibition of morphine dependence (Lee et al., 2012)

Enhancing LXRalpha-ABCA1-dependent cholesterol efflux

Inhibition of formation offoam cells by macrophages

Anti-Atherosclerosis effect (Lee et al., 2010b)

Inhibition of gp91super (phox) expression

Reduction of intracellularsuperoxide in macrophages

Anti-Atherosclerosis effect (Sarna et al., 2010)

Induction of humanserum paraoxonase 1

Inhibition of oxidativemodification of LDL

Anti-Atherosclerosis effect (Cheng et al., 2011)

Increasing NO productionvia PI3K/AKT/eNOS pathway

Up-regulation ofendothelial progenitor cellsmobilization and function

Improvement ofendothelial function

(Xu et al., 2008;Xu et al., 2009a;Xiao et al., 2014)

AMPK-dependentRaf-1 activation

Up-regulation of LDLR expression Anti-hypercholesterolemia (Kong et al., 2008;Li et al., 2014b)

Activating AMPK andPI3K-Akt-eNOS signaling

Antiapoptotic effectin cardiomyocytes

Protection againstmyocardial ischemia

(Yu et al., 2009;Yu et al., 2015)

Inhibition of p38 MAPK Promoting autophagy Attenuation of leftventricular remodeling after MI.

(Zhang et al., 2014c)

Suppression of transientreceptor potential vanilloid 4

Direct vasorelaxation andreducing vascular stiffness

Anti-hypertension (Wang et al., 2015a)

Expression ofNa+/H+ exchanger

Enhancing the absorptionof Na+ and water

Anti-diarrhea (Zhang et al., 2012b)

Activation of Runx2 by p38 MAPK Promotion of osteoblast differentiation Anti-osteoporosis (Lee et al., 2008)Suppressing p38MAPK activity

Suppression ofchondrocyte apoptosis

Anti-osteoarthritis (Zhou et al., 2015)

5-HT, serotonin; AMPK, AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; MAPK, mitogen activated protein kinase; MI, myocardial infarction; MS, multiple sclerosis; NE, norepinephrine;NO, nitric oxide.



Hypercholesterolemia

Berberine has been identified as a novel cholesterol-lowering drug acting through different mechanismsincluding up-regulation of low-density lipoproteinreceptor expression via AMPK-dependent Raf-1 activa-tion (Kong et al., 2008; Li et al., 2014b), down-regulationof PCSK9 through sterol regulatory element bindingprotein-2 activation (Cameron et al., 2008; Li et al.,2009a; Jia et al., 2014), and reducing the inhibition ofPDE (Zhou et al., 2011). The mechanism of berberinediffers from that of statins and combination of berberine(90mg/kg/day, oral) with simvastatin (6mg/kg/day, oral)in hyperlipidemic rats, reduce serum LDL cholesteroland serum triglyceride more effective than that of thesimvastatin or berberine monotherapy. Therefore,combination therapy using simvastatin and berberinecan be a new regimen for hypercholesterolemia (Konget al., 2008).In rabbits feeding with high fat diet, berberine reduced

the serum total cholesterol, low-density lipoproteincholesterol, and triglycerides levels, and aortic atheroscle-rosis, which the mechanisms were associated with theinhibition of iNOS activity and down-regulation ofPPARγ mRNA level (Luo et al., 2012). Berberine alsopromotes CPT I A mRNA expression through stimulat-ing PPARα (Shi et al., 2008; Wang et al., 2011a). Berber-ine elevates expressions of insulin-induced gene 2(Chang et al., 2009; Luo et al., 2011), vitamin D receptor(Luo et al., 2011) low-density lipoprotein receptor, andscavenger receptor class-B type 1 genes in liver ofhigh-fat diet rats that can inhibit the cholesterol synthe-sis of liver (Jin et al., 2010). The low dose of berberine(28mg/kg) is more effective in countering hyperlipid-emia than high dose in rabbits (112mg/kg) (Changet al., 2009; Jin et al., 2010; Luo et al., 2011).In male Sprague-Dawley rats which fed by

cornstarch-casein-sucrose-based high-cholesterol (2%,w:w) and high-fat (27.5%) diet, berberine reducedplasma triglycerides levels by 31% but had no effecton both T-C and non-HDL-C (Jia et al., 2008). Althoughthe bioavailability of oral berberine is much lower thanthat of intraperitoneal administration, it had a strongerlipid-lowing effect, indicating that the gastrointestinaltract is important for the hypolipidemic effect of berber-ine (Gu et al., 2015). A part of this effect is throughinhibiting the intestinal absorption and further by de-creasing enterocyte cholesterol uptake and secretionand interfering with intraluminal cholesterolmicellarization (Wang et al., 2014a). Berberine has alsobenefit effects on HDL-C. In non-obese diabetic mice,oral administration of 50, 150, or 500mg ofberberine/kg over 14weeks, have increased HDL-Clevels (Chueh and Lin, 2011).Clinical studies also show that berberine is effective

and safe to mildly improve lipid profile. In a clinicalstudy in 228 subjects with primary hypercholesterol-emia, berberine showed more effective than ezetimibein reducing LDL cholesterol (31.7% vs. 25.4%,p<0.001) and better tolerated (Pisciotta et al., 2012).In a double-blind and placebo-controlled design, 144

subjects were enrolled and received 500mg berberineb.i.d., for 3months. Berberine reduced the body weight,body mass index, total cholesterol, triglycerides, andLDL cholesterol and increased HDL cholesterolcompared with placebo (Derosa et al., 2013).

Cardioprotective effect on ischemia-reperfusion injury

Berberine has protective effect in ischemia reperfusioninjury of the heart (Zeng et al., 2003). Recent studieshave reviled the mechanisms of this protective effect.Berberine significantly decreases AMPK proteinconcentration, and the ratio of adenosine diphosphate/adenosine triphosphate (ATP) and AMP/ATP in themyocardial of ischemic areas and increased AMPKprotein concentration, and the ratio of AMP/ATP andadenosine diphosphate/ATP in the non-ischemia areas(Chang et al., 2012). In cultured neonatal ratcardiomyocytes, berberine shows antiapoptotic effectand improves cardiac functional recovery followingmyocardial I/R via activating AMPK and PI3K-Akt-eNOS signaling (Yu et al., 2009; Yu et al., 2015). Berber-ine regulates high mobility group box 1 and toll-likereceptor to protect myocardial ischemia (Zhang et al.,2014a).

Promoting autophagy through inhibition of p38 mito-gen activated protein kinase (MAPK) and activation ofphospho-Akt signaling pathway (Zhang et al., 2014c)and up-regulating Notch1/Hes1-PTEN/Akt signaling(Li et al., 2014a; Yu et al., 2015), are another mechanismthat attenuate left ventricular remodeling and cardiacdysfunction after myocardial infarction.

In a clinical study undertaken on 130 acute coronarysyndrome patients undergoing percutaneous coronaryintervention, berberine (300mg, three times a day, for30days) in addition to standard therapy, has shownbenefit effects via reducing circulating inflammatorymarkers including MMP-9, intercellular adhesionmolecule-1, vascular cell adhesion molecule-1,interleukin-6, C-reactive protein, and monocytechemoattractant protein (Meng et al., 2012).

Cardiotonic

Berberine exerts positive inotropic effects and hasbeen used in the treatment of congestive heart failure(Salehi, 2009). The high dose of berberine (63mg/kg)can decrease left ventricular end-diastolic pressure, im-prove [-dp/dt(max)], decurtate left ventricular relaxtime constant quantity and decrease [Ca2+]i level in di-astole heart failure rat models (Zhang et al., 2008b).Berberine also decreases plasma brain natriureticpeptide in rats with chronic congestive heart failure(Li et al., 2009c).

Cardiotonic and protective effect of berberine werealso exerted in cardiac dysfunction induced byhyperglycemia/hypercholesterolemia through alleviat-ing cardiac lipid accumulation and promoting glucosetransport (Dong et al., 2011).

Hypertension

In traditional medicine, B. vulgaris has been used inhypertension and arrhythmia (Fatehi-Hassanabadet al., 2005). Several pharmacological studies demon-strated this effect of B. vulgaris and berberine (Fatehi-Hassanabad et al., 2005; Guo et al., 2015; Liu et al.,2015a; Wang et al., 2015a). Different mechanismsproposed for this effect including α1-adrenoceptorantagonism, ACE-inhibition (Salar et al., 2010) and



directly release of NO/cGMP, inhibition of intracellularCa2+ release from caffeine-sensitive pools, blocking ofL-type calcium channels and the potentiation of acetyl-choline (Derosa et al., 2012).A recent work has suggested that berberine could in-

hibit the activities of RAS and pre-inflammatory cyto-kines IL-6, IL-17, and IL-23, which are involved in thepathophysiology of hypertension (Guo et al., 2015). Ber-berine induces direct vascular relaxation and lowers vas-cular stiffness through suppression of transient receptorpotential vanilloid 4 (Wang et al., 2015a). Berberine alsoreduces endothelium-dependent contractions throughactivating AMPK, which reduces endoplasmic reticulumstress and down-regulates cyclooxygenase-2 (COX-2)in spontaneously hypertensive rats carotid arteries(Liu et al., 2015a) The cardiovascular effects of berber-ine were cited in Table 3.

IMMUNE SYSTEM EFFECTS

Anti-inflammatory and immunosuppressive effects

Berberine reduces the production and mRNA expres-sion of thymic stromal lymphopoietin (TSLP) in humanmast cell line-1 cells and inhibits the production of TSLPin primary mast cells and activation of caspase-1 in hu-man mast cell line-1 cells. Regarding the role of TSLPin allergic diseases such as atopic dermatitis, asthma,and chronic obstructive pulmonary disease, berberinecan help to treat these diseases (Moon et al., 2011). Ber-berine also suppresses IgE production by human B cellsand may consider as a treatment for IgE-mediated foodallergy (Yang et al., 2014).Berberin possess anti-inflammatory effects trough dif-

ferent mechanisms. Berberine reduces the leukocyte-endothelium adhesion and vascular cell adhesionmolecule-1 expression in lung and decreases the numberof adhered THP-1 cells and vascular cell adhesionmolecule-1 expression at both RNA and protein levels(Wu et al., 2012).Berberine attenuates lipopolysaccharide-induced

expression of inflammatory genes (inducible nitric oxidesynthase [iNOS], COX-2, interleukin [IL]-6), and thegeneration of nitric oxide and reactive oxygen species,but enhances the transcription of Nrf2-targeted antioxi-dative genes (nicotinamide adenine dinucleotide phos-phate quinone oxidoreductase-1 [NQO-1], hemeoxygenase-1), as well as the nuclear localization andphosphorylation of Nrf2 protein. Berberine-inducedactivation of Nrf2 is AMPK-dependent (Jeong et al.,2009; Lee et al., 2013; Mo et al., 2014). Berberine effec-tively reduces Src expression and activity and inhibitsTLR-mediated cell motility in macrophages (Chenget al., 2015). It is also a potent natural inhibitor of phos-pholipase A (2) (Chandra et al., 2011).Berberine significantly inhibits splenocyte prolifera-

tion, IL-2, TNF-α, and IFN-γ secretion. Berberine hasalso inhibitory effects on the Th17 response via a directeffect on T cells and an indirect action via dendritic cells.Therefore, berberine may act as a potential immunosup-pressive drug (Ma et al., 2013a; Yang et al., 2013).The ethanolic extract of barberry is able to decrease

the formalin and acetic acid injection-induced inflamma-tion in foot and peritoneum and also can ameliorate an

external body-induced chronic inflammation as well. Inaddition, the reduction of late phase of chronic pain inparallel with chronic inflammation suppression is con-siderable (Kiasalari et al., 2011).

ENDOCRINE EFFECTS

Contraceptive

Berberine can inhibit in vitro development of zygotes toblastocysts of mice and receiving of berberine by matedfemale mice decreases the proportions of recoveredblastocysts and full-term fetuses (Tsunoda and Kato,2011). This berberine-induced inhibition of the develop-ment of mouse zygotes is reversible (Sugimoto et al.,2012).

Polycystic ovary syndrome

Insulin resistance and hyperinsulinemia play an impor-tant role in the pathogenesis of polycystic ovary syn-drome (PCOS), which is characterized by ovulatorydysfunction, hyperandrogenism, and presence of poly-cystic ovaries on pelvic scanning. Insulin resistance issignificantly associated with the long-term risks ofmetabolic syndrome and cardiovascular disease.Berberine reduces insulin resistance similar to metfor-min (Li et al., 2013c). Some studies have evaluatedthe effect of berberine on insulin resistance inwomen with PCOS (Wei et al., 2012; Li et al., 2013b;Li et al., 2013c).

For example, in a prospective study in 150 infertilewomen with PCOS undergoing in vitro fertilizationtreatment, patients were randomized to receive berber-ine, metformin, or placebo tablets for 3months beforeovarian stimulation. In the berberine and metformingroups, greater reductions in total testosterone, fastingglucose, and fasting insulin, free androgen index and in-creases in sex hormone-binding globulin, were observedin comparison with placebo group. Three months oftreatment with metformin or berberine before thein vitro fertilization cycle increased the pregnancy rateand reduced the incidence of ovarian hyperstimulationsyndrome. Totally, berberine had a more pronouncedtherapeutic property and achieved more live births withfewer side effects than metformin (An et al., 2014). In anin vitromodel of insulin resistant ovary, using dexameth-asone to induce insulin resistance, berberine could alle-viate the degree of insulin resistance and the androgensynthesis, indicating that that this compound has favor-able therapeutic effect for the treatment of polycysticovaries (Wang et al., 2010).

Antiabortion

Traditional Chinese medicinal herbs containing berber-ine have been historically used to prevent miscarriage.In a study in mouse pronuclear embryos, berberinesignificantly increased the cell numbers of mouseblastocysts and decreased apoptotic cell rates in vitro.Berberine significantly increased miRNA-21 and Bcl-2transcription and protein levels and significantly



Table3.

Cardiov

asculareffectsof

berberine

The

rape

utic

effect

Mec

hanism

Kindof

stud

yDos

e(orco

ncen

tration)

Referen

ce

Anti-A

theros

cleros

isEn

hanc

ingch

oles

terole

fflux

Cellc

ulture

(5,10,an

d20μM

)for12h

Leeet

al.,2010b

Inhibition

ofgp

91su

per(pho

x)ex

pres

sion

Cellc

ulture

(10–50μM

)for(6–24h)

Sarna

etal.,2010

Indu

ctionof

human

serum

paraox

onas

e1

Cellc

ulture

1,3an

d10μM

Che

nget

al.,2011

Inhibition

ofmatrixmetalloproteina

se-9

expres

sion

Cellc

ulture

5–50μM

Hua

nget

al.,2011

Red

ucingtheac

tivity

ofNF-ka

ppaB

inox

LDL-indu

cedmac

roph

ages

Cellc

ulture

1–50μM

Hua

nget

al.,2012

improv

emen

tof

endo

thelialfun

ction

Upreg

ulationof

EPCsviathePI3K/A

KT/eNOSsign

alingpa

thway

Cellc

ulture

20μM

Xiaoet

al.,2014

Red

ucingcirculatingCD31+/C

D42�

micropa

rticles

Hum

an(1.2

g/d)

Wan

get

al.,2009b

Anti-a

rrhy

thmic

Sup

pres

sing

theHCN4ch

anne

lsAnimal

(rab

bit)

(1-300μM

)Che

net

al.,2014b

Rec

overingde

pres

sedI(to)an

dI(Ca)

curren

tsAnimal

(rat)

(100mg/kg

)Cao

etal.,2012

Hyp

erch

oles

terolemia

Up-regu

lation

ofLD

LRex

pres

sion

Cellc

ulture

2.5–20μM

Liet

al.,2014b

Dow

n-regu

lation

ofPCSK9

Animal

(rat)

400mg/kg

/dJiaet

al.,2014

Red

ucingthecA

MP-in

duce

dlip

olys

isviaPDE

Cellc

ulture

1–100μM

Zho

uet

al.,2011

Promotionof

CPTIA

mRNA

expres

sion

Animal

(rat)

60an

d300mg/kg

Wan

get

al.,2011

aElev

atingex

pres

sion

ofinsu

lin-in

duce

dge

ne2

Animal

(rab

bit)

28an

d11

2mg/kg

Luoet

al.,2011

Increa

sing

expres

sion

ofsc

aven

gerrece

ptor

clas

s-Btype

1ge

neAnimal

(rab

bit)

28an

d11

2mg/kg

Jinet

al.,2010

Inhibiting

theintestinal

abso

rption

ofch

oles

terol

Animal

(rat)

150mg/kg

Wan

get

al.,2014a

Hum

an500mg,

b.i.d

.Deros

aet

al.,2013

isch

emia-rep

erfusion

injury

Dec

reas

ingtheAMPKproteinco

ncen

trationan

dtheratioof

ADP/ATP

Animal

(rat)

100mg/kg

/dCha

nget

al.,2012

ActivatingAMPKan

dPI3K-A

kt-eNOSsign

aling

Animal

(rat)

200mg/kg

/dYuet

al.,2015

Reg

ulationof

high

mob

ility

grou

pbo

x1an

dtoll-lik

erece

ptor

Animal

(rat)

30an

d60mg/kg

/dZha

nget

al.,2014a

Promotingau

toph

agythroug

hinhibition

ofp3

8MAPK

Animal

(rat)

10an

d50mg/kg

/dZha

nget

al.,2014c

Up-regu

lating

Notch

1/H

es1-PTEN

/Akt

sign

aling

Animal

(rat)

200mg/kg

/dYuet

al.,2015

Red

ucingcirculatinginflam

matorymarke

rsHum

an300mg,

t.i.d

.Men

get

al.,2012

Cardioton

icPromotinggluc

osetran

sport

Animal

(rat)

30mg/kg

/dDon

get

al.,2011

Dec

reas

ingplas

mabrainna

triureticpe

ptide

Animal

(rat)

20mg/kg

Liet

al.,2009c

Hyp

ertens

ion

Inhibition

ofRASan

dpre-inflam

matorycy

tokine

sAnimal

(rat)

100mg/kg

/dGuo

etal.,2015

Direc

tva

scular

relaxa

tion

throug

hsu

ppressionof

TRPV4

Animal

(mice)

100mg/kg

/dWan

get

al.,2015a

ADP,

aden

osinediph

osph

ate;

AMPK,AMP-activated

proteinkina

se;EP

C,en

dothelialp

roge

nitorce

lls;MAPK,mitog

enac

tiva

tedproteinkina

se;RAS,renin-an

gioten

sinsy

stem

.



decreased caspase-3 and chromosome ten transcriptionand protein levels. It can be concluded that berberinehas anti-apoptotic and pro-growth effects in mouseblastocysts (Zhang et al., 2015a).

Diabetes

In China, in 1986, a hypoglycemic effect was acciden-tally found when berberine was used to diabetic patientswith diarrhea (Pang et al., 2015).Moreover, berberine has positive effects in treating

diabetic nephropathy, diabetic neuropathy, and diabeticcardiomyopathy (Pang et al., 2015). During 2009–2015,more than 110 clinical trials and animal studies haveevaluated and demonstrated antidiabetic effect ofberberine. Many mechanisms such as increasing insulinsensitivity, modulating gut microbiota, activating theadenosine AMPK pathway, promoting intestinalglucagon-like protein-1 secretion, stimulating glycolysisin peripheral tissue cells, inhibiting gluconeogenesis inliver, increasing glucose transporter, and upregulatinghepatic low-density lipoprotein receptor mRNA expres-sion have been proposed for antidiabetic activity ofberberine (Vuddanda et al., 2010; Xiao et al., 2011;Derosa et al., 2012). Regarding there are more thanten review articles about berberine and diabetes (Ciceroand Tartagni, 2012; Dong et al., 2012; Pang et al., 2015),we refer the readers to those papers.

Obesity

Many studies suggest that berberine has an anti-obesityeffect in animals and cell culture via inhibition of adipo-genesis (Liu et al., 2008b; Hwang et al., 2009; Zhanget al., 2014d). Promotion of AMPK activity (Kim et al.,2009), decrease in the expression of PPARγ and C/EBPα,and increase in expression of GATA-2 and GATA-3both at the gene and protein levels (Hu, 2010),inhibition of of IkB kinase β (ser 181)(Shang et al.,2010), increasing mitochondrial SirT3 activity (Teodoroet al., 2013), inhibition of proinflammatory IL-6 andTNF-alpha protein release (Spatuzza et al., 2014) andregulating gut microbes (Xie et al., 2011) have proposedas mechanisms of anti-obesity effect of berberine inin vitro and in vivo studies. In a pilot study in obesehuman subjects, administration of 500mg berberineorally t.i.d. for 12weeks produced a mild weight loss(average 5 lb/subject) in obese human subjects. Tests ofcardiovascular, hematological, liver, and kidneyfunction following berberine treatment showed nodetrimental side effects to this natural compound.Collectively, this study has showed that berberine has amoderate weight loss effect (Hu et al., 2012b)

GASTEROINTESTINAL TRACT

Liver

Liver fibrosis. The proliferation of hepatic stellate cellshas important role in the development of fibrosis duringliver injury. 48h incubation of rat hepatic stellate cellswith berberine has inhibited the proliferation of these

cells and induced cell cycle arrest in G1 phase. There-fore, berberine can prevent hepatic fibrosis by inhibitionof hepatic stellate cell proliferation (Sun et al., 2009).Another study has shown that berberine can prevent ex-perimental liver fibrosis through regulation of lipid per-oxidation and anti-oxidant system (Zhang et al., 2008a).

Nonalcoholic Fatty liver disease. The NonalcoholicFatty liver disease (NAFLD) is one of the most preva-lent causes of liver enzymes enhancement and has aclose relationship with obesity, dyslipidemia, type II dia-betes, and hypertension (Kashkooli et al., 2015). Berber-ine can alleviate fatty liver in db/db and ob/ob mice(Chang et al., 2010), rat (Zhan et al., 2010), and human(Kashkooli et al., 2015). Proposed mechanisms includereversing the methylation state of genes involved in lipidmetabolism (Chang et al., 2010), lowering blood lipidlevel and improving hepatic anti-oxidative capability(Zhan et al., 2010), down-regulation of uncouplingprotein-2 mRNA and protein expressions in hepatic tis-sue (Yang et al., 2011), improving insulin resistance ofNAFLD by up-regulating mRNA and protein levels ofIRS-2, a key molecule in the insulin signaling pathway(Xing et al., 2011), up-regulating the mRNA expressionof leptin receptor (Yin et al., 2009), down-regulation ofthe LXRalpha/FAS signaling pathway of hepatocytes(Han et al., 2015) and restoring the expression of L-typePyruvate Kinase gene (Zhang et al., 2015b).

Carbon tetrachloride induced liver toxicity. Berberinehas hepatoprotective effects against Carbon tetrachlo-ride (CCl4)-induced hepatotoxicity (Feng et al., 2010).The hepatoprotective mechanisms of berberine may berelated to the attenuation of oxidative/nitrosative stressand free radical scavenging, as well as to the inhibitionof TNF-alpha, inducible nitric oxide synthase, andcyclooxygenase-2 (Domitrovic et al., 2011). In a clinicaltrial on 184 patients with NAFLD, administration ofberberine (0.5 g t.i.d) has been resulted in a significantreduction of NAFLD and related metabolic disorders(Yan et al., 2015).

Berberis vulgaris L. root, stem, and fruit extracts alsohave protective effect against the CCl4-induced oxida-tive damage via modulation on detoxification enzymesand antioxidant and free radical scavenger effects(Fallah Huseini et al., 2010; Eidi et al., 2011; FallahHuseini et al., 2012).

Anti-diarrhea

Berberine has been widely used for treating of gastroen-teritis and diarrhea patients in China for a long time(Zhang et al., 2012b). Previously, we reviewed antidiar-rheal effects of berberine (Derosa et al., 2012). Duringrecent years several studies indicated that berberinehas various pharmacological effects, including inhibitionof intestinal fluid accumulation and ion secretion(Alzamora et al., 2011), anti-inflammatory (Amashehet al., 2010), anti-microbial (Gu et al., 2011), anti-inhibition of smooth muscle contraction (Li et al.,2011a), each of which may contribute to the anti-diarrhea effect. For example, it has been shown thatberberine reduces epithelial gut permeability via rein-forcing tight junctions (Gu et al., 2009) and amelioratespro-inflammatory cytokines involve in intestinal



epithelia tight junction damaging (Li, et al., 2010b; Caoet al., 2013). Several studies have also demonstrated ef-fects of berberine on ion exchange and water transfer in-cluding inhibition of cAMP-activated potassium current[I K (cAMP)] (Yin et al., 2010), inhibitory effect on co-lonic Cl� secretion (Alzamora et al., 2011), enhancingthe absorption of Na+ and water via the expression ofNa+/H+ exchanger (Zhang et al., 2012b).

Inflammatory diseases of gut

Berberine prevents damage to the intestinal mucosalbarrier in early phase of sepsis (Amasheh et al., 2010).In animal models of endotoxinemia, berberine protectsgut damage through different mechanisms includingattenuation of disruption of tight junctions in intestinalepithelium (Gu et al., 2011), suppressing the increasedTNF-alpha, reducing enterocyte apoptosis (Li et al.,2011a), IL-1beta, and nitrite oxide (NO) (Zhang et al.,2011) and attenuating the overexpression of inducibleCOX-2 (Feng et al., 2012). Berberine also can attenuatethe impairment of glutamine transport and glutaminaseactivity in rat sepsis (Niu et al., 2011). Collectively, itseems that berberine is a promising agent for preventingsepsis. Berberine also has some effects in other inflam-matory diseases of intestine including of inflammatorybowel disease (Hao et al., 2012), postoperative abdomi-nal adhesion and inflammation (Zhang et al., 2014b) andgastrointestinal injury caused by acute heavy alcoholexposure (Wang et al., 2015b). Also in a rat model of ir-ritable bowel syndrome, berberine has shown protectiveeffect on visceral hypersensitivity via reducing IL-6 and5-HT (Tang et al., 2014).

SKIN EFFECTS

Berberine has proposed as an anti-skin aging agent dueto its inhibitory effect on basal and UV-induced matrixmetalloproteinase-1 and matrix metalloproteinase-9expressions in human dermal fibroblasts and normalhuman keratinocytes, respectively (Kim and Chung,2008a; Kim et al., 2008b). Berberine has inhibitoryeffects on subcutaneous preadipocytes differentiationand facilitates lipolysis in adipocytes and therefore, isexpected to be useful for slimming and related skintroubles such as skin swelling, cellulite, and so on(Yashiki et al., 2010).As we mentioned in the previous review article, B.

vulgaris L. has shown antilipogenic effect in the seba-ceous glands of hamster (Derosa et al., 2012). In 2012,in a clinical study in adolescents aged 12–17 years withmoderate to severe acne vulgaris, oral capsules contain-ing aqueous extract of dried barberry (600mg daily for4weeks, n=25) significantly reduced the mean numberof non-inflamed, inflamed, and total lesions as well asmean Michaelson’s acne severity score. It seems thatoral aqueous extract of barberry is a safe, well-tolerated,and effective in adolescents with moderate to severeacne vulgaris (Fouladi, 2012) In another study on pa-tient with mild-to-moderate acne, B. vulgaris fruit juicewas effective against acne lesions (Johnson andRafikhah, 2014).

ANTIMICROBIAL EFFECTS

Antibacterial effects

Berberine is widely used as an anti-infective in tradi-tional medicine (Boberek et al., 2010). Berberine hasbeen shown to exhibit antibacterial activity against a va-riety of bacteria, including Streptococcus agalactiae(MIC=78 mug/mL) (Peng et al., 2015), Actinobacilluspleuropneumoniae (MIC=0.3125mg/mL) (Kang et al.,2015), different strains of Staphylococccus (MIC= from16 to 512 micro g/mL) (Wojtyczka et al., 2014) and, Shi-gella dysenteriae (Kong et al., 2010). Berberine also ef-fectively prevents the formation of S. epidermidisbiofilm on the surface of the titanium disk and is a po-tential agent for the treatment of periprosthetic infec-tion (Wang et al., 2009c; Wang et al., 2009d).

There are several studies about possible berberinemechanism(s) of antibacterial actions. A number ofstudies demonstrate that berberine is a DNA ligand,able to bind both single-stranded and double-strandedDNA in vitro (Bae, Lee, Kim, et al., 2013; Chi et al.,2014a; Chi et al., 2014b; Liu et al., 2014). Therefore,binding of berberine to DNA in bacteria can lead toDNA damage. A Recent study indicates that the pri-mary mechanism of antibacterial action of berberine isdue to inhibition of the cell division protein FtsZ(Boberek et al., 2010). Berberine has a synergistic effectwith some common antibiotics especially with linezolid,cefoxitin, and erythromycin (Wojtyczka et al., 2014).This suggests the potential use of berberine in combina-tions with other antibiotics as an efficient therapeutictool for antibiotic-resistant bacterial infections.

Antiparasitic effects

Several studies show that berberine via its antioxidantactivity exerts beneficial effects on Schistosomamansoni-induced organ toxicity in splenic (Al-Quraishyet al., 2013), hepatic (Dkhil, 2014), renal and testiculartissues of mice (Dkhil et al., 2014).

A similar protective effect has been shown in Plasmo-dium chabaudi-induced spleen injury (mice malaria)(Dkhil et al., 2015).

B. vulgaris methanolic extract and berberine alonehave demonstrated good scolicidal activities againstprotoscoleces of hydatid cysts in low concentration andshort exposure time on in vitro model. But in vivo effi-cacy of B. vulgaris and berberine has been not evaluated(Mahmoudvand et al., 2014b).

Berberine also has a promising anti-leishmanial ef-fect, with IC50=7.1μM in L. donovani promastigotes(Saha et al., 2009), and IC50 values varying from 2.1 to26.6μg/mL in L. major and L. tropica promastigotes(Mahmoudvand et al., 2014a). Berberine exerts anapoptosis-like death (Saha et al., 2009) and modulatesmacrophage effector responses via the MAPK pathway(Saha et al., 2011).

The ethanolic extract of B. vulgaris fruits, also ex-hibits an effective leishmanicidal activity against L.tropica on in vitro model (IC50=4.83μg/ml)(Mahmoudvand et al., 2014c). A lotion prepared fromroot bark extract of B. vulgaris has shown good



suppression effects (90% recovery) in mice infectedwith cutaneous leishmaniasis. (L. major) (Salehabadiet al., 2014).

Antiviral

Berberine has shown antiviral properties against herpessimplex virus types 1 and 2 (HSV-1, 2) in Vero cells (Chinet al., 2010; Dkhil and Al-Quraishy, 2014). Berberine at150μg/mL provided 76.5% inhibition of plaque ofHSV-1 and 80% inhibition against HSV-2 (Dkhil et al.,2014). Berberine strongly inhibits the growth of twoH1N1 strains (PR/8/34 or WS/33) of the influenza Avirus. Berberine does not prevent the expression of keyviral proteins, but can reduce the growth of the virus byinducing the formation of viral protein aggregates withinthe host cell cytoplasm (Cecil, 2011; Cecil et al., 2011).An in vivo influenza virus model in mice also has shownthat berberine reduced mice mortality from 90% to 55%and decreased virus titers in the lungs on day 2 postinfec-tion (Wu et al., 2011). Berberine also suppresses thereplication of respiratory syncytial virus in epithelialcells, probably via inhibition of RSV-mediated earlyp38 MAPK activation (Shin et al., 2015).

Antifungal

Berberine has shown antifungal activity against Candidaalbicans (MIC=34.52μg/mL) (Zhao et al., 2010),Microsporum canis (Xiao et al., 2015) and B. cinerea(Parvu et al., 2010). B. vulgaris bark extract also hassignificant antifungal activity against B. cinerea, andits effect is stronger than that of pure berberine(Parvu et al., 2010). There are some studies about syner-gistic effects of berberine and fluconazole againstfluconazole-resistant C. albicans. (Xu et al., 2009b; Liet al., 2013a). In this synergism effect, berberine plays amajor antifungal role, while fluconazole plays a role inincreasing the intracellular berberine concentration(Li et al., 2013a). Endogenous ROS augmentation andmitochondrial aerobic respiration shift contribute to thesynergistic action of fluconazole plus berberine againstfluconazole-resistant C. albicans (Xu et al., 2009b).

MUSCULOSKELETAL EFFECTS

Osteoporosis

Berberine inhibits osteoclastogenesis and bone resorp-tion through amelioration of RANKL-mediated osteo-clast formation and survival (Hu et al., 2008). In a cellculture system, the strongest inhibitory effect has beenexhibited at the concentration of 10μmol/L (Wei et al.,2009). On the other hand, in osteoblastic cells; berberineenhances osteoblast differentiation through activationof Runx2 by p38 MAPK (Lee et al., 2008). Takentogether, berberine may have a therapeutic potentialfor treatment of osteoporosis.Berberine has prevented glucocorticoid-induced oste-

oporosis in rats by inhibiting bone resorption andimproving bone formation (Xu et al., 2010).

Osteoarthritis

Several studies suggest a protective role for berberine inthe development of osteoarthritis. In an IL-1β-inducedrat osteoarthritis model, berberine has showed ananticatabolic effect and in IL-1β-induced rat articularchondrocytes, berberine has decreased IL-1β-inducedNO production and glycosaminoglycan release(Hu et al., 2011a). Berberine also ameliorates cartilagedegeneration by promoting matrix production ofchondrocytes, partly via activation of Akt (Zhao et al.,2014). Berberine suppresses chondrocyte apoptosisand ameliorates cartilage degeneration via activatingAMPK signaling and suppressing p38 MAPK activity(Zhou et al., 2015).

Rheumatoid arthritis

Berberine proposed to have therapeutic potentials inthe treatment of rheumatoid arthritis (Wang et al.,2011d). Berberine selectively induces apoptosis in den-dritic cells (Hu et al., 2011b) and exerts antiprolifera-tive effects against activated rheumatoid arthritisfibroblast-like synoviocytes which play a key role inthe initiation and progression of rheumatoid arthritis(Wang et al., 2011d). In rats with bovine type IIcollagen-induced arthritis, an animal model for rheu-matoid arthritis, berberine decreases arthritic scoresand suppresses collagen–specific immune responses(Wang et al., 2014b).

RENAL EFFECTS

Urolithiasis

B. vulgaris is a widely used plant for the treatment ofurolithiasis (Bashir et al., 2010). Animal studies rational-ize its medicinal use for the treatment of urolithiasis. Forexample, the aqueous-methanolic extract of B. vulgarisroot bark, inhibited deposition of calcium oxalate crystalin renal tubules and protected against related changesincluding polyuria, impaired renal function, and the de-velopment of oxidative stress in kidneys of rats were un-dergone a model of calcium oxalate urolithiasis(developed in male Wistar rats by adding 0.75% ethyl-ene glycol in drinking water) (Bashir et al., 2010). Insame animal model of calcium oxalate urolithiasis, ber-berine has also shown antiurolithic property through acombination of antioxidant, diuretic, urinary alkaliniz-ing, and hypocalciuric effects (Bashir, Gilani, Siddiqui,et al., 2010).

Renal ischemia/ reperfusion

Ischemia/reperfusion injury plays a crucial role in renaltransplantation. Berberine pretreatment has beenshown to attenuate ischemia/reperfusion injury bysuppression of mitochondrial stress and endoplasmicreticulum stress pathways (Yu et al., 2013). Berberinehas also an ameliorative effect on pulmonary and he-patic injuries following renal ischemia/reperfusion inrats (Gholampour et al., 2014; Gholampour et al., 2015).



PREVENTION OFADVERSE DRUG REACTIONS

Cisplatin-induced kidney damage

In a study inmice, berberine has shown nephroprotectiveactivity against Cisplatin-induced renal injury throughthe inhibition of oxidative/nitrosative stress, apoptosis,inflammation, and autophagy (Domitrovic et al., 2013).

Isoniazid-induced hepatotoxicity

Concurrent administration of berberine and isoniazid inrats protects against isoniazid-induced oxidative stressand inflammation leading to liver injury. This protectiveeffect can be related to its ability to up-regulate PPARand suppression of NF-kB, iNOS, and release of thepro-inflammatory cytokines (Mahmoud et al., 2014).

Acute radiation intestinal syndrome in abdomenradiotherapy

Radiation-induced acute intestinal symptoms are themost relevant complication of abdominal and pelvic ra-diation. In a clinical trial on 36 patients, pretreatmentwith berberine ameliorated the incidence and severityof radiation-induced acute intestinal symptoms in pa-tients with abdominal/pelvic radiotherapy (Li et al.,2010a).

Bleomycin induced pulmonary toxicity

Berberine administration exhibited the beneficialeffects against bleomycin-induced lung injury andfibrosis in rats through activating Nrf2 and suppressingNF-kappaB dependent inflammatory and TGF-beta1mediated fibrotic events (Chitra et al., 2013).

Weight gain associated with antipsychotics

Weight gain is a common adverse effect of second gen-eration antipsychotics such as clozapine and risperi-done. Increased peripheral adipogenesis via the sterolregulatory element binding factor-1 pathway is onecritical mechanism proposed for antipsychotic drug-induced weight gain. In a cell culture study, berberinediminished the induction of adipogenesis and down-regulated mRNA and protein expression levels ofsterol regulatory element binding factor-1-relatedproteins (Hu et al., 2010). In a rat model ofolanzapine-induced weight gain, 2weeks administrationof metformin and berberine significantly reduced thewhite fat accumulation and olanzapine-induced weightgain (Hu et al., 2014).

Doxorubicin-induced cardiotoxicity

Pretreatment with berberine has significantly attenu-ated doxorubicin-induced cardiotoxicity in mice (Zhaoet al., 2011). Another study in rat has shown that

berberine attenuates doxorubicin-induced cardiomyo-cyte apoptosis via inhibiting an increase in theAMP/ATP ratio and AMPKα phosphorylation,protecting mitochondria as well as elevating Bcl-2 ex-pression (Lv et al., 2012).

Berberine also has inhibited the metabolism of doxo-rubicin in the cytoplasm of rat heart and decreased theaccumulation of doxorubicinol (a metabolite of doxoru-bicin) in heart (Hao et al., 2015). On the other hand,berberine has sensitized A549, HeLa, and HepG2 cellsto the anticancer effects of doxorubicin (Tong et al.,2012). Therefore, it seems that berberine decreasescardiotoxicity and increases anticancer effects ofdoxorubicin.

Gastric damage induced by nonsteroidalanti-inflammatory drugs

The protective effect of berberine on gastric damageinduced by nonsteroidal anti-inflammatory drugs hasevaluated in rats and demonstrated that berberineexerts protective effect on gastric damage inducedby nonsteroidal anti-inflammatory drugs and theincrease of PGE2 and COX-1, as well as decreaseof NO and COX-2 are probable mechanisms (Wanget al., 2012).

CONCLUSION

The pharmacological properties of berberine and B.vulgaris propose them as natural drugs for clinical usesin different diseases and pathological conditions includ-ing diabetes, cancers, cardiovascular disease, hyperlipid-emia, hypertension, diarrhea, inflammation, bacterialand viral infections, cerebral ischemia, mental disease,Alzheimer, osteoporosis, and etc. Cancer comprisesmost numbers of published articles followed bydiabetes, cardiovasculare, central nervous system,gasterointestinal, antimicrobial, pharmacokinetic, mus-culoskeletal, and prevention of adverse drug reactions.Regarding toxicity, berberine seems to be almost safein customary doses but there are not enough clinicaldocuments about berberine and B. vulgaris safeties.Interaction with other drugs is another aspect must beconsidered in clinical use of berberine. Metformin, keto-conazole, digoxin, and cyclosporine are among moststudied drug interactions of berberine. The inhibitionof intestinal P-gp and CYPs are two major mechanismsin drug–drug interaction of berberine and other drugs.The effect of berberine on CYPs activity is dose-dependent. Lower doses of berberine appear to have alow risk of drug–drug interactions, but high doses of ber-berine may suppress CYPs activity and cause drug–druginteractions. Regarding common use of berberine in di-abetic patients, this drug–drug interaction is very impor-tant. In future, more reliable clinical trials are needed toevaluate the efficacy of berberine in treating differentpathological conditions. Poor bioavailability of berber-ine (less than 1%) limits clinical use of berberine andseveral strategies have been tested to improve the bio-availability of berberine.



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