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The Scientific World Journal / 2012 / Article
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Natural Products: Bioactivity, Biochemistry, and Biological Effects in Cancer and Disease Therapy

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Review Article | Open Access

Volume 2012 |Article ID 708292 | https://doi.org/10.1100/2012/708292

Xiao-Wu Chen, Yuan Ming Di, Jian Zhang, Zhi-Wei Zhou, Chun Guang Li, Shu-Feng Zhou, "Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine", The Scientific World Journal, vol. 2012, Article ID 708292, 31 pages, 2012. https://doi.org/10.1100/2012/708292

Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine

Academic Editor: L.-Y. Chuang
Received07 Jun 2012
Accepted08 Jul 2012
Published13 Nov 2012

Abstract

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer’s disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach.

1. Introduction

The majority of clinical drugs achieve their effect by binding to a cavity and regulating the cavity, of its protein targets [1]. In general, drugs act on four main types of regulatory proteins that mediate the actions of hormones, neurotransmitters, and autacoids. These four types of regulatory proteins are carriers, proteins, ion channels, and receptors [2]. Certain characteristics are expected for therapeutic targets [3]. A potential target needs only not to be druggable but also linked to disease, most preferably playing critical and inimitable roles in disease state. Binding sites are to have certain structural and physiochemical properties to accommodate high-affinity site-specific binding and subsequent regulation of protein activity by drugs. They are not significantly involved in other important biological processes to avoid potential side effects. Useful information about these targets may be investigated by analysing their sequence properties, protein families, structural folds, biochemical classes, similarity proteins, gene location in the human genome, and associated pathways [4]. This information can be potentially useful in derivation of rule and developing predictive tools in the search for druggable and potential targets [4].

The number of molecular targets acted on by current drug therapy is still in dispute. In 1996, Drews and Ryser identified a total of 483 drug targets addressed by drug therapy [5, 6]. Approximately 45% are cell membrane receptors, 28% are enzymes, and the remaining classes comprise hormones (11%), ion channels (5%), nuclear receptors (2%), and DNA (2%). About 7% of the targets are not known biochemically. Later, Hopkins and Groom challenged this figure and suggested that “rule-of-five” compliant drugs acted primarily through only 120 underlying molecular targets [3, 7]. However, the statistical analysis of disease genes and related proteins suggested that the total number of the estimated potential targets in the human genome ranges from 600 to 1,500 [3]. In the meantime, another report showed the estimated total number of distinct targets is in the range of 1,700–3,000 [8]. Chen et al. reported targets collected in the Therapeutic Target Database [9] is 997 distinct proteins, 1,494 distinct protein subtypes, and 41 nucleic acids, which are only targeted by at least one marketed drug and 1,267 research targets, which are only targeted by investigational agents that are not approved for clinical use at present [4]. Targets for neoplasm diseases, circulatory system diseases, infectious diseases, and nervous system and sense organs disorders constitute the largest number of targets [1]. An increase in target numbers is made possible by advances in genomics, proteomics, better molecular understanding of diseases, and increased effort in the exploration of new therapeutic targets as well as increased knowledge of unknown or unreported targets of previous existing drugs. An improvement in technology for target identification and validation also contributes greatly.

Chinese herbal medicine (CHM) has always been an integral part of traditional Chinese medicine (TCM), which has been practiced in the east for thousands of years. Chinese herbs are usually in the forms of dried whole plants or parts of the plants (roots, leaves, body, etc.); sometimes shells and even minerals are used. Chinese herbs are often used in a compound formula, consisting of several different herbs hosting different roles according to the principle of Jun-Chen-Zuo-Shi described by the ancient Chinese. Each of Jun, Chen, Zuo, and Shi function together to harmonise the body, with Shi (courier) herbs are included in many formulae to ensure that all components in the prescription are well absorbed and to help to deliver or guide them to the target organs [10]. On some level, the guiding function of Shi herbs relates to modern drug delivery techniques, guiding the drug compound to target tissues. In the modern world, complementary medicine has gained vast popularity in the West. There has been increased use of herbal medicine to manage chronic diseases and promote wellbeing, in countries such as Australia, New Zealand, USA, and Europe [11]. Reports show that 18.9% of the American population used natural products in the precedent year [12]. This increase in popularity is closely related to its proven effectiveness in clinical practice over the past centuries. To date, more than 11,000 species of plants are used medicinally and about 300 are commonly used [13].

Despite its widespread use, CHM is associated with high levels of uncertainty. This is mainly due to lack of evidence, base of efficacy, targets, and safety data. During the process of therapeutic drug development, owing to the preselection of targets, researchers have a basic if not full understanding of which molecular structures the drug will react with or which biological pathway in the body it might alter. Knowledge on molecular interactions and modulations of the drug is anticipated and researched on. However, this is not the case for CHM. There is no preselection of molecular targets in the body but CHM has been used for thousands of years and is proven to be effective. The exact mechanism of the herbs actions is yet to be elucidated.

The proven clinical efficacy of some herbal medicines is considered to be due to the interaction of pharmacologically active components from the herbs with molecular targets in the body. Similar to synthetic drugs, active compounds of herbal medicine may bind to and undergo interactions with molecular structures or herbal targets to produce therapeutic or adverse effects. However, there is a lack of understanding of how CHMs exert their biological and clinical effects at a molecular level, which impedes development of CHMs and the incorporation of CHMs into mainstream medicine in the West.

Berberine (Figure 1, molecular formula C20H19NO5 and a molecular weight of 353.36) is an isoquinoline alkaloid found in many medicinal plants [14]. It is a major constituent of many medicinal plants of families Papaveraceae, Berberidaceae, Fumariaceae, Menispermaceae, Ranunculaceae, Rutaceae, and Annonaceae [15]. It is present in Hydrastis canadensis (goldenseal), Coptis chinensis (Coptis or goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree turmeric). The berberine alkaloid can be found in the roots, rhizomes, and stem bark of the plants. Berberine is one of the main alkaloids found in the Chinese herb Huang Lian (Rhizoma coptidis) [16]. Huang Lian has traditionally been used to treat diarrhoea and diabetes. In China, berberine has been manufactured into the over-the-counter drug Huang Lian Su Pian, also known as Coptis Extract Tablets for the treatment of traveler’s diarrhoea [14, 17]. In recent years, there has been a growing interest in the pharmacological activities of berberine and many studies have been carried out to elucidate the mechanisms of action of berberine. This study aims to review molecular targets of berberine based on in vitro studies. Berberine has shown to have good hypoglycaemic effects, so we also reviewed the effects of berberine in animal and human studies, with a focus on diabetes mellitus.

2. Methods

2.1. Data Retrieval from the Literature

In vitro studies related to berberine and its targets were searched using Pubmed (from inception to April 2012). Search terms used were a combination of “berberine,” “in vitro,” “human cell,” and “mechanism.” Only studies using human cell lines were used to extract current berberine targets. Studies using animal cell lines or berberine derivatives or in a language other than English were excluded. Information extracted from these studies includes molecular targets of berberine (name and gene symbols), cell type, effects of berberine, and possible clinical applications.

2.2. PANTHER Analysis

Using the PANTHER Classification System, in vitro berberine targets were analysed using three approaches: molecular function, biological process, and pathway involvement Table 2. PANTHER is a publicly available database that relates protein sequence evolution to evolution of protein functions and biological roles (http://www.pantherdb.org/).

3. Results

3.1. Targets of Berberine

A total of 90 berberine targets were identified in our literature search, as shown in Table 1.


Target namesTarget gene symbolCellsEffectsPossible clinical applicationsReferences

72 kDa type IV collagenaseMMP2HUVECs, tongue cancer SCC-4 cells, gastric carcinoma SNU-5 cells, lung cancer A549 cells, and U-87 glioma cellsDownregulation of MMP2 mRNA and protein expression, reduced MMP-2 levelsAntimetastatic [18, 6972]

Acetyl-Coenzyme A carboxylase-αACACAHepG2 hepatoma cellsPhosphorylationAntihyperlipidemic[73]

α-FetoproteinAFPHepG2 hepatoma cellsReduced secretion of alpha fetoproteinApoptosis[74]

Amyloid-β (A4) precursor protein (peptidase nexin-II, Alzheimer disease)APPNeuroglioma H4 cellsReduces amyloid-β peptide (Aβ) levels via modulation of APPAlzheimer disease[75]

Bcl-XBCL2L1Colonic carcinoma cells, HepG2 cells/A549 cells, prostate carcinoma cells (DU145 and PC-3, LNCaP), Jurkat cellsJNK/p38 pathway and induction of ROS production. Decreased expression Cell apoptosis, anticancer, and anti-inflammatory[1921, 30, 76, 77]

Arylamine -acetyltransferase 1NATLeukemia HL-60 cells, colon tumour cells, brain tumour cells (G95/VGH and GBM 8401)Decrease in -acetyltransferase (NAT) protein and expression of mRNA Anticancer (leukemia, colon cancer, brain tumour, etc.)[7880]

ATP-binding cassette subfamily G member 2ABCG2MCF-7 breast cancer cellsDecrease in ABCG2 expressionBreast cancer[81]

Baculoviral IAP repeat-containing protein 2 (antiapoptosis factor c-IPA-1)BIRC2Jurkat cells, colonic carcinoma cells (SW620)Suppresses expression of antiapoptosis factor IAP1Anticancer [19, 77]

Baculoviral IAP repeat-containing protein 3BIRC3Jurkat cellsSuppresses expression of antiapoptosis factor IAP2Anticancer [77]

Baculoviral IAP repeat-containing protein 5 (Survivin)BIRC5Jurkat cellsSuppresses expression of survivinAnticancer and anti-inflammatory agent[77]

B-cell CLL/lymphoma 2BCL2HepG2 cells, oral squamous cell carcinoma, tongue cancer SCC-4 cells, colonic carcinoma cells, lung cancer cells, breast cancer MCF-7 (estrogen receptor+) cells, prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Bcl-2 DownregulationCell apoptosis, cancer, and ER antagonist adjuvant therapy [1923, 30, 34, 82, 83]

B-cell lymphoma 3-encoded proteinBcl-3Gastric carcinoma SNU-5 cells Downregulation of Bcl-3Gastric cancer[24]

Bcl2 antagonist of cell deathBADHuman oral squamous cell carcinomaIncreased expression of proapoptotic BAD proteinAntitumour [23]

BCL2-associated X proteinBAXGastric carcinoma SNU-5 cells, prostate carcinoma cells (DU145, PC-3, LNCaP and PWR-1E), leukemia HL-60, tongue cancer SCC-4 cells, lung cancer cells, activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) Upregulation of Bax, increased expression. G2/M phase arrestCell apoptosis, gastric cancer[18, 20, 21, 24, 29, 30, 83, 84]

BH3-interacting domain death agonist p11BIDColonic carcinoma cells/HepG2 cellsJNK/p38 pathway and induction of ROS productionInduction of apoptosis [19, 76]

C/EBP homologous protein (CHOP) or growth arrest- and DNA damage-inducible gene 153 (GADD153) or DNA damage-inducible transcript 3GADD153/DDIT3Cervical cancer
Ca Ski cells
Induced expression of GADD153 Cervical cancer [85]

CASP8 and FADD-like apoptosis regulator subunit p12CFLAR/cFLIPJurkat cellsSuppresses expression of cFLIPAnticancer and anti-inflammatory [77]

Caspase 3CASP3Tongue cancer SCC-4 cells, neuroblastoma (SK-N-SH), glioblastoma T98G cells, gastric carcinoma SNU-5 cells, HL-60 cells, prostate carcinoma cells (DU145, PWR-1E, PC-3 and LNCaP), colonic carcinoma cells, hepatoma cells, oral squamous cell carcinoma, promonocytic U937 cells, lung cancer A549, H1301 cells, activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs), BIU-87 and T24 bladder cancer cellsActivation of caspase-3, G2/M phase arrestAnticancer[1821, 2325, 30, 33, 76, 83, 8689]

Caspase 8CASP8Tongue cancer SCC-4 cells, colonic carcinoma cells, hepatoma cells, oral squamous cell carcinomaActivated caspase 8 Anticancer[18, 19, 23, 76]

Caspase 9CASP9Tongue cancer SCC-4 cells, glioblastoma T98G, oral squamous carcinoma, promonocytic U937 cells, prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs), BIU-87 and T24 bladder cancer cellsActivation of caspase 9Cell apoptosis, anticancer[18, 21, 23, 30, 33, 83, 86, 87, 89, 90]

Cdc42 effector protein 1CDC42EP1Nasopharyngeal carcinoma (HONE1) cellsSuppression of Rho GTPases activation (Cdc42)Cancer metastasis inhibition[91]

Cell division protein kinase 6CDK6Prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in Cdk6Cell apoptosis, cancer[21, 30, 83]

Cellular tumor antigen p53TP53Gastric carcinoma SNU-5 cells, osteosarcomaIncreased expression of p53 protein, cell cycle arrest at G1G2/M phase arrestAnticancer (gastric cancer, osteosarcoma)[24, 92]

Chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1)CCL2Retinal pigment epithelial cell lineInhibits CCL2 (MCP-1) expressionAnti-inflammatory[93]

Cyclic AMP-dependent transcription factor ATF-3ATF3Colorectal cancer cellsInduces ATF3 expressionColorectal cancer [94]

Cyclin-dependant kinase 1/cell division control protein 2 homologCDK1/CDC2HL-60 cell, gastric carcinoma SNU-5 cells Inactivation of Cdc2 (CDK1) or decreased protein expression Antiproliferative and proapoptotic[24, 95]

Cyclin E1CCNE1Neuroblastoma (SK-N-SK), glioblastoma T98G cells, activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in cyclin EAnticancer [25, 83, 90]

Cyclin-dependent kinase 2CDK2Neuroblastoma (SK-N-SK), glioblastoma T98G cells, prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in Cdk2Cell apoptosis, anticancer[21, 25, 30, 83, 90]

Cyclin-dependent kinase 4CDK4Neuroblastoma (SK-N-SK), glioblastoma T98G cells, prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in Cdk4Cell apoptosis, anticancer[21, 25, 30, 83, 90]

Cyclin-dependent kinase inhibitor 1 (p21)CDKN1ABrest cancer MCF-7 (estrogen receptor+) cells, epidermoid carcinoma A431 cells, activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Increased expression of p21Breast cancer, ER antagonist adjuvant therapy [21, 30, 82, 83]

Cyclin-dependent kinase inhibitor 1B (P27/KIP1)CDKN1BEpidermoid carcinoma A431 cells, activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Increased expression of Cdki proteins Cell apoptosis, cancer[21, 30, 83]

Cytochrome c-1CYC1Tongue cancer SCC-4 cells, colonic carcinoma cells, promyelocytic leukemia HL-60 cellsRelease of cytochrome c-1Anticancer[18, 19, 84, 86]

CYP2C9CYP2C9Recombinant CYPInhibition of CYP2C9Drug interactions[96]

CYP2D6CYP2D6Recombinant CYPInhibition of CYP2D6Drug interactions[96]

CYP3A4CYP3A4Caco-2 cells, patientsCYP3A4 Downregulation and inhibition Drug interactions[97, 98]

Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2)DPP4Recombinant DPP4Inhibition of DPP4[99]

Early activation antigen CD69CD69Human peripheral lymphocytes Reduced expression of CD69 Immunosuppressive agent[100]

Epidermal growth factor receptorEGFRBrest cancer MCF-7 (estrogen receptor+) cellsEGFRdownregulatedBreast cancer, ER antagonist adjuvant therapy [82]

EzrinEZRNasopharyngeal carcinoma 5–8F cellsEzrin inhibitionAnticancer [26]

G1/S-specific cyclin-D1CCND1Giant cell carcinoma cell line, HL-60 cell, prostate carcinoma cells (DU145 and PC-3, LNCaP), Jurkat cells, neuroblastoma (SK-N-SK), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Inhibits expression of cyclin D1Antiproliferative and proapoptotic, anticancer, anti-inflammatory [21, 25, 30, 32, 77, 83, 95]

G1/S-specific cyclin-D2CCND2Prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in cyclin D2Cell apoptosis, cancer[21, 30, 83]

G1/S-specific cyclin-E1CCNE1Prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Decrease in cyclin ECell apoptosis, cancer[21, 30, 83]

G2/mitotic-specific cyclin-B1CCNB1Gastric carcinoma SNU-5 cells Decreased cyclin B, G2/M phase arrestCell apoptosis, anticancer[24]

Glucagon-like peptide (GCG/GLP-1/GLP-2)GCGNCI-H716 cellsEnhanced glucagon-like peptide (GLP)-1 Antidiabetic agent[42]

Growth/differentiation factor 15 (NAG-1)GDF15Colorectal cancer cellsInduces NAG-1 expressionColorectal cancer [94]

Hypoxia-inducible factor 1αHIF1AHUVECs, HepG2 cellsPrevention and reduction of HIF-1 alpha expressionTumour angiogenesis[101, 102]

Induced myeloid leukemia cell differentiation protein Mcl-1MCL1Oral cancer cellsInhibition of Mcl-1 expressionInduced apoptosis[103]

Inhibitor of NF-κB kinase subunit alpha (IκB kinase)CHUK(IKK)Jurkat cellsInhibition of IκB kinase (IKK)Anticancer and anti-inflammatory agent[77]

Interferon-γIFNB1Brest cancer MCF-7 (estrogen receptor+) cellsIFN-beta upregulated Breast cancer, ER antagonist adjuvant therapy [82]

Interleukin 8IL8Retinal pigment epithelial cell lineInhibits IL-8 expressionAnti-inflammatory[93]

Interleukin-1βIL1BFibroblasts (HFL1)Induces IL-1B productionsPulmonary inflammation[104]

Interleukin-2 receptor α-chainIL2RA/CD25Human peripheral lymphocytes Reduced expression of CD25Immunosuppressive agent[100]

Interleukin-6IL6KeratinocytesReduces and IL-6 expressionAntiskin ageing agent[105]

Low-density lipoprotein receptor (familial hypercholesterolemia)LDLRHepG2 cellsIncreased mRNA and protein expressionHyperlipidemia [106108]

Matrix metallopeptidase 1 (27 kDa interstitial collagenase)MMP1Dermal fibroblasts, U-87 glioma cellsMMP-1 expression decreased Antiskin ageing agent, anticancer [70, 109]

Matrix metallopeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase)MMP9Tongue cancer SCC-4 cells, keratinocytes, gastric carcinoma SNU-5InhibitionAnticancer[34, 70, 105]

Matrix metalloproteinase-16MMP16Jurkat cellsSuppresses expression of MMP-16Anticancer and anti-inflammatory agent[77]

Mitogen-activated protein kinase 3ERK1/MAPK3Peripheral blood monocytes (PBMC) ERK1 protein expression inhibitionAntiatherosclerotic effects[110]

Mitogen-activated protein kinase 4ERK2/MAPK4Peripheral blood monocytes (PBMC) ERK2 protein expression inhibitionAntiatherosclerotic effects[110]

Mitogen-activated protein kinase 8 (JNK)MAPK8Peripheral blood monocytes (PBMC) Jun N-terminal kinase (JNK) protein expression inhibited at high levels of BBRAntiatherosclerotic effects[19, 110]

M-phase inducer phosphatase 1CDC25AHL-60 cell Phosphorylation and degradation of Cdc25AAntiproliferative and proapoptotic[95]

Multidrug resistance protein 1 (P-gp, P-gp-170)ABCB1Tumour cell lines Significant inhibited P-gp multidrug resistance (MDR) activity MDR activity reversal[111]

Hepatoma
HepG2 cells
Upregulated multidrug resistance transporter (P-gp-170) expressionReduced retention of chemotherapeutic agents[112]

Myc proto-oncogene proteinMYCU-87 glioma cellsMyc level decreasedMalignant glioma and cancer development [71]

NF-κB inhibitor-αNFKBIALung epithelial cells (A-549)Inhibition of κB-α phosphorylation and degradation Pulmonary inflammation[104]

Nuclear factor NF-κB p50 subunit (NF-κB)NFKB1Jurkat cells, osteoblastic cells, HepG2 cellsInhibit NF-κB production and suppress NF-κB Anticancer and anti-inflammatory agent, alcohol liver disease, osteoclast formation [77, 113115]

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)NR3C1HepG2 cellsReduced GR levelsCell growth arrest [74]

Nucleophosmin (nucleolar phosphoprotein B23) and telomeraseNPM1Leukemia HL-60 cells Downregulation of nucleophosmin/B23 and telomerase activity Cancer [116]

Peroxisome proliferator-activated receptor-γPPARGFree-fatty-acid-induced insulin resistance muscle cells-L6 myotubes, 3T3-L1 preadipocytesDecreased expressionAntidiabetic [37, 117]

Platelet glycoprotein 4CD36/FATFree-fatty-acid-induced insulin resistance muscle cells-L6 myotubesDecreased expressionAntidiabetic [37]

Poly (ADP-ribose) polymerase family, member 1PARPHepG2 cells/hepatoma cells, colonic carcinoma cells, prostate cancer cells (PC-3), prostate carcinoma cells (DU145 and PC-3, LNCaP), activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs)Cleavage of poly (ADP-ribose) polymerase. Activation of PARPCell apoptosis, Anticancer [19, 21, 22, 30, 76, 83, 87]

Potassium voltage-gated channel subfamily H member 2KCNH2/HERG1Leukemic stem cells (LSCs)Inhibits HERG1 K (+) channels of leukemic cells Inhibits AML cell migration [35]

Processed sterol regulatory element-binding protein 2SREBP2HepG2 cellsReduction of SREBP2Hyperlipidemia[101]

Proprotein convertase subtilisin/kexin type 9PCSK9HepG2 cells Suppression of PCSK9 mRNA and protein levelsHyperlipidemia [101, 107]

Prostaglandin G/H synthase 2PTGS2/COX2Peripheral blood monocytes (PBMC), oral cancer cell lines OC2 and KB cells, breast cancer MCF-7 (estrogen receptor+) cells, Jurkat cells, colon cancer cellsDecrease of Cox-2 mRNA and protein expressionAntiatherosclerotic effects, anti-inflammatory, anticancer, breast cancer ER antagonist adjuvant therapy, Anticancer[27, 77, 82, 103, 110, 118]

Proto-oncogene tyrosine-protein kinase ROSROS1HUVECsInhibition of ROS generationProtects LDL oxidation and prevents ox-LDL-induced cellular dysfunction[19, 119]

Ras-related C3 botulinum toxin substrate 1RAC1Nasopharyngeal carcinoma (HONE1) cellsSuppression of Rho GTPases activation (Rac1)Cancer metastasis inhibition[91]

Receptor tyrosine-protein kinase erbB-2 ERBB2/HER2Brest cancer MCF-7 (estrogen receptor+) cellsHER2 downregulatedBreast cancer, ER antagonist adjuvant therapy [82]

Rho-associated protein kinase 1ROCK1/RHONasopharyngeal carcinoma 5–8F cellsSuppression of Rho kinase activity Anticancer [91]

Runt-related transcription factor 2RUNX2Osteoblast cellsPromotes transcriptional activity of Runx2Osteoblast differentiation and bone formation in osteoporosis[120]

SDF-1-α (3–67) (SDF-1)CXCL12Acute myeloid leukemia (AML)Reduces SDF-1 chemokine Inhibits AML cell migration [35]

Sucrase-isomaltase (α-glucosidase)SICaco-2 cellsInhibit alpha-glucosidaseAntihyperglycaemic[39]

Topoisomerase (DNA) ITop1Recombinant human topoisomerase ITop1 inhibitionAnticancer[121]

Transcription factor AP-1AP-1Hepatoma cells, MDA-MB-231 breast cancer cells, giant cell carcinoma cell line, colon cancer cells, U-87 glioma cells, HeLa cellsInhibition of AP-1 activity, AP-1 DNA suppression Antitumor activity, Anticancer[27, 32, 71, 115, 118, 122124]

Transforming protein RhoARHOANasopharyngeal carcinoma (HONE1) cellsSuppression of Rho GTPases activation (RhoA)Cancer metastasis inhibition[91]

Tumor necrosis factor-αTNFAMacrophages, fibroblasts (HFL1)Inhibition of TNF-αAnti-inflammatory[104, 125]

Urokinase-plasminogen activatorPLAULung cancer A549 cells, tongue cancer SCC-4 cells Reduced urokinase-plasminogen activator (u-PA)Antimetastatic, Anticancer[34, 72]

Vascular endothelial growth factor AVEGFAHUVECsPrevention of VEGF expressionTumour angiogenesis[102]

Wee1-like protein kinaseWee1Gastric carcinoma SNU-5 cells Increased expression of Wee1protein, G2/M phase arrestGastric cancer[24]


Target namesTarget gene symbolPANTHER molecular functionBiological processPathway categories

Multidrug resistance protein 1 (Pgp, Pgp-170)ABCB1ATPase activity, coupled to transmembrane movement of substances, transmembrane transporter activityImmune system process, extracellular transport, carbohydrate metabolic process, response to toxinATP-binding cassette (ABC) transporter

ATP-binding cassette sub-family G member 2ABCG2ATPase activity, coupled to transmembrane movement of substances, transmembrane transporter activity, anion channel activityImmune system process, anion transport, lipid transport, oxygen and reactive oxygen species, metabolic process, lipid metabolic process, response to stressN/A

Acetyl-coenzyme A carboxylase-αACACAOther ligaseGluconeogenesis, monosaccharide metabolism, fatty acid biosynthesis, coenzyme metabolismN/A

α-FetoproteinAFPOther transfer/carrier protein Transport, mesoderm development, oncogenesis N/A

Transcription factor AP-1AP-1DNA binding, transcription factor activityCell cycle, intracellular signaling cascade, nucleobase, nucleoside, nucleotide, and nucleic acid, metabolic process, cell cycle, signal transductionToll receptor signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway, apoptosis signaling pathway, oxidative stress response, angiogenesis, TGF-beta signaling pathway, T-cell activation, B-cell activation, Ras Pathway, FAS signaling pathway, PDGF signaling pathway

Amyloid-β (A4) precursor protein (peptidase nexin-II, Alzheimer disease)APPOther signaling moleculesOther signal transduction, cell communication, other intracellular protein trafficAlzheimer disease-amyloid secretase pathway, Alzheimer disease-presenilin pathway, blood coagulation, Alzheimer disease-presenilin pathway, Alzheimer disease-amyloid secretase pathway

Cyclic AMP-dependent transcription factor ATF-3ATF3DNA binding, transcription factor activityTranscription factor activity, immune system process, neurological system process, induction of apoptosis, nucleobase, nucleoside, nucleotide, and nucleic acid metabolic processApoptosis signaling pathway

Bcl2 antagonist of cell deathBADN/AN/APDGF signaling pathway, apoptosis signaling pathway, angiogenesis, PI3 kinase pathway, VEGF signaling pathway, interleukin signaling pathway

BCL2-associated X proteinBAXOther signaling moleculeInduction of apoptosis, gametogenesis, hematopoiesis, cell cycle control, cell proliferation and differentiation, tumor suppressorp53 pathway, apoptosis signaling pathway, Huntington disease

B-cell CLL/lymphoma 2BCL2Other signaling moleculeInhibition of apoptosis, oncogenesisOxidative stress response, apoptosis signaling pathway

Apoptosis regulator Bcl-XBCL2L1Receptor bindingGamete generation, induction of apoptosis, negative regulation of apoptosis, cell cycle, mesoderm development, hemopoiesisApoptosis signaling pathway

B-cell lymphoma 3-encoded proteinBcl-3N/ANucleobase, nucleoside, nucleotide, and nucleic acid metabolic processInflammation mediated by chemokine and cytokine signaling pathway

BH3-interacting domain death agonist p11BIDN/AN/AApoptosis signaling pathway, FAS signaling pathway

Baculoviral IAP repeat-containing protein 2 (anti-apoptosis factor c-IPA-1)BIRC2N/AN/AApoptosis signaling pathway

Baculoviral IAP repeat-containing protein 3BIRC3N/AN/AApoptosis signaling pathway

Baculoviral IAP repeat-containing protein 5 (Survivin)BIRC5N/AN/AAngiogenesis

Caspase 3, apoptosis-related cysteine peptidaseCASP3Cysteine proteaseProteolysis, apoptosisHuntington disease, FAS signaling pathway, apoptosis signaling pathway

Caspase 8, apoptosis-related cysteine peptidaseCASP8Cysteine proteaseProteolysis, apoptosis Apoptosis signaling pathway, FAS signaling pathway, Huntington disease

Caspase 9, apoptosis-related cysteine peptidaseCASP9Cysteine proteaseProteolysis, apoptosisAngiogenesis, apoptosis signaling pathway, FAS signaling pathway, VEGF signaling pathway, PI3 kinase pathway

Chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1)CCL2Nonreceptor serine/threonine, protein kinase Protein phosphorylation, cell cycle control, mitosis N/A

G2/mitotic-specific cyclin-B1CCNB1Protein binding, kinase activator activity, kinase regulator activityMitosisCell cycle, p53 pathway

G1/S-specific cyclin-D1CCND1Protein binding, kinase activator activity, kinase regulator activitySpermatogenesis, mitosisPI3 kinase pathway, cell cycle, Wnt signaling pathway

G1/S-specific cyclin-D2CCND2Protein binding, kinase activator activity, kinase regulator activitySpermatogenesis, mitosisPI3 kinase pathway, cell cycle

Cyclin E1CCNE1Kinase activatorCell cycle control, mitosis, cell proliferation and differentiation p53 pathway, cell cycle, Parkinson disease, p53 pathway feedback loops 2

G1/S-specific cyclin-E1CCNE1Protein binding, kinase activator activity, kinase regulator activityMitosisp53 pathway, cell cycle, Parkinson disease, p53 pathway feedback loops 2

Interleukin-2 receptor alpha chainIL2RA/CD25Cytokine receptor activityImmune system process, cell surface receptor-linked signal transduction, intracellular signaling cascade, cell-cell signalling, signal transduction, cell-cell signalling, cellular defense responseInterleukin signaling pathway

Platelet glycoprotein 4CD36/FATReceptor activityMacrophage activation, lipid transport, apoptosis, signal transduction, cell adhesion, lipid metabolic process, signal transduction, cell adhesion, cellular component, morphogenesisN/A

Early activation antigen CD69CD69Receptor activity, receptor bindingB-cell-mediated immunity, natural killer cell activation, cellular defense responseMembrane-bound signaling molecule

M-phase inducer phosphatase 1CDC25AHydrolase activity, acting on ester bonds, phosphatase activityPhosphatase activity cell cycle, phosphate metabolic process, protein metabolic process, cell cyclep53 pathway

Cdc42 effector protein 1CDC42EP1N/AN/AN/A

Cyclin dependant kinase 1/cell division control protein 2 homologCDK1/CDC2Kinase activityImmune system process, mitosis, intracellular signaling cascade, protein metabolic process, cell motion, mitosis, signal transduction, response to stressp53 pathway

Cyclin-dependent kinase 2CDK2Nonreceptor serine/threonine protein kinase Protein phosphorylation, cell cycle control, mitosisp53 pathway, p53 pathway feedback loops 2

Cyclin-dependent kinase 4CDK4Nonreceptor serine/threonine protein kinase Protein phosphorylation, cell cycle control, mitosisN/A

Cell division protein kinase 6CDK6Kinase activityImmune system process, mitosis, intracellular signaling cascade, protein metabolic process, cell motion, mitosis, signal transduction, response to stressN/A

Cyclin-dependent kinase inhibitor 1 (p21)CDKN1AProtein binding, kinase inhibitor activity, kinase regulator activityCell cycleInterleukin signaling pathway, p53 pathway feedback loops 2, p53 pathway

Cyclin-dependent kinase inhibitor 1B (P27/KIP1)CDKN1BProtein binding, kinase inhibitor activity, kinase regulator activityCell cycleInterleukin signaling pathway

CASP8-and FADD-like apoptosis regulator subunit p12CFLAR/cFLIPPeptidase activity, protein binding, peptidase inhibitor activityApoptosis, protein metabolic processApoptosis signaling pathway, FAS signaling pathway

Inhibitor of NF-κB kinase subunit alpha (IκB kinase)CHUK(IKK)Kinase activityImmune response, intracellular signaling cascade, protein metabolic process, signal transduction, response to stimulusInterleukin signaling pathway, apoptosis signaling pathway, T-cell activation, toll receptor signaling pathway, B-cell activation

SDF-1-α (3–67) (SDF-1)CXCL12N/AN/AAxon guidance-mediated by Slit/Robo

Cytochrome c-1CYC1Reductase Oxidative phosphorylation FAS signaling pathway, ATP synthesis, Huntington disease

Cytochrome P450, family 2, subfamily C, polypeptide 9CYP2C9Oxygenase Fatty acid metabolism, steroid metabolism, electron transport N/A

Cytochrome P450, family 2, subfamily D, polypeptide 6CYP2D6Oxygenase Other lipid, fatty acid and steroid metabolism, steroid metabolism, electron transportVitamin D metabolism and pathway

Cytochrome P450, family 3, subfamily A, polypeptide 4CYP3A4Oxygenase Steroid hormone metabolism, electron transport N/A

Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2)DPP4Serine protease Proteolysis, cell surface receptor mediated signal transduction, T-cell-mediated immunity N/A

Epidermal growth factor receptorEGFRKinase activity, transmembrane receptor protein tyrosine kinase activity, transmembrane receptor protein kinase activity, receptor bindingFemale gamete generation, immune system process, negative regulation of apoptosis, cell cycle, cell surface receptor-linked signal transduction, intracellular signaling cascade, cell-cell signalling, cell-cell adhesion, protein metabolic process, cell motion, cell cyclesignal transduction, cell-cell signalling, dorsal/ventral axis specification, ectoderm development, mesoderm development, embryonic development, nervous system developmentEGF receptor signaling pathway, cadherin signaling pathway

Receptor tyrosine-protein kinase erbB-2 ERBB2/HER2Kinase activity, transmembrane receptor protein tyrosine kinase activity, transmembrane receptor protein kinase activity, receptor bindingFemale gamete generation, immune system process, negative regulation of apoptosis, cell cycle, cell surface receptor linked signal transduction, intracellular signaling cascade, cell-cell signalling, cell-cell adhesion, protein metabolic process, cell motion, cell cyclesignal transduction, cell-cell signalling, dorsal/ventral axis specification, ectoderm development, mesoderm development, embryonic development, nervous system developmentEGF receptor signaling pathway, cadherin signaling pathway

Mitogen-activated protein kinase 3ERK1/MAPK3Kinase activityImmune system process, mitosis, cell surface receptor linked signal transduction, intracellular signaling cascade, carbohydrate metabolic process, protein metabolic process, cell motion, signal transduction, segment specification, ectoderm development, mesoderm development, embryonic development, nervous system development, response to stressApoptosis signaling pathway, Alzheimer disease-amyloid secretase pathway, B-cell activation, Ras pathway, interleukin signaling pathway, angiogenesis, T-cell activation, toll receptor signaling pathway, insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade, FGF signaling pathway, Parkinson disease, PDGF signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway, VEGF signaling pathway, interferon-gamma signaling pathway, endothelin signaling pathway, angiogenesis, TGF-beta signaling pathway, integrin signalling pathway, EGF receptor signaling pathway

Mitogen-activated protein kinase 4ERK2/MAPK4Kinase activityImmune system process, mitosis, cell surface receptor linked signal transduction, intracellular signaling cascade, carbohydrate metabolic process, protein metabolic process, cell motion, mitosis, signal transduction, segment specification, ectoderm development, mesoderm development, embryonic development, nervous system development, response to stressAlzheimer disease-amyloid secretase pathway, interleukin signaling pathway, angiogenesis, VEGF signaling pathway, integrin signalling pathway

EzrinEZRStructural constituent of cytoskeletonCellular component, morphogenesisN/A

C/EBP homologous protein (CHOP) or growth arrest- and DNA damage-inducible gene 153 (GADD153) or DNA damage-inducible transcript 3GADD153/DDIT3N/AN/AOxidative stress response

Glucagon-like peptide (GCG/GLP-1/GLP-2)GCGReceptor bindingSignal transduction, cell-cell signalling, carbohydrate metabolic process, lipid metabolic process, signal transduction, cell-cell signalling, cellular glucose homeostasisPeptide hormone

Growth/differentiation factor 15 (NAG-1)GDF15Receptor bindingFemale gamete generation, cell surface receptor linked signal transduction, signal transduction, ectoderm development, mesoderm development, skeletal system development, heart development, muscle organ developmentTGF-beta signaling pathway

Hypoxia-inducible factor 1αHIF1ADNA binding, transcription factor activityNucleobase, nucleoside, nucleotide, and nucleic acid metabolic process, ectoderm development, nervous system developmentHypoxia response via HIF activation, VEGF signaling pathway, angiogenesis

Interferon-βIFNB1Receptor bindingResponse to interferon-gamma, induction of apoptosis, negative regulation of apoptosis, cell surface receptor linked signal transduction, intracellular signaling cascade, cell-cell signalling, signal transduction, cell-cell signalling, cellular defense responseToll receptor signaling pathway

Interleukin-1βIL1BReceptor bindingImmune response, macrophage activation, cell surface receptor linked signal transduction, cell-cell signalling, signal transduction, cell-cell signalling, response to stimulusInflammation mediated by chemokine and cytokine signaling pathway

Interleukin-6IL6Receptor bindingImmune system process, negative regulation of apoptosis, cell surface receptor linked signal transduction, intracellular signaling cascade, cell-cell signalling signal transduction, cell-cell signalingInflammation mediated by chemokine and cytokine signaling pathway, interleukin signaling pathway

Interleukin 8IL8ChemokineCytokine- and chemokine-mediated signaling pathways, calcium-mediated signalling, NF-kappaB cascade, ligand-mediated signalling, T-cell-mediated immunity, macrophage-mediated immunity, granulocyte-mediated immunity, angiogenesis, cell proliferation and differentiation, cell motilityInflammation mediated by chemokine and cytokine signaling pathway, interleukin signaling pathway

Potassium voltage-gated channel subfamily H member 2KCNH2/HERG1Receptor activity, cation transmembrane transporter activity, voltage-gated potassium channel activity, cation channel activity, cyclic nucleotide-gated ion channel activityCation transport, signal transductionLigand-gated ion channel

Low-density lipoprotein receptor (familial hypercholesterolemia)LDLROther receptorOogenesisAlzheimer disease-presenilin pathway

Mitogen-activated protein kinase 8 (JNK)MAPK8Kinase activityImmune system process, mitosis, cell surface receptor linked signal transduction, intracellular signaling cascade, carbohydrate metabolic process, protein metabolic process, cell motion, mitosis, signal transduction, segment specification, ectoderm development, mesoderm development, embryonic development, nervous system development, response to stressAlzheimer disease-amyloid secretase pathway, Ras pathway, EGF receptor signaling pathway, Parkinson disease, angiogenesis, FGF signaling pathway, FAS signaling pathway, toll receptor signaling pathway, TGF-beta signaling pathway, PDGF signaling pathway, Huntington disease, integrin signalling pathway, T-cell activation, B-cell activation, interferon-gamma signaling pathway, oxidative stress response, apoptosis signaling pathway, integrin signalling pathway

Induced myeloid leukemia cell differentiation protein Mcl-1MCL1Receptor bindingGamete generation, induction of apoptosis, negative regulation of apoptosis, cell cycle, mesoderm development, hemopoiesisApoptosis signaling pathway

Matrix metallopeptidase 1 (27 kDa interstitial collagenase)MMP1Peptidase activityProtein metabolic processPlasminogen activating cascade, Alzheimer disease-presenilin pathway, plasminogen activating cascade

Matrix metalloproteinase-16MMP16Peptidase activity Protein metabolic process Alzheimer disease-presenilin pathway

72 kDa type IV collagenaseMMP2Metalloprotease, other extracellular matrixProteolysisAlzheimer disease-presenilin pathway

Matrix metallopeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase)MMP9Metalloprotease, other extracellular matrixProteolysis Alzheimer disease-presenilin pathway, plasminogen activating cascade

Myc proto-oncogene proteinMYCDNA binding, transcription factor activityInduction of apoptosis, cell cycle, nucleobase, nucleoside, nucleotide, and nucleic acid, metabolic process, cell cycleOxidative stress response, p53 pathway feedback loops 2, Wnt signaling pathway, interleukin signaling pathway, PDGF signaling pathway

Arylamine N-acetyltransferase 1NATAcyltransferase activityMetabolic processAcetyltransferase

Nuclear factor NF-κB p50 subunit (NF-κB)NFKB1DNA binding, transcription factor activityB-cell-mediated immunity, negative regulation of apoptosis, intracellular signaling cascade, nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process, signal transduction, cellular defense responseT-cell activation, B-cell activation, toll receptor signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway, apoptosis signaling pathway

NF-κB inhibitor-αNFKBIAProtein bindingImmune system process, intracellular protein transport apoptosis, intracellular signaling cascade, nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process, signal transduction, response to stressApoptosis signaling pathway, toll receptor signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway, T-cell activation, B-cell activation

Nucleophosmin (nucleolar phosphoprotein B23) and telomeraseNPM1N/ANucleobase, nucleoside, nucleotide, and nucleic acid metabolic process N/A

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)NR3C1Nuclear hormone receptor, transcription factor, nucleic acid bindingN/AN/A

Poly(ADP-ribose) polymerase family, member 1PARPGlycosyltransferaseDNA repair, protein ADP-ribosylation, stress responseFAS signaling pathway

Proprotein convertase subtilisin/kexin type 9PCSK9Serine protease ProteolysisN/A

Urokinase-plasminogen activatorPLAUPeptidase activityImmune system process, signal transduction, protein metabolic process, cell motion, signal transduction, blood coagulationBlood coagulation, plasminogen activating cascade

Peroxisome proliferator-activated receptor-γPPARGNuclear hormone receptor, transcription factor, nucleic acid bindingMonosaccharide metabolism, regulation of lipid, fatty acid, and steroid metabolism, mRNA transcription regulation, ligand-mediated signalling, stress response, developmental processes, cell proliferation and differentiationN/A

Prostaglandin G/H synthase 2PTGS2/COX2Oxidoreductase activityImmune system processEndothelin signaling pathway, toll receptor signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway

Ras-related C3 botulinum toxin substrate 1RAC1GTPase activity, protein bindingIntracellular protein transport, endocytosis, cell surface receptor linked signal transduction, intracellular signaling cascade, signal transductionAxon guidance mediated by Slit/Robo, integrin signalling pathway, inflammation mediated by chemokine and cytokine signaling pathway, Huntington disease, axon guidance mediated by Slit/Robo, FGF signaling pathway, T-cell activation, axon guidance mediated by netrin, EGF receptor signaling pathway, inflammation mediated by chemokine and cytokine signaling pathway, cytoskeletal regulation by Rho GTPase, aAxon guidance mediated by semaphorins, cytoskeletal regulation by Rho GTPase, B-cell activation, Ras pathway

Rho-associated protein kinase 1ROCK1/RHOKinase activityMitosis, intracellular signaling cascade, cell adhesion, protein metabolic process, cell motion, mitosis, signal transduction, cell adhesion, embryonic developmentInflammation mediated by chemokine and cytokine signaling pathway, cytoskeletal regulation by Rho GTPase

Transforming protein RhoARHOAGTPase activity, protein bindingIntracellular protein transport, endocytosis, cell surface receptor linked signal transduction, intracellular signaling cascade, signal transductionAxon guidance mediated by Slit/Robo, angiogenesis, heterotrimeric G-protein signaling pathway-Gq alpha; and Go alpha mediated pathway, axon guidance mediated by semaphorins, inflammation mediated by chemokine and cytokine signaling pathway, integrin signalling pathway, Ras pathway, cytoskeletal regulation by Rho GTPase, PDGF signaling pathway

Proto-oncogene tyrosine-protein kinase ROSROS1Kinase activity, transmembrane receptor protein tyrosine kinase activity, transmembrane receptor protein kinase activity, receptor bindingFemale gamete generation, immune system process, visual perception, sensory perception, negative regulation of apoptosis, cell cycle, cell surface receptor linked signal transduction, intracellular signaling cascade, cell-cell signalling, cell-cell adhesion, protein metabolic process, cell motion, cell cycle, signal transduction, ectoderm development, mesoderm development, embryonic development, nervous system developmentN/A

Runt-related transcription factor 2RUNX2DNA binding, transcription factor activityMesoderm development, skeletal system development, hemopoiesisN/A

Sucrase-isomaltase (Alpha-glucosidase)SIHydrolase activity, hydrolyzing O-glycosyl compoundsCarbohydrate metabolic process, protein metabolic processN/A

Processed sterol regulatory element-binding protein 2SREBP2DNA binding, transcription factor activityNucleobase, nucleoside, nucleotide and nucleic acid metabolic process, lipid metabolic processBasic helix-loop-helix transcription factor

Tumor necrosis factor/tumor necrosis factor-αTNFATumor necrosis factor family memberCytokine- and chemokine-mediated signaling pathways, ligand-mediated signalling, immunity and defense, induction of apoptosisWnt signaling pathway, apoptosis signaling pathway

Topoisomerase (DNA) ITop1DNA topoisomeraseDNA replication, general mRNA transcription activitiesDNA replication

Cellular tumor antigen p53TP53DNA binding, transcription factor activityInduction of apoptosis, cell cycle, nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process, cell cycleApoptosis signaling pathway, Huntington disease, P53 pathway feedback loops 1, p53 pathway, p53 pathway by glucose deprivation, p53 pathway feedback loops 2, Wnt signaling pathway

Vascular endothelial growth factor AVEGFAReceptor bindingImmune system process, cell cycle, cell surface receptor linked signal transduction, intracellular signaling cascade, cell-cell signalling, cell cyclesignal transduction, mesoderm development, angiogenesis, response to stressAngiogenesis, VEGF signaling pathway

Wee1-like protein kinaseWee1Kinase activityMitosis, protein metabolic processProtein kinase

Extensive research has been carried out to study the effects of berberine on cancer cells in vitro. This may be related to recent discovery of anti-cancer drugs with natural compound origin, for example, paclitaxel and topotecan.

Various human cancer cell lines were used to demonstrate the anti-cancer effects of berberine in vitro. These include cancer cell lines of the tongue, stomach, lung, colon, liver, breast, prostate, nasopharyngeal, neurones, epidermal, and blood [1828]. Berberine has shown to induce cancer cell death via several mechanisms such as regulation of apoptosis proteins and cell cycle arrest.

Berberine treatment increased the expression of apoptotic cell death proteins, promotes cell cycle arrest, and induces cell death in human cancer cell lines. For instance, in human prostate epithelial cells (PWR-1E), berberine-increased expression of BCL2-associated X protein (Bax) was observed after berberine treatment, inducing cell death and demonstrating pro-apoptotic properties [29]. Similar effects of berberine were observed in prostate carcinoma cells (DU145, PC-3, and LNCaP) [21, 30]. Berberine also increased levels of Bax in promyelocytic leukemia cells [31], gastric carcinoma cells [24], and lung cancer cells [20].

Berberine can also promote cell death by the regulation of antiapoptotic proteins. Decreased expression of antiapoptotic Bcl-2 protein was observed in human oral squamous cell carcinoma after berberine treatment [23]. Studies done in other cancer cell lines such as lung cancer, gastric cancer, and prostate cancer also showed reduced levels of Bcl-2 after berberine treatment [20, 21, 24, 30]. Cell cycle arrest at different phases has also been observed in human cancer cell lines after treatment with berberine. In giant cell carcinoma and prostate carcinoma cells, berberine also decreased G0/G1 phase-associated cyclins (D1, D2, E, Cdk2, Cdk4, and Cdk6), inducing G0/G1 arrest and suppressing cell proliferation [21, 25, 30, 32]. Further, in HepG2 cells, berberine acted on B-cell CLL/lymphoma 2 (BCL2), procaspase-3 and -9, and poly (ADP-ribose) polymerase (PARP), induced cell cycle arrest at G2/M phase and inhibited cell proliferation [22].

Further, berberine can promote cell death via the regulation of pro- and antiapoptotic proteins. In addition to this, berberine can also promote apoptosis via mitochondrial/caspase pathway. In cancer cell lines (tongue cancer, oral squamous cell carcinoma and prostate epithelial) [18, 23, 29, 33], activation of caspases-3 & -9 promotes G1 cell cycle arrest in different human cancer cell lines (lung, stomach, and prostate) [20, 21, 24, 30, 33].

Berberine also showed anti-metastatic properties in several cancer cell lines, acting on 72 kDa type IV collagenase (MMP2), Cdc42 effector protein 1 (CDC42EP1), and ras-related C3 botulinum toxin substrate 1 (RAC1), transforming protein RhoA (RHOA) and urokinase-plasminogen activator A (PLAU) [34, 35]. Further, berberine showed antitopoisomerase I properties [36]; this observation can be useful as topoisomerase I is responsible for DNA replication and antitopoisomerase I compounds can be effective in cancer treatments.

In addition to its effects on cancer cells, berberine also acts on molecular targets related to insulin resistance. In free-fatty-acid-induced insulin resistance muscle cells, berberine improves insulin resistance and improves glucose uptake by decreasing PPAR and FAT/CD36 protein expression [37]. Another study reported increased insulin receptor (InsR) mRNA and protein expression increases insulin sensitivity in liver cells after berberine treatment [38]. In Caco-2 cells, berberine inhibited alpha-glucosidase and disaccharidases activities, leading to reduced glucose levels [39]. In Hep G2 cells, berberine also improved insulin signal transduction through various mechanisms such as decreased phosphorylation of PERK and eLF2- , increased phosphorylation of IRS-1 tyrosine and AKT serine [40]. In intestinal NCI-H716 cells, berberine enhanced glucagon-like peptide 1 (GLP-1) release and promotes proglucagon mRNA expression [41]. These results demonstrate that berberine has great potential for insulin resistance treatment and should be explored further in animal and human studies.

3.2. PANTHER Analysis of Berberine Targets

Distribution of berberine therapeutic targets in vitro varied in each of these functional classifications. Tables 3, 4, and 5 show various distributions of the most frequent occurring berberine targets in vitro based on molecular functions, biological processes, and pathways, respectively.


PANTHER molecular functionNumber
of targets

Acyltransferase activity1
Anion channel activity1
ATPase activity, coupled to transmembrane movement of substances2
Cation channel activity1
Cation transmembrane transporter activity1
Chemokine1
Cyclic nucleotide-gated ion channel activity1
Cysteine protease3
Cytokine receptor activity1
DNA binding9
DNA topoisomerase1
Glycosyltransferase1
GTPase activity2
Hydrolase activity, acting on ester bonds1
Hydrolase activity, hydrolyzing O-glycosyl compounds1
Kinase activator1
Kinase activator activity4
Kinase activity11
Kinase inhibitor activity2
Kinase regulator activity6
Metalloprotease2
Not classified10
Non-receptor serine/threonine protein kinase 3
Nuclear hormone receptor2
Nucleic acid binding2
Other extracellular matrix 2
Other ligase1
Other receptor1
Other signaling molecule3
Other transfer/carrier protein 1
Oxidoreductase activity1
Oxygenase 3
Peptidase activity4
Peptidase inhibitor activity1
Phosphatase activity1
Protein binding10
Receptor activity3
Receptor binding12
Reductase 1
Serine protease 2
Structural constituent of cytoskeleton1
Transmembrane transporter activity2
Transcription factor2
Transcription factor activity9
Transmembrane receptor protein kinase activity3
Transmembrane receptor protein tyrosine kinase activity3
Tumor necrosis factor family member1
Voltage-gated potassium channel activity1


PANTHER biological functionsNumber of targets

Angiogenesis2
Anion transport1
Apoptosis6
B-cell-mediated immunity2
Blood coagulation1
Calcium-mediated signaling1
Carbohydrate metabolic process7
Cation transport1
Cell adhesion3
Cell communication1
Cell cycle11
Cell cycle control5
Cell cycle intracellular signaling cascade1
Cell cycle signal transduction1
Cell motility1
Cell motion10
Cell proliferation and differentiation3
Cell proliferation and differentiation 1
Cell surface receptor linked signal transduction14
Cell surface receptor-mediated signal transduction1
Cell-cell adhesion3
Cell-cell signaling9
Cellular component morphogenesis2
Cellular defense response4
Cellular glucose homeostasis1
Coenzyme metabolism1
Cytokine- and chemokine-mediated signaling pathways2
Developmental processes1
DNA repair1
DNA replication2
Dorsal/ventral axis specification1
Ectoderm development1
Ectoderm development8
Electron transport3
Embryonic development7
Endocytosis2
Extracellular transport2
Fatty acid biosynthesis1
Fatty acid metabolism1
Female gamete generation4
Gamete generation2
Gametogenesis1
General mRNA transcription activities1
Gluconeogenesis1
Granulocyte-mediated immunity1
Heart development1
Hematopoiesis1
Hemopoiesis3
Immune response2
Immune system process16
Immune system processMitosis1
Immunity and defense1
Induction of apoptosis9
Intracellular protein transport3
Intracellular signaling cascade18
Ligand-mediated signaling3
Lipid metabolic process4
Lipid transport2
Macrophage activation2
Macrophage-mediated immunity1
Mesoderm development12
Metabolic process1
Mitosis4
Monosaccharide metabolism2
mRNA transcription regulation1
Muscle organ development1
Not classified9
Natural killer cell activation1
Negative regulation of apoptosis8
Nervous system development7
Neurological system process1
NF-κB cascade1
Nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process10
Oncogenesis3
Other intracellular protein traffic1
Other lipid, fatty acid and steroid metabolism1
Other signal transduction1
Oxidative phosphorylation 1
Oxygen and reactive oxygen species metabolic process1
Phosphatase activity cell cycle1
Phosphate metabolic process1
Protein ADP-ribosylation1
Protein metabolic process17
Protein phosphorylation3
Proteolysis7
Regulation of lipid, fatty acid and steroid metabolism1
Response to interferon-γ1
Response to stimulus2
Response to stress8
Response to toxin2
Segment specification3
Sensory perception1
Signal transduction25
Skeletal system development2
Spermatogenesis2
Steroid hormone metabolism1
Steroid metabolism2
Stress response2
T-cell-mediated immunity2
Transcription factor activity immune system process1
Transport1
Tumor suppressor1
Visual perception1


PANTHER pathway categoriesNumber of targets

Acetyltransferase1
Alzheimer disease-amyloid secretase pathway11
Alzheimer disease-presenilin pathway14
Angiogenesis11
Apoptosis signaling pathway21
ATP synthesis1
ATP-binding cassette (ABC) transporter2
Axon guidance mediated by netrin1
Axon guidance mediated by semaphorins1
Axon guidance mediated by Slit/Robo4
B-cell activation7
Basic helix-loop-helix transcription factor1
Blood coagulation3
Cadherin signaling pathway2
Cell cycle4
Cytoskeletal regulation by Rho GTPase3
DNA replication2
EGF receptor signaling pathway4
Endothelin signaling pathway2
FAS signaling pathway13
FGF signaling pathway4
Heterotrimeric G-protein signaling pathway—Gq alpha- and Go alpha-mediated pathway1
Huntington disease9
Hypoxia response via HIF activation1
Inflammation mediated by chemokine and cytokine signaling pathways13
Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade1
Integrin signalling pathway6
Interferon-gamma signaling pathway2
Interleukin signaling pathway10
Ligand-gated ion channel1
Membrane-bound signaling molecule1
Pathway unclassified19
Oxidative stress response5
p53 pathway12
p53 pathway by glucose deprivation1
p53 pathway feedback loops1
P53 pathway feedback loops 11
p53 pathway feedback loops 24
Parkinson disease3
PDGF signaling pathway6
Peptide hormone1
PI3 kinase pathway4
Plasminogen activating cascade8
Protein kinase1
Ras Pathway5
T-cell activation7
TGF-β signaling pathway4
Toll receptor signaling pathway9
VEGF signaling pathway7
Vitamin D metabolism and pathway1
Wnt signaling pathway4

As shown in Table 3, berberine acts on a diverse range of molecular targets in vitro. The most common classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Known berberine targets in vitro from the receptor binding class include epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), interleukin-1 (IL1B) and interleukin-6 (IL6), growth/differentiation factor 15 (NAG-1), and glucagon-like peptide (GLP1).

Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved (Table 4). In vitro berberine targets involved signal transduction include cyclin-dependant kinases (CDK1 and CDK6), inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK), epidermal growth factor receptor (EFGR), receptor tyrosine-protein kinase (ERBB2), glucagon-like peptide (GCG), growth/differentiation factor 15 (GDF15), interferon beta (IFNB1), interleukins (IL1B, IL2RA, and IL6), potassium voltage-gated channel subfamily H member 2 (KCNH1), mitogen-activated protein kinases (ERK1, ERK2, and MAPK8), nuclear factor-kappa-B p50 subunit (NFKB1), NF-kappa-B inhibitor alpha (NFKB1A), urokinase-plasminogen activator (PLAU), Ras-related C3 botulinum toxin substrate 1 (RAC1), Rho-associated protein kinase 4 (RHO), transforming protein RhoA (RHOA), proto-oncogene tyrosine-protein kinase ROS (ROS1), vascular endothelial growth factor A (VEGFA).

According to the PANTHER Classification System, in vitro berberine targets correlate with a mixture of biological pathways, such as Alzheimer disease-presenilin and secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Huntington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways (Table 5).

The targets of berberine distributed across a large number of PANTHER classifications of molecular functions, biological processes, and pathways. This can be an advantage in terms of drug discovery using berberine. Seen that berberine targets are involved in a wide range of molecular activities, in turn, can alter many pathological states of the body. Thus, berberine can be explored for the treatment of different diseases. On the other hand, the nature of multitargeting of berberine lacks in target specificity which can become difficult for drug design. Further, because berberine can have interactions with so many molecular structures and involve in different pathways, much attention must be paid to avoid interactions with other therapeutic drugs.

3.3. Data from In Vivo Studies with a Focus on Diabetes Mellitus

In China, Huang Lian (Rhizoma coptidis) has been used to treat diabetes for more than 1,400 years [16]. Berberine is one of the main active alkaloids present in Rhizoma Coptidis and has shown to have good hypoglycaemic effects in vitro [3739, 42]. Further, the chemical structure of berberine is different from the commonly used other hypoglycaemic agents such as sulphonylureas, biguanides, thiazolidinediones, or acarbose [14]. Thus, it is meaningful to investigate the efficacy and safety of berberine treatments for diabetes mellitus to confirm the possibility of berberine serving as a new class of antidiabetic medications. Extensive research has been done to investigate the hypoglycaemic effects of berberine in animal models. This section will highlight the effects of berberine in diabetic animal studies, focusing on different mechanisms of actions of berberine.

Hyperglycemia is a hallmark metabolic abnormality associated with metabolic diseases such as type 2 diabetes. Berberine has shown to significantly decrease fasting blood glucose levels in diabetic rats (diet or drug induced), this has been observed in a number of studies [4346]. Berberine can reduce fasting blood glucose level via different mechanisms. For example, Liu et al. [43] reported that berberine reduced fasting blood glucose (FBG) levels by inhibiting intestinal disaccharidases in a concentration-dependent manner. Xia et al. [46] reported berberine reduced fasting glucose level via the inhibition of gluconeogenesis, via decreased PEPCK and G6Pase genes in the liver, reduced hepatic steatosis, and inhibition of FAS expression.

Current diabetes therapies do not address the key driver of this condition, -cell dysfunction [47, 48], and do not alter the progressive nature of insulin secretory deficit [49]. Berberine increased pancreatic -cell numbers and -cell mass in streptozotocin-induced diabetic rats [41, 50]. It also reversed pathological changes of pancreatic -cells in diabetic rats induced by streptozotocin and diet [51]. Further, in berberine treated diabetic rats, the pancreatic and plasma insulin levels increased after glucose load, reducing blood glucose levels [41, 50]. These observations are significant as berberine may be explored further as an additional therapy to existing antidiabetic drugs to effectively preserve -cell functions, reverse -cell damage, and promote insulin secretion in diabetes patients.

Further to -cell dysfunction and insulin secretory deficit in diabetes, defects in insulin receptor (InsR) expression or function can cause insulin resistance and diabetes mellitus [52]. Thus, regulation of InsR expression may improve insulin resistance in diabetes mellitus. Berberine increases InsR mRNA and protein expression in human liver cells and in animal model in a dose- and time-dependent manner [38]. Berberine upregulates InsR and leads to enhanced insulin signalling pathway, confirming berberine as an insulin sensitiser.

Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone released in response to food ingestion [53]. GLP-1 enhances meal-related insulin secretion and promotes glucose tolerance. In streptozotocin-induced rats, berberine enhanced GLP-1 release and promotes proglucagon mRNA expression, increased beta cell mass and pancreas insulin levels after glucose load [41]. This observation was in line with the groups, previous experiments in vitro. Lu et al. [50] also reported that berberine increased proglucagon mRNA expression and plasma insulin levels in streptozotocin-induced diabetic rats. The glucagon gene encodes GLP-1 and the increased expression of proglucagon mRNA assists in controlling the blood glucose homeostasis.

Berberine also reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice [54]. Oral glucose tolerance improvement in diabetic rats after berberine treatment has also been observed in other studies [55, 56].

Long-term hyperglycaemia can lead to increased risk of cardiovascular complications. In hyperglycemia and hypercholesterolemia rats with injured cardiac functions, berberine (15, 30 mg/kg/day, i.g for 6 weeks) increased cardiac output, left ventricular systolic pressure, and by 64, 16, and 79%, but decreased left ventricular end diastolic pressure and by 121 and 61% in the rats receiving HSFD/streptozotocin, respectively, when compared with the untreated rats of hyperglycemia and hypercholesterolemia [57]. Berberine caused significant increase in cardiac fatty acid transport protein-1 (159%), fatty acid transport proteins (56%), fatty acid beta-oxidase (52%), and glucose transporter-4. These results demonstrate the cardioprotective functions of berberine in hyperglycemia/hypercholesterolemia through alleviating cardiac lipid accumulation and promoting glucose transport 4 [57]. Another study also showed improved vasorelaxation in impaired aorta in diabetic rats after berberine treatment (100 mg/kg/day, 8 weeks) [45]. Thus, in addition to its hypoglycaemic effects, berberine can also be investigated for cardiomyopathy in diabetes.

Berberine also regulates lipid metabolism which is closely related to diabetes. In rats with induced diabetic hyperlipidemia, berberine (75, 150, 300 mg/kg/day for 16 weeks) effectively reduced liver weight and liver/body weight ratio, levels of total cholesterol, triglycerides, and low-density lipoprotein-cholesterol [58]. In rats with a high fat diet, berberine significantly reduced body weight, alleviated liver steatosis, and improved insulin resistance [59]. This observation indicates that berberine can be an effective treatment for diabetes with obesity.

Clinically, preeminent factors for monitoring glycaemia and evaluating the risks of complications of diabetes include FBG, haemoglobin A1c (HbA1c) [60]. Triglyceride synthesis is closely associated with glucose metabolism so serum triglyceride levels are determined. Clinical studies often measure FBG, HbA1c, and triglyceride levels, along with other factors to study the hypoglycaemic effects of berberine. The efficacies of berberine in type 2 diabetes patients have been reported. Through literature search, key clinical studies on berberine effects on type 2 diabetes patients are summarised.

Zhang et al. [61] conducted a randomized, double-blind, placebo-controlled multicenter trial ( ). The authors found that when berberine (1.0 g daily) was administered for 3 months in type 2 diabetes patients with dyslipidemia, the fasting and postload plasma glucose levels decreased from to and from to  mM/L, HbA1c from to . Further, in the treatment group, triglyceride levels were reduced from to  mM/L, total cholesterol from to  mM/L, and LDL-cholesterol from to  mM/L. Results from the treatment group was significant compared to the control group. In the treatment group, patient’s body weight was also significantly reduced. Mild-to-moderate constipation was reported in 5 patients from the treatment group and 1 patient from the control group; however, this finding was not statistically significant. No other adverse events were reported. At 3 months, berberine was found to be effective in lowering blood glucose, lipids, body weight, and blood pressure with a good safety profile.

Yin et al. reported a 3-month study comparing berberine to antidiabetic drug metformin (0.5 g t.i.d) [14]. In this study, berberine exhibited identical effect as metformin in the regulation of glucose metabolism, significant decreases in HbA1c (by 2%, ), FBG (by 3.8 mmol/L; ), and postprandial blood glucose (PBG) (by 8.8 mmol/L; ). Further, the regulation of lipid metabolism was better in the berberine group than the metformin group. Triglycerides and total cholesterol levels were significantly lower than in the metformin group ( ). At the same time, the same group of researchers used berberine as a combination therapy to evaluate its additive or synergistic effects on the commonly used hypoglycemic agents, such as sulphonylureas, biguanides, thiazolidinediones, and acarbose. Patients were given 500 mg berberine three times daily for 3 months in addition to their previous treatment. At week 5, berberine significantly ( ) reduced HbA1c (from 8.1% to 7.3%), FBG, PBG, and fasting insulin levels. Blood lipids including triglyceride, total cholesterol, and LDL-C decreased significantly lowered compared to baseline. In both studies, incidences of gastrointestinal adverse events were observed, including diarrhea, constipation, flatulence, and abdominal pain. Interestingly, patients did not suffer from severe gastrointestinal adverse events when berberine was used alone and in combination therapy; adverse effects disappeared after berberine dosage was reduced. No pronounced elevation in liver enzymes or creatinine was observed, suggesting that berberine did not cause damage to the liver or kidneys.

Another clinical study [62] randomly divided 97 type 2 diabetes mellitus patients into berberine treatment (1 g/day) for 2 months, using metformin therapy (1.5 g/day) and rosiglitazone group (4 mg/b.i.d) as reference groups. Blood samples were taking before and after treatments to measure FBG, HbA1c, triglyceride, and serum insulin levels. Compared to values prior to treatment, berberine significantly lowered FBG by 25.9% ( ), HbA1c by 18.1% ( ), and triglycerides by 17.6% ( ). The hypoglycaemic effects of berberine were comparable to metformin and rosiglitazone. Serum insulin level was declined significantly ( ) by 28.2%; this indicates increased insulin sensitivity in peripheral tissues by berberine treatment. Peripheral blood lymphocytes from berberine treated patients were isolated to examine the InsR expression. The surface expression of InsR significantly elevated by 3.6-fold after berberine treatment.

Metformin and rosiglitazone are not recommended for use in diabetic patients with liver function damage [54, 63]. So the effect of berberine was tested in hyperglycaemic patients with hepatitis. Hepatitis B and C patients with hyperglycaemia received berberine at 1 g/day for 2 months. In both diabetic hepatitis B and C patients, berberine significantly reduced FBG and triglyceride levels. Berberine treatment also reduced the elevated alanine transaminase and aspartate aminotransferase levels in these patients. Overall, berberine is safe and effective in hyperglycaemic patients with liver function damage.

Table 6 compares clinical studies of berberine in diabetes patients. Across the studies, berberine has shown to significantly reduce FBG, PBG, and HbA1c levels. Berberine also demonstrated ability to reduce triglyceride and cholesterol levels. Minimal gastrointestinal side effects were shown but no liver or kidney damage was observed. These observations in diabetes patients demonstrate that berberine is a safe and effective antidiabetic agent.


Study typeStudy subjectsBerberine dosageControl treatmentMajor findingsSide effectsReference

Randomised, double-blind, placebo-controlled, multiple-centerType 2 diabetes and dyslipidemia ( )0.5 g, b.i.d for 3 monthsPlacebo Significantly reduced fasting and postload plasma glucose, HbA1c
Significantly reduced triglyceride, total cholesterol, and LDL-cholesterol
Mild to moderate constipation in 5 patients[61]

Randomised, blinded, placebo-controlledType 2 diabetes ( )0.5 g, t.i.d for 3 monthsMetformin (0.5 g t.i.d)Significantly reduced FBG, PBG, and HbA1c
Significantly reduced plasma triglycerides
Transient gastrointestinal adverse effects. No liver or kidney damage [14]
Type 2 diabetes poorly controlled ( )0.5 g, t.i.d for 3 monthsExisting anti-diabetic treatmentLowered FBG and PBG
Significantly decreased HbA1c
Significantly reduced fasting plasma insulin and HOMA-IR

Randomised
Type 2 diabetes ( )1 g/day for 2 monthsMetformin (1.5 g/day); rosiglitazone (4 mg/day)Significantly reduced FBG, HbA1c, and triglycerides
Serum insulin level was declined significantly ( ), increased insulin sensitivity in peripheral tissues
Significantly elevated surface expression of InsR by 3.6-fold
No adverse events [62]
Type 2 diabetes with chronic hepatitis C virus infection ( )1 g/day for 2 monthsN/ASignificantly reduced FBG and triglyceride levels
Reduced the elevated ALT and aspartate aminotransferase levels

b.i.d: twice daily; t.i.d: three times daily; FBG: fasting blood glucose; HOMA-IR: homeostasis model of assessment—insulin resistance; PBG: postprandial blood glucose.

4. Discussion

The “rule-of-five” analysis by Lipinski et al. [7] shows that poor absorption or permeation of a compound is more likely when there are more than five hydrogen-bond donors; the molecular mass is more than 500 Da; the lipophilicity is high (expressed as   ); the sum of nitrogen and oxygen is more than 10. Specific structural and physiochemical properties, such as “rule-of-five,” are required for clinical drugs to have sufficient levels of efficacy, bioavailability, and safety, which define target sites to which drug-like molecules can bind [4].

Plant compounds exhibit enormous structural diversity and only a small portion of the diversity has been explored for its pharmacological potential [64]. In recent years, herbal compounds have been source of new drugs [64]. Approximately 28% of new molecular entities (NMEs) between 1981 and 2002 were natural products or natural product derived; further to this, 20% of these NMEs were natural product mimics [65]. There are a number of successful plant-derived drugs, especially in anti-cancer treatment. Medicinal herbal compounds have become an important source for the discovery of new drugs. Further, drugs derived from medicinal plants can also be used as drug leads suitable for optimization by medicinal and synthetic chemists [65].

As Chinese herbal medicine becomes increasingly popular in the west, researchers are spending more time looking into mechanisms of actions of crude extracts and herbal compounds such as berberine. In recent years, extensive research has been done to explore the effects of berberine on various cell lines in vitro. In cell-based studies, berberine has shown effects on multiple molecular targets and alters various biological pathways. Berberine associates with a range of conditions, particularly diabetes, hyperlipidemia, and cancer. Many in vitro studies showed potent anticancer properties of berberine against various cancer cells. This observation is valuable in the search for new anti-cancer therapeutics with potent anti-cancer effects but reduced side effect. So berberine may potentially be developed into an anticancer agent, like other natural compounds (taxol, camptothecin) that have been developed and used as anticancer agents.

Diabetes mellitus is a major health problem around the world and its prevalence is on the rise. Diabetes mellitus drug therapy is limited by availability of effective medications, as existing oral hypoglycaemic agents often have side effects and fails in long-term administration [14]. Berberine has shown significant results in fasting blood glucose levels reduction, increase in insulin sensitivity, and improvement in insulin resistance in vitro, in diabetic animal models and in diabetic patients. Further, berberine shows mechanism that current antidiabetic drugs do not have. For instance, berberine has shown effects on pancreatic -cell number and mass improvement [41, 50, 51]. In addition, berberine has a good safety profile and does not show side effects such as hypoglycaemia, weight gain, or liver and kidney damage. Metformin and rosiglitazone are not recommended for use in diabetic patients with liver function damage [54, 63]. Berberine has shown to be effective in the reduction of blood glucose level and is safe in diabetic patients with viral hepatitis [62]. Berberine can therefore be investigated as an effective diabetes therapy with patients with liver function damage. In addition to its hypoglycemic effects in diabetic patients, berberine also reduced triglyceride and cholesterol levels. Abnormalities in lipid metabolism often deteriorate diabetes and cause complications. The regulation of lipid metabolism in diabetes patients by berberine may have clinical significance in managing diabetic patients with hyperlipidemia. Although there are only a small number of clinical studies and evidence is limited, current reports still show a promising future for berberine being developed into a new antidiabetic agent.

In China, berberine has been manufactured into the over-the-counter drug Huang Lian Su Pian, also known as Coptis Extract Tablets for the treatment of traveler’s diarrhea [14, 17]. However, in vitro and in vivo studies have shown that berberine has potent anti-cancer, antidiabetic, antilipidemic, and anti-inflammatory effects. Therefore, further clinical studies are warranted to investigate the potential of berberine in the application of cancer and diabetes treatments in the future.

Pharmacological activity of CHMs begins with the binding of the active components to their molecular targets. CHMs are considered as typical multitherapeutics that can interact simultaneously with multiple targets. The origins and the progression of diseases are multifactorial. Complex disorders such as cancer, cardiovascular disease, and depression tend to result from multiple molecular abnormalities, not from a single defect [66]. Biochemical and genetic studies revealed the molecular mechanism that underlie common illnesses [66]. Reports show that targets for neoplasm diseases, circulatory system diseases, infectious diseases, and nervous system and sense organs disorders constitute the largest number of targets [1]. Because drug targets are presented at the molecular level, increased knowledge of herbal targets can facilitate deeper understanding of complex diseases at its fundamental level. In turn, it is likely to determine the optimal molecular targets for therapeutic intervention [6].

Further to assisting the molecular dissection of the mechanism of action of CHMs, knowledge on herbal targets makes it possible to use disease specific targets and design more desirable herbal drugs/formulas with increased specificity and efficacy. Target-oriented synthesis in drug discovery involves in preselected protein targets [67]. Binding of drugs to preselected protein target/s is dependent on which biological pathway the drug is aimed to modulate the target or the diseased pathway(s) [67]. Target and disease specific drug design results in improved efficacy and reduced side effects, especially in high impact diseases that require more effective and more treatment options. However, due to the fact that diseases often involve in multiple molecular abnormalities, diversity-oriented syntheses are used in efforts to identify simultaneously therapeutic protein targets and their small-molecule regulators [67]. Target-oriented drug design allows more focused drug design, which in turn costs less time and money for pharmaceutical companies.

Protein structure of well-validated old and new targets should be able to guide the chemical effort directed at new drugs [68]. Study of various aspects of known targets including molecular mechanism of their binding agents and related adverse effects is useful for finding clues to new target identification [9]. Based on the knowledge of molecular targets and molecular understanding of disease state and using this knowledge will allow some direction in identifying potential targets. Potential herbal targets may come from the same class as confirmed therapeutic targets and have similar physiological functions, or maybe a structure along a biological pathway. Additionally, with increased number of potential targets from ~500 to >5,000, the nature of pharmaceutical research has changed. This increase in numbers has given researchers more opportunities to discover and design new and improved drugs.

Target selection may be one of the most important determinants of attrition and the overall R&D productivity. There are few ways to overcome this challenge and improve the target selection process, in turn, improving R&D productivity. First of all, researchers can discover new target classes. Targets of herbal medicine are becoming a popular resource to find new target classes. In addition, increased understanding of genetic variations/polymorphisms of drug targets or drug metabolising enzymes can assist in target selection and drug metabolism. Further, the use of new technology can help to speed up the early exploratory discovery phase of drug discovery.

In summary, updated knowledge of herbal targets is valuable contribution to complex disease understanding and clinical responses. Further, drug discovery and development from herbal medicines can be supported by new target discovery and target-focused drug design. This will speed up the exploratory phase of drug R&D and benefit the pharmaceutical industry in terms of cost and time.

Abbreviations

Bax:BCL2-associated X protein
FBG:Fasting blood glucose
GLP-1:Glucagon like peptide 1
:Hemoglobin
InsR:Insulin receptor
PBG:Postprandial blood glucose.

Authors’ Contribution

Xiao-Wu Chen and Yuan Ming Di contributed equally to this work.

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