review article potential benefits of berberine in the...

Review ArticlePotential Benefits of Berberine in the Management ofPerimenopausal Syndrome

Cristiana Caliceti1 Paola Rizzo12 and Arrigo Francesco Giuseppe Cicero3

1Department of Medical Sciences University of Ferrara Ferrara Italy2Laboratory for Technologies of Advanced Therapies (LTTA) University of Ferrara Ferrara Italy3Department of Medicine and Surgery Sciences University of Bologna Bologna Italy

Correspondence should be addressed to Cristiana Caliceti cristianacalicetigmailcom

Received 27 November 2014 Accepted 28 January 2015

Academic Editor Angel Catala

Copyright copy 2015 Cristiana Caliceti et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cardiovascular diseases are one of the leading causes of morbidity and mortality in women after menopause and 56 of all causesof death in Western European countries Nowadays with increasing life span women spend approximately one-third of their life-time in postmenopausal state therefore the development of new strategies to improve the prevention and treatment ofmenopause-associated pathologies is important topic in clinical practice The studies to assess the safety of hormone replacement therapy inwomen with estrogen deficiency have not been conclusive due to the relative contraindications therefore hormone replacementtherapy is prescribed only in selected cases and for a limited time For this reason today women are encouraged to use naturallyavailable compounds to prevent or to attenuate menopausal symptoms and correlated pathologies with fewer side effects Amongthese compounds berberine an isoquinoline alkaloid derived from plants of the generis Berberis has been recognized as beingcapable of decreasing oxidative stress LDL triglycerides and insulin resistance and of improving the mood This review describesthe cellular and clinical effects associated with the use of berberine which suggest that this molecule could be an effective naturalsupplement to ensure a smooth peri- and postmenopausal transition

1 Introduction

Cardiovascular diseases are one of the leading causes ofmorbidity and mortality in women after menopause and56 of all causes of death in Western European countries[1] Menopause is characterized by an altered hormonalstatus and a subsequent decrease in life quality affecting eachwoman differently Specifically the decline and eventual ces-sation of estrogen production are associated with the appear-ance of uncomfortable symptoms (hot flashes night sweatsbreast tenderness vaginal dryness irregular menses moodchanges and vaginal atrophy) as well as pathologies such asosteoporosis heart disease hypercholesterolemia endothe-lial dysfunction vascular inflammation hyperglycemia anddepression [2] Currently women may expect to spend morethan a third of their lives after menopause therefore theunderstanding of menopause-associated pathologies and thedevelopment of new strategies to improve the treatment ofmenopause-associated symptoms are important topics in the

clinical practice Results from different studies indicate thatthe use of hormone replacement therapy (HRT) in men-opause needs to be carefully assessed and risks and benefitsof the therapy should be evaluated by the clinician for eachindividual woman Clearly the possible problems associatedwithHRT in a subpopulation in womenmay be attenuated byother molecules safer than estrogens as well as by lifestylemodifications such as diet food supplements and exercise[3] In recent years there has been renewed interest inthe potential of purified natural products to provide healthand medical benefits and to prevent disease Antioxidantcompounds have been shown to be of great benefit in womenexperiencing menopausal symptoms [4]

Berberine (BBR) a quaternary ammonium salt from theprotoberberine group of isoquinoline alkaloids (56-dihy-drodibenzoquinolizinium derivative) found in the bark rhi-zomes roots and stems of Berberis vulgaris L (Berberi-daceae) exhibits many different types of biological activities

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 723093 9 pageshttpdxdoiorg1011552015723093

2 Oxidative Medicine and Cellular Longevity

[5] Among them the best characterized ones are antioxidantanti-inflammatory cholesterol-lowering antihyperglycemicand antidepressive effects

This paper will discuss the studies that have shown thepotential benefits of berberine supplementation for thereduction at least partially of menopause-associated pathol-ogies (oxidative stress inflammation and hypercholesterole-mia-related cardiovascular diseases hyperglycemia-relateddiabetesmellitus type 2 and depression) and for the improve-ment of quality of life in menopausal women

2 Role of Berberine in Oxidative Stress

Estrogen deficiency increases cardiovascular risk as a resultof atherogenic modifications of plasma lipid profile activa-tion of the renin-angiotensin system and overproductionof reactive oxygen species (ROS) which quench nitric oxide(NO) [6 7] Overproduction of ROS has been shown inpathological situations and can be highly injurious to adja-cent structures in cells including lipid membranes DNAand proteins [8] Increased oxidative stress and reducedNO bioavailability are important contributing factors ofmenopause-related endothelial dysfunction atherosclerosishypertension cardiovascular and renal diseases [9 10]

Impaired vascular function due to ROS overproductionwhich occurs during estrogen deficiency could be normalizedby HRT in women and animal models of menopause [1112] In fact following the onset of either permanent ortransient estrogens deprivation oxidative stress increases sig-nificantly [4] Serum concentrations of inflammatory cytok-ines and prooxidant biomarkers such as glutathione 4-hy-droxynonenal andmalondialdehyde were found to be higherin postmenopausal than in premenopausal women [13]The elevation of cytokines and prooxidant makers suggeststhat there is a high degree of oxidative stress in the post-menopausal state [13 14]

One of the major sources of ROS production in cells is afamily of membrane-associated enzymatic complexes callednicotinamide adenine dinucleotide phosphate (NADPH)oxidase (NOX) [15] its activation is often associated withhigh levels of fatty acids cholesterol glucose or advancedglycation end products (AGEs) all linked tomenopausal state[16ndash18] Among various NOX isoforms BBR was reported tosuppress the overexpression of NOX 2 4 and to decrease ROSproduction inmacrophages and endothelial cells upon stimu-lation with inflammatory stimuli [19 20] In endothelial cellsBBR attenuates LDL oxidation induced by ROS and reducesthe collapse of mitochondrial membrane potential the chro-mosome condensation the cytochrome C release and thecaspase-3 activation [21] Circulating endothelial micro-particles (EMPs) vesicular structures found in plasma frompatients with vascular diseases so utilized as a surrogatemarker of endothelial dysfunction are oxidative stress induc-ers they promote upregulation of NOX4 expression and ROSproduction It has been reported that BBR reversed NOX4-derived ROS production in human umbilical vein endothelialcells (HUVECs) [22]

NOX could be negatively regulated by adenosine mon-ophosphate-activated protein kinase (AMPK) activation

[23 24] in fact AMPK activators such as metformin mayexert their cardiovascular protective function through NOXinhibition [25] AMPK pathway is activated by BBR [26] andit seems to play a pivotal role in mediating its antioxidantactivity [27 28]

AMPKplays also an important role in regulating functionof NO synthesis in endothelial cells In fact AMPK is anupstream kinase of endothelial nitric oxide synthase (eNOS)which promotes the phosphorylation of eNOS at Ser1177 siteaswell as the formation of eNOS andHSP90 complex andNOproduction [9 29] Menopause-related decrease in estrogenreceptors correlates with lower eNOS expression and activa-tion [30] in both animal and humanmodels ofmenopause [712] as eNOS activity is notably regulated by estrogens throughthe modulation of the eNOScaveolin-1 (Cav-1) complex for-mation [31] Zhang and colleagues observed that in HUVECsBBR ameliorates palmitate-induced endothelial dysfunctionby upregulating eNOS and downregulating NOX4 throughthe activation of AMPK [32] In both cultured endothelialcells and blood vessels isolated from rat aorta BBR enhancedeNOS phosphorylation and attenuated high glucose-inducedgeneration of ROS cellular apoptosis NF-120581B activation andexpression of adhesion molecules through AMPK signalingcascade activation a key event in preventing oxidative andinflammatory signaling [33]

Besides NADPH oxidase downregulation and NO pro-duction AMPK activation has been linked to upregulation ofthe antioxidant enzyme superoxide dismutase (SOD) [34 35]which induces the dismutation of anion superoxide in hydro-gen peroxide An increased SOD expression in BBR treateddiabetic mice was observed [36 37] Glutathione (GSH) isanother antioxidant enzyme which helps to maintain thebalance of redox state in organisms and it is a substrateof glutathione peroxidase (GSH-Px) in the clearance ofperoxides [38] BBR treatment promotes a GSH-Px and SODhyperactivation in the liver of mice [39] attenuates H

2O2-

induced ROS production and increases detoxifying enzymesGSH-Px and SOD in NSC34 motor neuron-like cells [40]

3 Role of Berberine inCardiovascular Disease Risk

The increased cardiovascular disease risk at the menopauseis associated with decreased ovarian function [41 42] and isin part due to arterial dysfunction and a less favorable bloodlipid profile Exogenous estrogen and progesterone in theform of HRT have been shown to reduce plasma concen-trations of LDL cholesterol and increase concentrations ofHDL cholesterol [43] even if their use in menopause is stillobject of debate because of the increased risk of breast cancerictus ischaemic cardiomyopathy and thrombus detachment[44 45]

High levels of low-density lipoprotein (LDL) and theiroxidized counterpart oxidized LDL (oxLDL) in the bloodvessels represent a major risk factor for endothelial dys-function and atherosclerosis [46] Inactivity of LDL receptor(LDLR) or its low-level expression initiates accumulation ofLDL in blood vessels [47] On the other hand the receptor of

Oxidative Medicine and Cellular Longevity 3

oxLDL lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) identified as the main endothelial receptor foroxLDL and also present in macrophages and smooth musclecells (SMC) activates a proatherogenic cascade by inducingendothelial dysfunction SMC proliferation apoptosis andthe transformation of macrophages into foam cells andplatelet activation via NF-120581B activation [48] LOX-1 containsa lectin-like extracellular C-terminal domain which interactswith oxLDL proteolytically cleaved and released as a solublecirculating form (sLOX-1) that reflects the increased expres-sion of membrane-bound receptors and disease activities[49]

Proinflammatory and oxidative stimuli related to athero-genesis [48] such as TNF120572 or interferon 120574 promote theoxLDL formation which in turn develops a vicious cycle bythe activation of LOX-1 linked to NF-120581B to promote tran-scription of proinflammatorymolecules [50] In arterial wallsoxidative stress and inflammation are closely linked LOX-1is undetectable in healthy vessels but overexpressed in ath-erosclerotic lesions and in acute coronary syndromes [51]Thus circulating sLOX-1 could be a potential cardiovasculardisease biomarker [49]

It has been reported that in cultured placental cells acombination of ethinyl estradiol and desogestrel increases theexpression and functional activity of LDLR and decreased theexpression of LOX-1 [52ndash54]

BBR elevates LDLR expression in human liver cells [55]through ERK activation with a sterol regulatory elementbinding proteins (SRPB) independent mechanism [56 57]In another report it has been reported that BBR inducesproprotein convertase subtilisinkexin type 9 (PCSK9) anenzyme that posttranscriptionally upregulates LDLR andSREBP-2 [58] In accordance with previous cited studies ithas been showed that in rat livers a combination of BBR withsimvastatin increased the LDLR gene expression to a levelsignificantly higher than that in monotherapies [59]

In human macrophage-derived foam cells treated withoxLDL BBR inhibits the expression of LOX-1 [60 61] as wellas the oxLDL uptake of macrophages and reduces foam cellformation in a dose-dependent manner [61] by activating theAMPK-SIRT1-PPAR120574 pathway [62] Chi and colleagues [63]demonstrated that BBR combined with atorvastatin is moreeffective in diminishing LOX-1 expression than atorvastatinalone in monocyte-derived macrophages both in vitro andin vivo in rats through modulation of endothelin-1 receptor[62] It is still unknown whether BBR could affect LOX-1expression in endothelial cells

BBR improves also the survival of TNF120572-treated endothe-lial progenitor cells (EPCs) via the activation of PI3KAKTeNOS signaling pathway [64] possibly throughAMPKactiva-tionWu and colleagues showed both in vitro and in vivo thatBBR reduces the leukocyte-endothelium adhesion and vascu-lar cell adhesion molecule-1 (VCAM-1) expression inducedby lipopolysaccharide (LPS) BBR was further confirmed toinhibit the nuclear translocation and DNA binding activityof LPS-activated NF-120581B signaling pathway [65]

The lipid-lowering activity of BBR alone or in associa-tion with other nutraceuticals has been clearly confirmedin a relatively large number of randomized clinical trials

involving a large part of women (usually a half almost allin peri- or postmenopausal age) [66] In a large placebo-controlled randomized clinical trial it has been reportedthat short-term consumption of a combined nutraceuticalcontaining isoflavones and BBR out on 120mild dyslipidemicpostmenopausal women significantly lowered plasma totalcholesterol (135 plusmn 07 versus 02 plusmn 05) LDL cholesterol(124 plusmn 15 versus 08 plusmn 07) and TG (189 plusmn 25 versus13 plusmn 12) improving menopausal symptoms compared withplacebo [67]

In a subsample of the same study it is shown that theassumption of isoflavones and BBR also improved the serumlevels of matrix metalloproteinases known to promote theinvasion of inflammatory cells by degrading the extracellularmatrix [2]

The anti-inflammatory effect of BBR was also confirmedin patients with acute coronary syndrome following percuta-neous coronary intervention [68]

Thus BBR seems to be a promising preventive treatmentin the initial key steps of atherogenesis

4 Role of Berberine inDiabetes Mellitus Type 2

Different studies have shown that the incidence of dia-betes mellitus type 2 (T2DM) is higher among menopausalwomen [69 70] In fact estrogen influences not only vas-cular functions but also insulin sensitivity [71] T2DM is achronic disease characterized by hyperglycemia and insulinresistance in peripheral tissues particularly in the livermuscles adipocytes and pancreatic 120573-cells Individuals withinsulin resistance have either decreased levels or absence ofinsulin receptor expression (InsR) [72ndash74] and subsequenthyperglycemia Oxidative stress participates in developmentand progression of T2DM in which changes of SOD andcatalase (CAT) were noted in T2DMmice [36]

It has been reported that taking a low dose of combinedHRT (a combination of estrogens and progesterone) ledto a decreased risk of developing diabetes and to betterglucose control in postmenopausal women [75] Moran andcolleagues compared the effects of estradiol and genisteintreatments on insulin signaling pathway in the cerebralcortex of ovariectomized young and aged female rats Theyobserved that aging decreases the translocation of the insulindependent glucose transporter-4 (GLUT4) and 17120573-estradiolbut not genistein which favours GLUT4 translocation [76]

BBR exhibited a high hypoglycemic potential it has beenshown that BBR activates AMPK with subsequent inductionof glycolysis [77] AMPK as an intracellular energy receptorhas attracted more attention and become a new target for thetreatment of diabetes and its cardiovascular complicationsdue to its regulatory effect on endothelial cell function andenergy homeostasis In H9c2 myoblast cell line treated withinsulin to induce insulin resistance BBR attenuated thereduction in glucose consumption and glucose uptake at leastin part via stimulation of AMPK activity [78] BBR enhancedacute insulin-mediated GLUT4 translocation and glucosetransport in insulin-resistant myotubes through activation ofAMPK and PI3K pathway [79]


Besides the role in AMPK signaling Kong and colleaguesshowed that BBR increased insulin receptor (InsR)messengerRNA and protein expression in a variety of human cell linesand hepatitis B virus transfected human liver cells [80] Ina clinical study the same group observed that BBR signifi-cantly lowered fasting blood glucose (FBG) hemoglobin A1ctriglycerides and insulin levels in patients with T2DM as wellas metformin and rosiglitazone (a combination commonlyused for the T2DM therapy) the percentages of peripheralblood lymphocytes expressing InsR were significantly ele-vated after therapy [81]

BBR exhibited similar hypoglycemic potential as gliben-clamide (an anti-T2DM drug that stimulates the release ofinsulin) to lower area under the curve of the fasting bloodglucose in the kidney liver and brain of mice with T2DM[36]

The dose-dependent antidiabetic properties of BBR havebeen clearly confirmed in a relatively large number of ran-domized clinical trials involving a large number of women(usually 50 almost all in peri- or postmenopausal age) [82]

Thus on the basis of the available evidence we can rea-sonably conclude that BBR could be an ideal supplementationfor T2DM since it acts with a mechanism different from thethree drugs commonly utilized in therapy glibenclamidemetformin and rosiglitazone

5 Role of Berberine in Depressive Disorder

During the menopausal transition between 15 and 50of women experience depressive symptoms in 15 to 30of perimenopausal women they are severe enough to beregarded as a depressive disorder Fluctuations in gonadalhormone levels are thought to contribute to these depressiveconditions and HRT is commonly used to alleviate climac-teric symptoms [83]

A combination of interactions betweenneurotransmitters[84] neuropeptides [85] oxidative and nitrosative stress [86]and cytokines [87] are thought to take part in pathogenesis ofdepression It is theorized that the additive effect of enhancingneurotransmission in three monoamine systems (serotoninnorepinephrine and dopamine) may lead to improved effi-cacy and quicker onset of antidepressant response [88]Clinical studies have reported that patients with depressionpresented also oxidative disturbances such as elevated lipidperoxidation products and reduced levels of SOD [89 90]NF-120581B activity is regulated at least in part by the intensityof intracellular oxidative and nitrosative stress and in turncontrols the regulation of genes encoding proteins involvedin immune and inflammatory responses [91] Depressedpatients often display enhanced cytokine levels includinginterleukin-6 (IL-6) C-reactive protein interleukin-1-beta(IL-1120573) and TNF120572 they can enter the brain and may causealterations of the metabolism of serotonin and dopamine[92] Thus these studies showed a correlation between oxida-tive and nitrosative stress increased levels of cytokines andaltered levels of biogenic amines

Mechanistically estrogen plays an important role inmood and cognitive regulation [93] It is reported thatmonoamine oxidase-A (MAO-A) total distribution volume

an index of MAO-A density is elevated in perimenopausalwomen [94]

BBR inhibited the immobility period in mice in bothforced swim and tail-suspension test two animal models ofdepression in a dose independent manner [95 96] Amongthe reported bioactivities of BBR there is the inhibition ofMAO-A enzyme activity [97] In fact acute and chronicadministration of BBR in mice resulted in increased levels ofnorepinephrine serotonin and dopamine neurotransmittersinduced by MAO-A enzyme [95] In accordance with Kulka-rni and colleague data Arora and Chopra showed the protec-tive antidepressant-like effect of BBR against the reserpine-induced biogenic amine depletion (a monoamine depletorcommonly used to induce depression in animals [98]) andagainst oxidative nitrosative stress-mediated inflammatorycascade and apoptotic signaling pathway in rats [99]

Recently the important role of endoplasmic reticulumprotein sigma-1 receptors (sigma receptors) in the modu-lation of various neurotransmitters has been identified Itseems to be a promising target for the pathophysiology ofneuropsychiatric disorders in particular for depression andsigma-1 receptor modulators are considered the drugs of thefuture for the treatment of major depression and anxiety It isreported that BBR has an effect on sigma receptor-1 similar tomany synthetic antidepressant drugs [100]

However at the best of our knowledge there are no avail-able data on the evaluation of the potential antidepressanteffects of BBR in human

6 Berberine Tolerability and Safety

Representative figures to summarize the molecular pathwaysmodulated by BBR and its effects on organs and tissuesare shown (Figures 1 and 2) Standard doses of BBR areusually well-tolerated and adverse reactions are rare Onthe contrary high doses have been associated with arterialhypotension dyspnoea flu-like symptoms gastrointestinaldiscomfort constipation and cardiac damage The LD50(lethal dose 50) of highly purified formulation of berberinesulfate is 25mgkg in mice while the one of Berberis vulgareis moderately high (LD50 = 26 plusmn 022 gkg bw inmice) [101]

By using sorbitol and breath hydrogen tests it has beenshown that BBR delays small intestinal transit time [102] thismay account for part of its gastrointestinal and antidiarrhealside effect [103] The main mechanism of pharmacologicalinteraction of BBR involves cytochrome CYP3A4 and intesti-nal P-glycoprotein the major determinants of bioavailabilityof orally administered drugs in renal transplant recipientsthe coadministration of BBR and cyclosporine A increasesthe mean cyclosporine A half-life by 27 hours [104] thuscausing increased cyclosporine A bioavailability and reducedmetabolism BBR is involved in different pharmacologicalinteractions the drug displaces bilirubin from the albuminabout tenfold more than phenylbutazone and also warfarinthiopental and tolbutamide from their protein binding sitesincreasing their plasma levels [105] For the cited effectsthe use of BBR should be avoided in jaundiced infants andpregnant woman even in small dosage [106]


Berberine

AMPK Insulin receptor

eNOS

NO

NADPHoxidase

ROS

SODCAT

GSHpxLOX1

LDLR MAO

NorepinephrineSerotonin DopamineLDL

Glut-4 translocation

Glycemia

a b c

d

OO

OO

CH3

CH3

N+

NF-120581B

Figure 1 Molecular pathways modulated by BBR (a) BBR could inhibit oxidative stress through AMPK activation that leads to adownregulation of NADPH oxidase expression and an upregulation of the antioxidant enzymes SOD CAT and GSHpx (b) BBRadministration could decrease glycemia through the increase of insulin receptor expression and the AMPK-modulated Glut-4 translocation(c) BBR could decrease circulating LDL by inhibiting NF-120581Bmodulated LOX-1 expression in endothelial cells and inducing LDLR expressionin hepatic cells (d) BBR could inhibit the expression of MAO leading to an upregulation of the mood-stabilizers neurotransmittersnorepinephrine serotonin and dopamine

Oxidative stressAtherosclerosis

Dyslipidemia

Depression

HyperglycemiaDiabetes mellitus type 2

Berberis extract

Figure 2 BBR actions and target organs Berberis extract administration could counteract at least partially depression oxidativestress atherosclerosis hypercholesterolemia hyperglycemia and diabetes mellitus type 2 protecting women from menopause-associatedpathologies


Although CYP3A4 is the well-known target BBR alsoinhibits CYP1A1 in vitro therefore potentially interactingwith drugs metabolized by this cytochrome isoform as well[107] The impact of this observation in clinical practice hasto be evaluated since some environmental contaminants suchas aryl-hydrocarbons are metabolized by CYP1A1 [108]

Lin and colleagues reported that 24 hours of BBR treat-ment upregulated the multidrug-resistant transporter (pgp-170) expression in oral gastric and colon cancer cell linescausing increased cell viability as compared to the effect of thechemotherapeutic agent Paclitaxel These results suggest thatBBR modulates the expression and function of pgp-170 thatleads to a reduced response to Paclitaxel in cancer cells [107]Again no clinical report of a significant pharmacologicalinteraction is yet available

Overall there are a large number of recent clinical trialssupporting the short-term safe use of this nutraceuticalespecially when used at a lipid-lowering dosage

7 Summary

The reduced estrogen level characterizingmenopause is asso-ciated with the insurgence of discomforts and pathologieswhich strongly affects the quality of life of many womenThere is growing evidence that berberine can at least par-tially minimize the negative consequences on the organismcaused by low estrogens levels without the unwanted sideeffects associated with commonly prescribed HRTWhile thesearch for a HRT completely free of risks continues BBRcould represent a safe and efficient tool to sustain womenduring the menopausal transition

Conflict of Interests

The authors declare no competing financial interests

Acknowledgment

This work was supported by a grant from Fondazione AnnaMaria Sechi per il Cuore (FASC) Italy The funders had norole in study design data collection and analysis decision topublish or preparation of the paper

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[2] A F G Cicero E Tartagni A Ferroni V de Sando E Grandiand C Borghi ldquoCombined nutraceutical approach to post-menopausal syndrome and vascular remodeling biomarkersrdquoThe Journal of Alternative and Complementary Medicine vol 19no 6 pp 582ndash587 2013

[3] S L Gudmundsdottir W D Flanders and L B AugestadldquoPhysical activity and cardiovascular risk factors at menopausethe Nord-Trondelag health studyrdquo Climacteric vol 16 no 4 pp438ndash446 2013

[4] S B Doshi and A Agarwal ldquoThe role of oxidative stress inmenopauserdquo Journal of Mid-Life Health vol 4 no 3 pp 140ndash146 2013

[5] S Spinozzi C Colliva C Camborata et al ldquoBerberine and itsmetabolites relationship between physicochemical propertiesand plasma levels after administration to human subjectsrdquoJournal of Natural Products vol 77 no 4 pp 766ndash772 2014

[6] MMaynar GMahedero IMaynar J IMaynar I R Tuya andM J Caballero ldquoMenopause-induced changes in lipid fractionsand total fatty acids in plasmardquo Endocrine Research vol 27 no3 pp 357ndash365 2001

[7] L M Yung W T Wong X Y Tian et al ldquoInhibition ofrenin-angiotensin system reverses endothelial dysfunction andoxidative stress in estrogen deficient ratsrdquo PLoS ONE vol 6 no3 Article ID e17437 2011

[8] B Halliwell ldquoFree radicals and antioxidants updating a per-sonal viewrdquo Nutrition Reviews vol 70 no 5 pp 257ndash265 2012

[9] V A Barbosa T F Luciano S OMarques et al ldquoAcute exerciseinduce endothelial nitric oxide synthase phosphorylation viaAkt and AMP-activated protein kinase in aorta of rats Roleof reactive oxygen speciesrdquo International Journal of Cardiologyvol 167 no 6 pp 2983ndash2988 2013

[10] S Taddei A Virdis L Ghiadoni et al ldquoMenopause is associatedwith endothelial dysfunction in womenrdquo Hypertension vol 28no 4 pp 576ndash582 1996

[11] N G Majmudar S C Robson and G A Ford ldquoEffects of themenopause gender and estrogen replacement therapy on vas-cular nitric oxide activityrdquoThe Journal of Clinical Endocrinologyamp Metabolism vol 85 no 4 pp 1577ndash1583 2000

[12] S Wassmann A T Baumer K Strehlow et al ldquoEndothelialdysfunction and oxidative stress during estrogen deficiency inspontaneously hypertensive ratsrdquoCirculation vol 103 no 3 pp435ndash441 2001

[13] S S Signorelli S Neri S Sciacchitano et al ldquoBehaviour of someindicators of oxidative stress in postmenopausal and fertilewomenrdquoMaturitas vol 53 no 1 pp 77ndash82 2006

[14] R R McLean ldquoProinflammatory cytokines and osteoporosisrdquoCurrent Osteoporosis Reports vol 7 no 4 pp 134ndash139 2009

[15] R S Frey M Ushio-Fukai and A B Malik ldquoNADPH oxidase-dependent signaling in endothelial cells role in physiology andpathophysiologyrdquo Antioxidants and Redox Signaling vol 11 no4 pp 791ndash810 2009

[16] S Furukawa T FujitaM Shimabukuro et al ldquoIncreased oxida-tive stress in obesity and its impact onmetabolic syndromerdquoTheJournal of Clinical Investigation vol 114 no 12 pp 1752ndash17612004

[17] D Bonnefont-Rousselot ldquoGlucose and reactive oxygen speciesrdquoCurrent Opinion in Clinical Nutrition andMetabolic Care vol 5no 5 pp 561ndash568 2002

[18] A Goldin J A Beckman A M Schmidt and M A CreagerldquoAdvanced glycation end products sparking the developmentof diabetic vascular injuryrdquo Circulation vol 114 no 6 pp 597ndash605 2006

[19] F Cheng Y Wang J Li et al ldquoBerberine improves endothe-lial function by reducing endothelial microparticles-mediatedoxidative stress in humansrdquo International Journal of Cardiologyvol 167 no 3 pp 936ndash942 2013

[20] L K Sarna N Wu S-Y Hwang Y L Siow and O KarminldquoBerberine inhibits NADPH oxidase mediated superoxideanion production in macrophagesrdquo Canadian Journal of Physi-ology and Pharmacology vol 88 no 3 pp 369ndash378 2010


[21] Y-S Hsieh W-H Kuo T-W Lin et al ldquoProtective effectsof berberine against low-density lipoprotein (LDL) oxidationand oxidized LDL-induced cytotoxicity on endothelial cellsrdquoJournal of Agricultural and Food Chemistry vol 55 no 25 pp10437ndash10445 2007


[23] J-E Kim Y-W Kim K L In J-Y Kim J K Young and S-Y Park ldquoAMP-activated protein kinase activation by 5-ami-noimidazole-4-carboxamide- 1-120573-d-ribofuranoside (AICAR)inhibits palmitate-induced endothelial cell apoptosis throughreactive oxygen species suppressionrdquo Journal of Pharmacolog-ical Sciences vol 106 no 3 pp 394ndash403 2008

[24] S Wang M Zhang B Liang et al ldquoAMPKalpha2 deletioncauses aberrant expression and activation of NAD(P)HOxidaseand consequent endothelial dysfunction in vivo role of 26SproteasomesrdquoCirculation Research vol 106 no 6 pp 1117ndash11282010

[25] G Ceolotto A Gallo I Papparella et al ldquoRosiglitazone reducesglucose-induced oxidative stress mediated by NAD(P)Hoxidase via AMPK-dependent mechanismrdquo ArteriosclerosisThrombosis and Vascular Biology vol 27 no 12 pp 2627ndash26332007

[26] K-H Lee H-L Lo W-C Tang H H Hsiao and P-MYang ldquoA gene expression signature-based approach revealsthe mechanisms of action of the Chinese herbal medicineberberinerdquo Scientific Reports vol 4 article 6394 2014

[27] N Turner J-Y Li A Gosby et al ldquoBerberine and its more bio-logically available derivative dihydroberberine inhibit mito-chondrial respiratory complex I a mechanism for the action ofberberine to activate amp-activated protein kinase and improveinsulin actionrdquo Diabetes vol 57 no 5 pp 1414ndash1418 2008

[28] Z Li Y-N Geng J-D Jiang andW-J Kong ldquoAntioxidant andanti-inflammatory activities of berberine in the treatment ofdiabetesmellitusrdquo Evidence-Based Complementary andAlterna-tive Medicine vol 2014 Article ID 289264 12 pages 2014

[29] V A Morrow F Foufelle J M C Connell J R Petrie GW Gould and I P Salt ldquoDirect activation of AMP-activatedprotein kinase stimulates nitric-oxide synthesis in human aorticendothelial cellsrdquo Journal of Biological Chemistry vol 278 no34 pp 31629ndash31639 2003

[30] K M Gavin D R Seals A E Silver and K L MoreauldquoVascular endothelial estrogen receptor 120572 is modulated byestrogen status and related to endothelial function and endothe-lial nitric oxide synthase in healthy womenrdquo Journal of ClinicalEndocrinology and Metabolism vol 94 no 9 pp 3513ndash35202009

[31] X Loyer T Damy Z Chvojkova et al ldquo17beta-estradiolregulates constitutive nitric oxide synthase expression differ-entially in the myocardium in response to pressure overloadrdquoEndocrinology vol 148 no 10 pp 4579ndash4584 2007

[32] M Zhang C-M Wang J Li et al ldquoBerberine protectsagainst palmitate-induced endothelial dysfunction involve-ments of upregulation of AMPKand eNOS and downregulationof NOX4rdquo Mediators of Inflammation vol 2013 Article ID260464 8 pages 2013

[33] Y Wang Y Huang K S L Lam et al ldquoBerberine pre-vents hyperglycemia-induced endothelial injury and enhancesvasodilatation via adenosine monophosphate-activated protein

kinase and endothelial nitric oxide synthaserdquo CardiovascularResearch vol 82 no 3 pp 484ndash492 2009

[34] D Kukidome T Nishikawa K Sonoda et al ldquoActivation ofAMP-activated protein kinase reduces hyperglycemia-inducedmitochondrial reactive oxygen species production and pro-motes mitochondrial biogenesis in human umbilical veinendothelial cellsrdquo Diabetes vol 55 no 1 pp 120ndash127 2006

[35] Z Xie J Zhang JWu B Viollet andM-H Zou ldquoUpregulationof mitochondrial uncoupling protein-2 by the AMP-Activatedprotein kinase in endothelial cells attenuates oxidative stress indiabetesrdquo Diabetes vol 57 no 12 pp 3222ndash3230 2008

[36] W Chatuphonprasert T Lao-Ong and K JarukamjornldquoImprovement of superoxide dismutase and catalase in strep-tozotocinndashnicotinamide-induced type 2-diabetes in mice byberberine and glibenclamiderdquo Pharmaceutical Biology vol 52no 4 pp 419ndash427 2014

[37] T Lao-Ong W Chatuphonprasert N Nemoto and KJarukamjorn ldquoAlteration of hepatic glutathione peroxidase andsuperoxide dismutase expression in streptozotocin-induceddiabetic mice by berberinerdquo Pharmaceutical Biology vol 50 no8 pp 1007ndash1012 2012

[38] I Ceballos-Picot V Witko-Sarsat M Merad-Boudia et alldquoGlutathione antioxidant system as a marker of oxidative stressin chronic renal failurerdquo Free Radical Biology and Medicine vol21 no 6 pp 845ndash853 1996

[39] A E Abd El-Wahab D A Ghareeb E E M Sarhan MM Abu-Serie and M A El Demellawy ldquoIn vitro biologicalassessment of berberis vulgaris and its active constituentberberine antioxidants anti-acetylcholinesterase anti-diabeticand anticancer effectsrdquo BMC Complementary and AlternativeMedicine vol 13 article 218 2013

[40] Y-Y Hsu C-S Chen S-N Wu Y-J Jong and Y-C LoldquoBerberine activates Nrf2 nuclear translocation and protectsagainst oxidative damage via a phosphatidylinositol 3-kinaseAkt-dependent mechanism in NSC34 motor neuron-like cellsrdquoEuropean Journal of Pharmaceutical Sciences vol 46 no 5 pp415ndash425 2012

[41] E Barrett-Connor and T L Bush ldquoEstrogen and coronary heartdisease in womenrdquo Journal of the AmericanMedical Associationvol 265 no 14 pp 1861ndash1867 1991

[42] A P Miller W Feng D Xing et al ldquoEstrogen modulatesinflammatory mediator expression and neutrophil chemotaxisin injured arteriesrdquo Circulation vol 110 no 12 pp 1664ndash16692004

[43] L C N Erberich V M Alcantara G Picheth and MScartezini ldquoHormone replacement therapy in postmenopausalwomen and its effects on plasma lipid levelsrdquoClinical Chemistryand Laboratory Medicine vol 40 no 5 pp 446ndash451 2002

[44] D Grady W Applegate T Bush C Furberg B Riggs andS B Hulley ldquoHeart and estrogenprogestin replacement study(HERS) design methods and baseline characteristicsrdquo Con-trolled Clinical Trials vol 19 no 4 pp 314ndash335 1998

[45] T Lagro-JanssenWW Rosser and C VanWeel ldquoBreast cancerand hormone-replacement therapy up to general practice topick up the piecesrdquo The Lancet vol 362 no 9382 pp 414ndash4152003

[46] V Lubrano and S Balzan ldquoLOX-1 and ROS inseparable factorsin the process of endothelial damagerdquoFree Radical Research vol48 no 8 pp 841ndash848 2014

[47] W-J Kong J Liu and J-D Jiang ldquoHuman low-density lipopro-tein receptor gene and its regulationrdquo Journal of MolecularMedicine vol 84 no 1 pp 29ndash36 2006


[48] L Cominacini M Anselmi U Garbin et al ldquoEnhanced plasmalevels of oxidized low-density lipoprotein increase circulatingnuclear factor-kappa B activation in patients with unstableanginardquo Journal of the American College of Cardiology vol 46no 5 pp 799ndash806 2005

[49] A Pirillo and A L Catapano ldquoSoluble lectin-like oxidizedlow density lipoprotein receptor-1 as a biochemical marker foratherosclerosis-related diseasesrdquoDisease Markers vol 35 no 5pp 413ndash418 2013

[50] J LWitztum ldquoThe oxidation hypothesis of atherosclerosisrdquoTheLancet vol 344 no 8925 pp 793ndash795 1994

[51] S Ehara M Ueda T Naruko et al ldquoElevated levels of oxidizedlow density lipoprotein show a positive relationship with theseverity of acute coronary syndromesrdquo Circulation vol 103 no15 pp 1955ndash1960 2001

[52] A Arjuman H Pandey and N C Chandra ldquoEffect of acombination oral contraceptive (desogestrel+ethinyl estradiol)on the expression of low-density lipoprotein receptor and itstranscription factor (SREBP2) in placental trophoblast cellsrdquoContraception vol 84 no 2 pp 160ndash168 2011

[53] G Ramakrishnan A Rana C Das and N C Chandra ldquoStudyof low-density lipoprotein receptor regulation by oral (steroid)contraceptives desogestrel levonorgestrel and ethinyl estradiolin JEG-3 cell line and placental tissuerdquo Contraception vol 76no 4 pp 297ndash305 2007

[54] H Pandey A Arjuman K K Roy and N C ChandraldquoReciprocal coordination of a combination oral contraceptivecontaining desogestrel+ethinyl estradiol on the expression ofLOX-1 and LDLR in placental trophoblast cellsrdquo Contraceptionvol 84 no 6 pp e43ndashe49 2011

[55] P Yang D Q Song Y H Li et al ldquoSynthesis and structure-activity relationships of berberine analogues as a novel class oflow-density-lipoprotein receptor up-regulatorsrdquoBioorganic andMedicinal Chemistry Letters vol 18 no 16 pp 4675ndash4677 2008

[56] P Abidi Y Zhou J-D Jiang and J Liu ldquoExtracellular signal-regulated kinase-dependent stabilization of hepatic low-densitylipoprotein receptor mRNA by herbal medicine berberinerdquoArteriosclerosis Thrombosis and Vascular Biology vol 25 no10 pp 2170ndash2176 2005

[57] W Kong JWei P Abidi et al ldquoBerberine is a novel cholesterol-lowering drug working through a unique mechanism distinctfrom statinsrdquo Nature Medicine vol 10 no 12 pp 1344ndash13512004

[58] Y-J Jia R-X Xu J Sun Y Tang and J-J Li ldquoEnhancedcirculating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed ratsrdquo Journal of TranslationalMedicine vol 12 no 1 article 103 2014

[59] W-J Kong J Wei Z-Y Zuo et al ldquoCombination of sim-vastatin with berberine improves the lipid-lowering efficacyrdquoMetabolism vol 57 no 8 pp 1029ndash1037 2008

[60] S Guan BWangW Li J Guan andX Fang ldquoEffects of berber-ine on expression of LOX-1 and SR-BI in human macrophage-derived foam cells induced by ox-LDLrdquo The American Journalof Chinese Medicine vol 38 no 6 pp 1161ndash1169 2010

[61] Z Huang F Dong S Li et al ldquoBerberine-induced inhibition ofadipocyte enhancer-binding protein 1 attenuates oxidized low-density lipoprotein accumulation and foam cell formation inphorbol 12-myristate 13-acetate-induced macrophagesrdquo Euro-pean Journal of Pharmacology vol 690 no 1ndash3 pp 164ndash1692012

[62] L Chi L Peng N Pan X Hu and Y Zhang ldquoThe anti-ath-erogenic effects of berberine on foam cell formation are medi-ated through the upregulation of sirtuin 1rdquo International Journalof Molecular Medicine vol 34 no 4 pp 1087ndash1093 2014

[63] L Chi L Peng X Hu N Pan and Y Zhang ldquoBerberinecombined with atorvastatin downregulates LOX1 expressionthrough the ET1 receptor in monocytemacrophagesrdquo Interna-tional Journal of Molecular Medicine vol 34 no 1 pp 283ndash2902014

[64] M Xiao L N Men M G Xu G B Wang H T Lv and C LiuldquoBerberine protects endothelial progenitor cell from damage ofTNF-120572 via the PI3KAKTeNOS signaling pathwayrdquo EuropeanJournal of Pharmacology vol 743 pp 11ndash16 2014

[65] Y-H Wu S-Y Chuang W-C Hong Y-J Lai G-J Changand J-H S Pang ldquoBerberine reduces leukocyte adhesion tolps-stimulated endothelial cells and VCAM-1 expression bothin vivo and in vitrordquo International Journal of Immunopathologyand Pharmacology vol 25 no 3 pp 741ndash750 2012

[66] A F Cicero E Tartagni and S Ertek ldquoNutraceuticals formetabolic syndrome management from laboratory to bench-siderdquoCurrent Vascular Pharmacology vol 12 no 4 pp 565ndash5712014

[67] A Cianci A F G Cicero N Colacurci M G Matarazzoand V de Leo ldquoActivity of isoflavones and berberine on vas-omotor symptoms and lipid profile in menopausal womenrdquoGynecological Endocrinology vol 28 no 9 pp 699ndash702 2012

[68] S Meng L-S Wang Z-Q Huang et al ldquoBerberine amelio-rates inflammation in patients with acute coronary syndromefollowing percutaneous coronary interventionrdquo Clinical andExperimental Pharmacology and Physiology vol 39 no 5 pp406ndash411 2012

[69] M I Harris K M Flegal C C Cowie et al ldquoPrevalence ofdiabetes impaired fasting glucose and impaired glucose tol-erance in US adults the Third National Health and NutritionExamination Survey 1988ndash1994rdquo Diabetes Care vol 21 no 4pp 518ndash524 1998

[70] S Wild G Roglic A Green R Sicree and H King ldquoGlobalprevalence of diabetes estimates for the year 2000 and projec-tions for 2030rdquoDiabetes Care vol 27 no 5 pp 1047ndash1053 2004

[71] E L Ding Y Song V S Malik and S Liu ldquoSex differencesof endogenous sex hormones and risk of type 2 diabetes asystematic review and meta-analysisrdquo The Journal of the Amer-ican Medical Association vol 295 no 11 pp 1288ndash1299 2006

[72] S I Taylor D Accili and Y Imai ldquoInsulin resistance or insulindeficiency which is the primary cause of NIDDMrdquo Diabetesvol 43 no 6 pp 735ndash740 1994

[73] B Zhang G Salituro D Szalkowski et al ldquoDiscovery of a smallmolecule insulin mimetic with antidiabetic activity in micerdquoScience vol 284 no 5416 pp 974ndash977 1999

[74] D Foti E Chiefari M Fedele et al ldquoLack of the architecturalfactorHMGA1 causes insulin resistance and diabetes in humansand micerdquo Nature Medicine vol 11 no 7 pp 765ndash773 2005

[75] Y Xu J Lin SWang J Xiong andQ Zhu ldquoCombined estrogenreplacement therapy on metabolic control in postmenopausalwomen with diabetes mellitusrdquo Kaohsiung Journal of MedicalSciences vol 30 no 7 pp 350ndash361 2014

[76] J Moran P Garrido E Cabello A Alonso and C GonzalezldquoEffects of estradiol and genistein on the insulin signalingpathway in the cerebral cortex of aged female ratsrdquoExperimentalGerontology C vol 58 pp 104ndash112 2014


[77] J Yin Z Gao D Liu Z Liu and J Ye ldquoBerberine improvesglucosemetabolism through induction of glycolysisrdquoTheAmer-ican Journal of PhysiologymdashEndocrinology and Metabolism vol294 no 1 pp E148ndashE156 2008

[78] W Chang M Zhang J Li et al ldquoBerberine improves insulinresistance in cardiomyocytes via activation of 51015840-adenosinemonophosphate-activated protein kinaserdquoMetabolism Clinicaland Experimental vol 62 no 8 pp 1159ndash1167 2013

[79] L-Z Liu S C K Cheung L-L Lan et al ldquoBerberinemodulatesinsulin signaling transduction in insulin-resistant cellsrdquoMolec-ular and Cellular Endocrinology vol 317 no 1-2 pp 148ndash1532010

[80] W-J Kong H Zhang D-Q Song et al ldquoBerberine reducesinsulin resistance through protein kinase C-dependent up-regulation of insulin receptor expressionrdquo Metabolism vol 58no 1 pp 109ndash119 2009

[81] H Zhang J Wei R Xue et al ldquoBerberine lowers blood glucosein type 2 diabetes mellitus patients through increasing insulinreceptor expressionrdquo Metabolism Clinical and Experimentalvol 59 no 2 pp 285ndash292 2010

[82] A Cicero and E Tartagni ldquoAntidiabetic properties of berberinefrom cellular pharmacology to clinical effectsrdquo Hospital Prac-tice vol 40 no 2 pp 56ndash63 2012

[83] E Toffol O Heikinheimo and T Partonen ldquoHormone therapyand mood in perimenopausal and postmenopausal women anarrative reviewrdquoMenopause 2014

[84] D L Goldenberg ldquoPaindepression dyad a key to a bet-ter understanding and treatment of functional somatic syn-dromesrdquo The American Journal of Medicine vol 123 no 8 pp675ndash682 2010

[85] F-M Werner and R Covenas ldquoClassical neurotransmittersand neuropeptides involved in major depression a reviewrdquoInternational Journal of Neuroscience vol 120 no 7 pp 455ndash470 2010

[86] M Maes P Galecki Y S Chang and M Berk ldquoA reviewon the oxidative and nitrosative stress (OampNS) pathwaysin major depression and their possible contribution to the(neuro)degenerative processes in that illnessrdquo Progress inNeuro-Psychopharmacology and Biological Psychiatry vol 35no 3 pp 676ndash692 2011

[87] Y Dowlati N HerrmannW Swardfager et al ldquoAmeta-analysisof cytokines in major depressionrdquo Biological Psychiatry vol 67no 5 pp 446ndash457 2010

[88] B P Guiard M El Mansari and P Blier ldquoProspect of adopamine contribution in the next generation of antidepressantdrugs the triple reuptake inhibitorsrdquo Current Drug Targets vol10 no 11 pp 1069ndash1084 2009

[89] HHerkenAGurel S Selek et al ldquoAdenosine deaminase nitricoxide superoxide dismutase and xanthine oxidase in patientswith major depression impact of antidepressant treatmentrdquoArchives of Medical Research vol 38 no 2 pp 247ndash252 2007

[90] A Sarandol E Sarandol S S Eker S Erdinc E Vatanseverand S Kirli ldquoMajor depressive disorder is accompanied withoxidative stress short-term antidepressant treatment does notalter oxidativemdashantioxidative systemsrdquoHuman Psychopharma-cology vol 22 no 2 pp 67ndash73 2007

[91] C K Sen and L Packer ldquoAntioxidant and redox regulation ofgene transcriptionrdquo FASEB Journal vol 10 no 7 pp 709ndash7201996

[92] C L Raison L Capuron and A H Miller ldquoCytokines sing theblues inflammation and the pathogenesis of depressionrdquoTrendsin Immunology vol 27 no 1 pp 24ndash31 2006

[93] J Studd ldquoPersonal view hormones and depression in womenrdquoClimacteric vol 18 no 1 pp 3ndash5 2014

[94] P V Rekkas A A Wilson V W H Lee et al ldquoGreater mono-amine oxidase a binding in perimenopausal age as measuredwith carbon 11-labeled harmine positron emission tomographyrdquoJAMA Psychiatry vol 71 no 8 pp 873ndash879 2014

[95] S K Kulkarni and A Dhir ldquoOn the mechanism of anti-depressant-like action of berberine chloriderdquo European Journalof Pharmacology vol 589 no 1ndash3 pp 163ndash172 2008

[96] W-H Peng K-L Lo Y-H Lee T-H Hung and Y-C LinldquoBerberine produces antidepressant-like effects in the forcedswim test and in the tail suspension test in micerdquo Life Sciencesvol 81 no 11 pp 933ndash938 2007

[97] C H K Cheng ldquoMonoamine oxidase inhibitors from rhizomaofCoptis chinensisrdquo PlantaMedica vol 67 no 1 pp 74ndash76 2001

[98] T Oe M Tsukamoto and Y Nagakura ldquoReserpine causesbiphasic nociceptive sensitivity alteration in conjunction withbrain biogenic amine tones in ratsrdquo Neuroscience vol 169 no4 pp 1860ndash1871 2010

[99] V Arora and K Chopra ldquoPossible involvement of oxido-nitro-sative stress induced neuro-inflammatory cascade and mono-aminergic pathway underpinning the correlation betweennociceptive and depressive behaviour in a rodent modelrdquoJournal of Affective Disorders vol 151 no 3 pp 1041ndash1052 2013

[100] S K Kulkarni and A Dhir ldquo120590-1 receptors in major depressionand anxietyrdquo Expert Review of Neurotherapeutics vol 9 no 7pp 1021ndash1034 2009

[101] A F G Cicero A Ferroni and S Ertek ldquoTolerability and safetyof commonly used dietary supplements and nutraceuticals withlipid-lowering effectsrdquo Expert Opinion on Drug Safety vol 11no 5 pp 753ndash766 2012

[102] M Sabir and N K Bhide ldquoStudy of some pharmacologicalactions of berberinerdquo Indian Journal of Physiology and Pharma-cology vol 15 no 3 pp 111ndash132 1971

[103] E Kupeli M Kosar E Yesilada and K H C Baser ldquoAcomparative study on the anti-inflammatory antinociceptiveand antipyretic effects of isoquinoline alkaloids from the rootsof Turkish Berberis speciesrdquo Life Sciences vol 72 no 6 pp 645ndash657 2002

[104] H-W Xin X-C Wu Q Li A-R Yu M-Y Zhong and Y-Y Liu ldquoThe effects of berberine on the pharmacokinetics ofciclosporin A in healthy volunteersrdquo Methods and Findings inExperimental and Clinical Pharmacology vol 28 no 1 pp 25ndash29 2006

[105] E Chan ldquoDisplacement of bilirubin from albumin by berber-inerdquo Biology of the Neonate vol 63 no 4 pp 201ndash208 1993

[106] F Affuso V Mercurio V Fazio and S Fazio ldquoCardiovascularandmetabolic effects of BerberinerdquoWorld Journal of Cardiologyvol 2 no 4 pp 71ndash77 2010

[107] H L Lin T Y Liu C W Wu and C W Chi ldquoBerberinemodulates expression of mdr1 gene product and the responsesof digestive track cancer cells to Paclitaxelrdquo British Journal ofCancer vol 81 no 3 pp 416ndash422 1999

[108] R Vrzal A Zdarilova J Ulrichova L Blaha J P Giesyand Z Dvorak ldquoActivation of the aryl hydrocarbon receptorby berberine in HepG2 and H4IIE cells biphasic effect onCYP1A1rdquoBiochemical Pharmacology vol 70 no 6 pp 925ndash9362005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


[5] Among them the best characterized ones are antioxidantanti-inflammatory cholesterol-lowering antihyperglycemicand antidepressive effects

This paper will discuss the studies that have shown thepotential benefits of berberine supplementation for thereduction at least partially of menopause-associated pathol-ogies (oxidative stress inflammation and hypercholesterole-mia-related cardiovascular diseases hyperglycemia-relateddiabetesmellitus type 2 and depression) and for the improve-ment of quality of life in menopausal women

2 Role of Berberine in Oxidative Stress

Estrogen deficiency increases cardiovascular risk as a resultof atherogenic modifications of plasma lipid profile activa-tion of the renin-angiotensin system and overproductionof reactive oxygen species (ROS) which quench nitric oxide(NO) [6 7] Overproduction of ROS has been shown inpathological situations and can be highly injurious to adja-cent structures in cells including lipid membranes DNAand proteins [8] Increased oxidative stress and reducedNO bioavailability are important contributing factors ofmenopause-related endothelial dysfunction atherosclerosishypertension cardiovascular and renal diseases [9 10]

Impaired vascular function due to ROS overproductionwhich occurs during estrogen deficiency could be normalizedby HRT in women and animal models of menopause [1112] In fact following the onset of either permanent ortransient estrogens deprivation oxidative stress increases sig-nificantly [4] Serum concentrations of inflammatory cytok-ines and prooxidant biomarkers such as glutathione 4-hy-droxynonenal andmalondialdehyde were found to be higherin postmenopausal than in premenopausal women [13]The elevation of cytokines and prooxidant makers suggeststhat there is a high degree of oxidative stress in the post-menopausal state [13 14]

One of the major sources of ROS production in cells is afamily of membrane-associated enzymatic complexes callednicotinamide adenine dinucleotide phosphate (NADPH)oxidase (NOX) [15] its activation is often associated withhigh levels of fatty acids cholesterol glucose or advancedglycation end products (AGEs) all linked tomenopausal state[16ndash18] Among various NOX isoforms BBR was reported tosuppress the overexpression of NOX 2 4 and to decrease ROSproduction inmacrophages and endothelial cells upon stimu-lation with inflammatory stimuli [19 20] In endothelial cellsBBR attenuates LDL oxidation induced by ROS and reducesthe collapse of mitochondrial membrane potential the chro-mosome condensation the cytochrome C release and thecaspase-3 activation [21] Circulating endothelial micro-particles (EMPs) vesicular structures found in plasma frompatients with vascular diseases so utilized as a surrogatemarker of endothelial dysfunction are oxidative stress induc-ers they promote upregulation of NOX4 expression and ROSproduction It has been reported that BBR reversed NOX4-derived ROS production in human umbilical vein endothelialcells (HUVECs) [22]

NOX could be negatively regulated by adenosine mon-ophosphate-activated protein kinase (AMPK) activation

[23 24] in fact AMPK activators such as metformin mayexert their cardiovascular protective function through NOXinhibition [25] AMPK pathway is activated by BBR [26] andit seems to play a pivotal role in mediating its antioxidantactivity [27 28]

AMPKplays also an important role in regulating functionof NO synthesis in endothelial cells In fact AMPK is anupstream kinase of endothelial nitric oxide synthase (eNOS)which promotes the phosphorylation of eNOS at Ser1177 siteaswell as the formation of eNOS andHSP90 complex andNOproduction [9 29] Menopause-related decrease in estrogenreceptors correlates with lower eNOS expression and activa-tion [30] in both animal and humanmodels ofmenopause [712] as eNOS activity is notably regulated by estrogens throughthe modulation of the eNOScaveolin-1 (Cav-1) complex for-mation [31] Zhang and colleagues observed that in HUVECsBBR ameliorates palmitate-induced endothelial dysfunctionby upregulating eNOS and downregulating NOX4 throughthe activation of AMPK [32] In both cultured endothelialcells and blood vessels isolated from rat aorta BBR enhancedeNOS phosphorylation and attenuated high glucose-inducedgeneration of ROS cellular apoptosis NF-120581B activation andexpression of adhesion molecules through AMPK signalingcascade activation a key event in preventing oxidative andinflammatory signaling [33]

Besides NADPH oxidase downregulation and NO pro-duction AMPK activation has been linked to upregulation ofthe antioxidant enzyme superoxide dismutase (SOD) [34 35]which induces the dismutation of anion superoxide in hydro-gen peroxide An increased SOD expression in BBR treateddiabetic mice was observed [36 37] Glutathione (GSH) isanother antioxidant enzyme which helps to maintain thebalance of redox state in organisms and it is a substrateof glutathione peroxidase (GSH-Px) in the clearance ofperoxides [38] BBR treatment promotes a GSH-Px and SODhyperactivation in the liver of mice [39] attenuates H

2O2-

induced ROS production and increases detoxifying enzymesGSH-Px and SOD in NSC34 motor neuron-like cells [40]

3 Role of Berberine inCardiovascular Disease Risk

The increased cardiovascular disease risk at the menopauseis associated with decreased ovarian function [41 42] and isin part due to arterial dysfunction and a less favorable bloodlipid profile Exogenous estrogen and progesterone in theform of HRT have been shown to reduce plasma concen-trations of LDL cholesterol and increase concentrations ofHDL cholesterol [43] even if their use in menopause is stillobject of debate because of the increased risk of breast cancerictus ischaemic cardiomyopathy and thrombus detachment[44 45]

High levels of low-density lipoprotein (LDL) and theiroxidized counterpart oxidized LDL (oxLDL) in the bloodvessels represent a major risk factor for endothelial dys-function and atherosclerosis [46] Inactivity of LDL receptor(LDLR) or its low-level expression initiates accumulation ofLDL in blood vessels [47] On the other hand the receptor of


































Berberine


eNOS

NO

NADPHoxidase

ROS

SODCAT

GSHpxLOX1

LDLR MAO



Glycemia

a b c

d

OO

OO

CH3

CH3

N+

NF-120581B



Dyslipidemia

Depression


Berberis extract






7 Summary




Acknowledgment


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































Berberine


eNOS

NO

NADPHoxidase

ROS

SODCAT

GSHpxLOX1

LDLR MAO



Glycemia

a b c

d

OO

OO

CH3

CH3

N+

NF-120581B



Dyslipidemia

Depression


Berberis extract






7 Summary




Acknowledgment


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















7 Summary




Acknowledgment


References






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article potential benefits of berberine in the...

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