BioMed Research International

Volume 2013 (2013), Article ID 379850, 9 pages

http://dx.doi.org/10.1155/2013/379850

Review Article

Pinocembrin: A Novel Natural Compound with Versatile Pharmacological and Biological Activities

Azhar Rasul,1,2 Faya Martin Millimouno,¹ Wafa Ali Eltayb,¹ Muhammad Ali,³ Jiang Li,² and Xiaomeng Li¹

¹The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China

²Dental Hospital, Jilin University, Changchun 130041, China

³Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan

Received 29 April 2013; Revised 1 July 2013; Accepted 9 July 2013

Academic Editor: Isabel C. F. R. Ferreira

Copyright © 2013 Azhar Rasul et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Pinocembrin (5,7-dihydroxyflavanone) is one of the primary flavonoids isolated from the variety of plants, mainly from Pinus heartwood, Eucalyptus, Populus, Euphorbia, and Sparattosperma leucanthum, in the diverse flora and purified by various chromatographic techniques. Pinocembrin is a major flavonoid molecule incorporated as multifunctional in the pharmaceutical industry. Its vast range of pharmacological activities has been well researched including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities. In addition, pinocembrin can be used as neuroprotective against cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antiexcitotoxic effects. Pinocembrin exhibits pharmacological effects on almost all systems, and our aim is to review the pharmacological and therapeutic applications of pinocembrin with specific emphasis on mechanisms of actions. The design of new drugs based on the pharmacological effects of pinocembrin could be beneficial. This review suggests that pinocembrin is a potentially promising pharmacological candidate, but additional studies and clinical trials are required to determine its specific intracellular sites of action and derivative targets in order to fully understand the mechanism of its anti-inflammatory, anticancer, and apoptotic effects to further validate its medical applications.

1. Introduction

Throughout the history of civilization, natural products have served human beings as a primary source of medicine [1]. The term “natural products” comprises chemical compounds that are derived from living organisms such as plants, fungi, bread molds, microorganisms, marine organisms, and terrestrial vertebrates and invertebrates [2]. In 2008, of the 225 drugs being developed, 164 were of natural origin, with 108 being derived from plants, 25 from bacterial sources, 7 from fungal, and 24 from animal sources, and, to throw some more numbers around, of the 108 plant-based drugs, 46 were in preclinical development, 14 in phase I, 41 in phase II, 5 in phase III, and two had already reached preregistration stage [3]. An analysis of medical indications by resource of compounds has established that natural products and related drugs, including anticancer, antibacterial, antiparasitic, anticoagulant, and immunosuppressant agents, are being used to treat 87% of all categorized human diseases [4]. Plants provide an extensive reservoir of natural products, demonstrating important structural diversity, and offer a wide variety of novel and exciting chemical entities in modern medicine [2, 4–9]. Historical experiences with plants as therapeutic tools have led to discoveries of many important, effective, and novel drugs including older drugs such as quinine and morphine and newer drugs such as paclitaxel (taxol), camptothecin, topotecan, and artemisinin [10].

The significance of natural products in health care is supported by a report that 80% of the global population still relies on plant derived medicines to address their health care needs [11]. It is also reported that 50% of all drugs in clinical use are natural products, or their derivatives, or their analogs [12], and 74% of the most important drugs consist of plant-derived active ingredients [13]. Until the 1970s, drug discovery was based on screening of a large number of natural and synthetic compounds, with the advent of computer and other molecular biology techniques, resulting in the modern and rational drug discovery [14]. Plant-based drugs have provided the basis of traditional medicine systems that have been employed in various countries such as Egypt, India, and China since prehistoric times [12]. The medicinal properties of plants have been documented already on Assyrian clay tablets dated about 2000 B.C. and reported in the Egyptian culture, the Indian Ayurveda [15], and traditional Chinese medicines (TCMs) [16].

All this said is implying that natural products including plants are important and valuable resources for drug development of natural origin [17]. Furthermore, a large number of natural compounds have been reported, which have been isolated from plants possessing wide variety of biological functions such as total glucosides of astragalus showing anti-inflammatory activity, tripterygium wilfordii multiglycoside, sinomenine [18], and camptothecin, taxol, vinblastine, vincristine, podophyllotoxin, and colchicine that demonstrate antineoplastic activity [19]. Indeed, molecules derived from natural sources including plants, marine organisms, and microorganisms have played and continue to play a dominant role in the discovery of leads for the development of conventional drugs for the treatment of the majority of human diseases. Chemoprevention was defined as the administration of agents to prevent induction, to inhibit, or to delay the progression of disease [20]. Mainly several scientific studies have been carried out on Euphorbia hirta Linn., widely spread in south China, which is extensively used in folk Chinese medicines for several ailments such as dysentery, eczema, hematuria, hypersensitivity, and gastroenteritis [21]. In addition, many studies have also reported that natural products have antimicrobial [22, 23], anticancer [24, 25], antioxidant [26, 27], anti-inflammatory [28, 29], and antifungal properties [30, 31]. The yield extract of leaves of Sparattosperma leucanthum (Vell.) K. Schum, that is, a native tree of Brazil, is popularly known as “caroba branca” or “ipê branco.” Previous phytochemical studies on the genus Sparattosperma described the isolation of the flavanone pinocembrin-7-O-(-d-neohesperidoside). Pinocembrin, one of the most important phytochemicals among flavonoids, acts as anti-inflammatory, antimicrobial, and antioxidant agent [24, 26, 32]. The extensive research indicated that pinocembrin has potential biological activities, which have made further interest among the chemists and biologists.

This review summarizes the recent researches on pinocembrin focusing on its biological and pharmacological activities. The literature was screened through various e-sites including PubMed, Scopus, and Elsevier Science Direct. Access to the Elsevier Science Direct Journals was made possible through the library of Northeast Normal University, Changchun, China. The searched literature mainly focused on recent advances, and additional manual searches were carried out on relevant medical journals and the google search Engine. Key words used for search were “pinocembrin,” “pinocembrin and biological activity,” “anticancer activity,” “inflammatory activity,” “cytotoxicity,” and “medicinal plants.” The data collected from primary sources and/or from data that superseded earlier work were included.

2. Natural Sources of Pinocembrin

Pinocembrin (Figure 1) has been identified in several plants such as the numerous genera of the Piperaceae family, which comprises fourteen genera and 1950 species that are reported as the rich source of pinocembrin. Of which, two genera, Peperomia and Piper, have been proved to be the most widespread and most diverse with 600 and 700 species, respectively [30, 33]. In addition to this family, pinocembrin has been also isolated from plants of Lauraceae and Asteraceae families, which comprise a large number of species. Of which, about 250 species of genus Cryptocarya are mainly distributed in tropical and subtropical regions, and 600 species of Helichrysum are located in Africa, of which some 244 species are found in South Africa [32]. Pinocembrin was also isolated from aerial parts of Flourensia oolepis S.F. Blake (Asteraceae) [34] and honey [35]. Further, pinocembrin, being a flavonoid natural compound, is located in fruits, vegetables, nuts, seeds, herbs, spices, stems, flowers, tea, and red wine [36, 37]. It has also shown a variety of pharmacological properties of interest in the therapy of several diseases including inflammation by inhibiting bacterial colonization, cancer, or vascular ailments [38, 39]. The summary of plants containing pinocembrin, parts used, and biological/pharmacological activities is shown in Table 1. As shown in Figure 1, accumulated data indicate that pinocembrin was isolated from many plant species such as Alpinia mutica [40, 41], Litchi chinensis [42], Lippia graveolens [43], Lippia origanoides [44, 45], Dalea elegans [46], Oxytropis falcate [47, 48], Glycyrrhiza glabra L. [49, 50], Sparattosperma leucanthum [51], Cleome droserifolia [52], Lychnophora markgravii [53], Helichrysum gymnocomum [54], Syzygium samarangense [55], Centaurea eryngioides [56], Cistus incanus [27], Turnera diffusa [57], and Eriodictyon californicum [58].

Table 1: Plants containing pinocembrin with their mode of actions.

Plants name
Part used/extract
Functions
References

Botanical name
Common name

Alpinia mutica
Orchid ginger
Air-dried Rhizome
Antiplatelet, antioxidant
[40, 41]

Alpinia katsumadai
Katsumadai
Seeds
Antibacterial, antiinflammatory
[96–99]

Alpinia pricei
Prospero Alpini
Roots
Antiinflammatory
[100, 101]

Alpinia galangal
Siamese ginger
Roots
Anticancer
[24]

Alpinia rafflesiana
Raffles' alpinia
Ripe fruits
DPPH free radical scavenger
[102]

Boesenbergia pandurata
Ginger
Fingerroot Rhizome
Antiinflammatory, antioxidant
[25, 85, 103, 104]

Centaurea eryngioides
Centory
—
Antitumor
[56]

Cleome droserifolia
Black thorn/egy
Aerial parts
Antirheumatic

Antifever and antiinflammation
[52]

Combretum collinum
Combretum
Pulverized leaves
Antimicrobial, antimalarial
[105]

Cryptocarya chinensis
—
Air-dried Leaves
Antituberculosis
[106]

Cryptocarya konishii
Brown Laurel
Woods
Antibacterial, anticancer
[107]

Cystus incanus
—
—
Antioxidant/antiestrogenic
[27]

Dalea elegans
Prairie clover/indigo bush
Roots
Antibacterial
[46]

Dysphania graveolens
Fetid goosefoot
—
Antimicrobial, larvicidal, hepatoprotective, antihyperlipidaemic
[108]

Eriodictyon californicum
Yerba santa
Leaves
Chemopreventive agents
[58]

Euphorbia hirta Linn
Asthma herb
Aerial part
Antitumour, antifilarial
[109]

Glycyrrhiza glabra L.
Liquorice
Aerial parts
Cognitive functions, cholinesterase activity
[49, 50]

Helichrysum gymnocomum
—
Flowers
Antimicrobial
[54]

Lippia graveolens
Oregano

Antigiardial
[43]

Lippia origanoides
Wild marjoram
Flowers, leaves, stems
Antimicrobial
[44, 45]

Litchi chinensis
Lychee
Seeds

[42]

Lychnophora markgravii
—
Aerial parts
Antileishmania
[53]

Oxytropis falcate
—
Whole plants
Antipain, antiarthritis
[47, 48]

Piper chimonantifolium
—
Leaves
Antifungal
[62, 110]

Piper lanceaefolium
—
Leaves
Antibacterial
[30, 62]

Piper sarmentosum
—
Aerial parts
Antifeedant, anticarcinogenic
[111]

Sparattosperma leucanthum
—
Leaves
—
[51]

Syzygium samarangense
Champoo
Pulp, seeds of the fruits
Antioxidants
[55]

Turnera diffusa
Damiana
Leaves
Antiaromatase
[57]

Figure 1: Chemical structure and natural sources of pinocembrin.

Apart from natural sources, it has been noted that pinocembrin can be biosynthesized. The strategy to produce pinocembrin, a flavanone, by microorganisms was to design and express an artificial phenylpropanoid pathway. This was accomplished by assembling of phenylalanine ammonia-lyase (PAL) from the yeast Rhodotorula rubra; 4-coumarate: CoA ligase (4CL) from the actinomycete S. coelicolor; chalcone synthase (CHS) from the licorice plant Glycyrrhiza echinata; and chalcone isomerase (CHI) from the plant Pueraria lobata on a single pET plasmid in E. coli [37–39, 59–61].

3. Biological Activity of Pinocembrin and Mechanisms of Action

The biological activity of natural compounds is generally investigated with emphasis on the mechanisms of actions. Several studies have been conducted in vitro and in vivo to determine the biological properties ascribed to pinocembrin and to elucidate its mechanisms of actions. In this case, some researchers pointed out the effect of functional groups on the biological activity of certain molecules to evaluate the effect of hydroxyl group on biological activity of pinocembrin and its analogues.

3.1. Antibacterial Activity

For centuries, natural products, including pinocembrin, have been used to treat microbial infections. Drewes and van Vuuren [54] investigated the antibacterial effect of pinocembrin with three kinds of Gram-negative bacteria (E. coli, P. aeruginosa, and K. pneumoniae) and three kinds of Gram-positive bacteria (B. subtilis, S. aureus, and S. lentus) by measuring the minimal inhibitory concentrations in microgram of DMSO extract (mg of extract/mL) determined by an adjustment of the agar streak dilution method based on radial diffusion. Another investigation was conducted to evaluate the effect of pinocembrin by the metabolic engineering technique for the production in bacteria under cultural conditions which were E. coli at a cell density of 50 g/L, incubated in the presence of 3 μM tyrosine or phenylalanine; the yields of pinocembrin reached about 60 mg/L. Phenylalanine ammonia lyase (PAL) from the yeast Rhodotorula rubra, 4-coumarate: CoA ligase (4CL) from an actinomycete Streptomyces coelicolor, and chalcone synthase (CHS) from a licorice plant Glycyrrhiza echinata, taken individually are each an active ingredient for fermentation production of flavanones; such as pinocembrin in Escherichia coli via different pathway including phenylpropanoid pathway. In the construction of set, they are placed in order under the control of pT7 promoter and the ribosome binding sequence (RBS) in the pET vector. These pathways bypassed cinnamate-4-hydroxylase (C4H), a cytochrome P-450 hydroxylase, because the bacterial 4CL enzyme legated coenzyme A to both cinnamic acid and 4-coumaric acid. E. coli cells containing the gene clusters produced two flavanones. The fermentative production of flavanones in E. coli is the sine qua non provided in the construction of a library of unnatural flavonoids in bacteria [37, 60, 61].

The mechanisms of actions of pinocembrin were studied to evaluate its effect on the bacterial membranes of Neisseria gonorrhoeae, E. coli, P. aeruginosa, B. subtilis, S. aureus, S. lentus, and K. pneumoniae by observing changes in membrane composition and monitoring the metabolic engineering technique, which revealed that pinocembrin induced cell lysis through a metabolic engineering technique [37, 60–62].

3.2. Anti-Inflammatory Activity

Although the type of inflammatory responses may differ among diseases, inflammation and disease conditions are linked through the production of inflammatory mediators by macrophages and neutrophils. Overexpression activity of the enzyme cyclooxygenases- (COX-) 1 and COX-2 produces inflammatory mediators such as prostaglandin E 2 (PGE 2). Anti-inflammatory drugs together with nonsteroidal anti-inflammatory drugs (NSAIDs) suppress the inflammatory response by inhibiting infiltration and activation of inflammatory cells as well as their synthesis or, secondly, release of mediators or effects of inflammatory mediators themselves [63].

The anti-inflammatory activity of pinocembrin against sheep red blood cell-induced mouse paw oedema as a model of delayed-type hypersensitivity reaction in vitro and in the mouse model of LPS-induced acute lung injury inhibited significantly enzymatic and nonenzymatic lipid peroxidation (IC₅₀ = 12.6 and 28 μM, resp.) [28]. Pulmonary edema, histological severities, and neutrophil, lymphocyte, and macrophage infiltration increased by LPS administration; this would mean that pinocembrin exhibited anti-inflammatory activity in the sheep red blood cell-induced delayed-type hypersensitivity reaction. Although it downregulated TNF-α, IL-1β, and IL-6 and significantly suppressed IκBα, JNK, and p38MAPK with (20 or 50 mg/kg, i.p.) in LPS-induced lung injury, having regard to the foregoing, pinocembrin is a natural compound recommended for the modulation of inflammatory responses [28, 29, 64].

3.3. Antimicrobial Activity

Flavonoid compounds in general and in particular pinocembrin are well-known plant compounds that have antimicrobial and anti-inflammatory properties [65]. Scientists and clinicians have demonstrated in vitro and in vivo the biological or pharmacological properties of pinocembrin and have elucidated mechanisms of action [23]. In this momentum, production of glucosyltransferase from microorganisms according to the results obtained on Staphylococcus aureus; Escherichia coli, Candida albicans, Bacillus subtilis, Candida albicans, Trichophyton mentagrophytes, Streptococcus mutans, Neisseria gonorrhoeae, treatment with pinocembrin at daily doses of 100 mg/kg body weight the animals as well as the controls died between the 6th and 24th day after beginning. The possible mechanisms of the antimicrobial action of pinocembrin demonstrated the highest inhibition of the enzyme activity, and growth of the bacteria indicates that pinocembrin inhibited 100% of the Neisseria gonorrhoeae panel at 64 g/mL and 128 g/mL, respectively, whereas cyclolanceaefolic acid methyl ester inhibited 44% of the strains at 128 g/mL [22, 66–68].

3.4. Anticancer Activity

Due to the toxic effects of synthetic drugs, accumulated data indicate that prevailing treatment options have limited therapeutic success in human cancers; therefore, there is considerable emphasis on identifying novel natural products that selectively induce apoptosis and growth arrest in cancer cells without cytotoxic effects in normal cells [69]. Apoptosis is defined as an extremely synchronized mode of cell death and is characterized by distinct morphological features, including cell membrane blabbing, chromatin condensation, and nuclear fragmentation [70, 71]. The normal cell regulation and during disease conditions the importance of signaling has been recognized, [72, 73] and many well-known targets at the signaling levels have been identified that are critical rapid proliferate of cancer cells. It is believed that in normal cells, certain cellular signals control and regulate their growth and all growth mechanisms, and when these signals are altered due to various mutations that prevent cells to undergo apoptosis, normal cells are transformed into cancerous cells and undergo hyperproliferation. Therefore, to arrest cancerous cell proliferation, regulation of apoptosis plays a critical role [74–76]. Accumulated data suggest that various anticancer chemopreventive agents can induce apoptosis which causes death in cancerous cells [77–84]. Although several studies revealed that pinocembrin can inhibit, delay, block, or reverse the initiation; promotional events associated with carcinogenesis are needed for the prevention and/or treatment of cancer. Here, we reviewed studies related to anticancer activity of pinocembrin to allow scientists and researchers to have a clearer view of this natural compound.

Based on the research anterior made, pinocembrin has shown cytotoxicity against certain cancer cell lines such as colon cancer cell line (HCT116), with relatively less toxicity toward human umbilical cord endothelial cells [24]. In colon cancer cell line (HCT116), pinocembrin increased increased the activity of heme oxygenase, caspase-3 and -9, and mitochondrial membrane potential (MMP) but did not affect the activities of cytochrome P450 reductase, quinone reductase, UDP glucuronosyltransferase, and glutathione-S-transferase [24, 25]. Although some in vivo and in vitro studies reveal that pinocembrin can promote the differentiation of EPCs and improve the biological functions in rat liver micronucleus and medium-term carcinogenicity; interestingly, pinocembrin slightly increased the number of GST-P positive foci, PI3 K-eNOS-NO signaling pathway when given prior to diethyl-nitrosamine injection, and adhesion of EPCs. The effect of pinocembrin may help to protect against chemical-induced hepatocarcinogenesis and suggest that the promoting effect of this compound might be due to lipid peroxidation [85]. The details of all the information regarding the molecular targets of pinocembrin in different cancer types are recorded in Table 2.

Table 2: Molecular targets of pinocembrin in different cancer types.

Cancer types
Cell lines
IC₅₀/concentration
Major targets
References

Colon
HCT-116, HT-29
26.33 to 143.09 µg mL⁻¹ 

1.6 to 13.6 μM
Superoxide anion radical↓, Bax↑, NO↓, ΔΨm↓
[24, 111, 112]

Leukaemia
HL-60
IC₅₀ < 100 ng/mL
Fas↑, FasL↑, caspase-3/8/9↑, tBid↑
[100, 113]

↓: downregulation; ↑: upregulation.

3.5. Antifungal Activity

Microbial infections especially fungal are a common public health problem ranging from superficial to deep infections. The superficial mycoses sometimes reach high endemic levels, especially in tropical areas. The treatment of fungal infections or mycoses is becoming more and more problematic due to the development of antimicrobial resistance to some kind of drugs. It is for that reason the natural products have been used to treat these infections and to demonstrate the ability to inhibit the growth of various pathogens agents. The antimicrobial activity against P. italicum and Candida albicans, with a minimal inhibitory concentration value of 100 microg/mL, shows that pinocembrin exhibited antifungal activity and inhibited the mycelial growth of P. italicum by interfering energy homeostasis and cell membrane damage of the pathogen [30, 31].

3.6. Neuroprotective Activity

The diverse array of bioactive nutrients present in the natural products plays a pivotal role in prevention and cure of various neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, and other neuronal dysfunctions [86]. Cerebral ischemic injury is a debilitating disease that can occur with great morbidity, during asphyxiation, shock, brain injury, extracorporeal circulation, and cardiac arrest [87, 88]. The neuroprotective effects of naturally occurring compound, pinocembrin, are being evaluated in this review. Previous studies demonstrated that pinocembrin can be used as neuroprotective against cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antiexcitotoxic effects [89] and decreased glutamate-induced SH-SY5Y cell injury and primary cultured cortical neuron damage in oxygen-glucose deprivation/reoxygenation (OGD/R). Pinocembrin alleviates cerebral ischemic injury in the middle cerebral artery occlusion rats [90–92] and also enhanced cognition by protecting cerebral mitochondria structure and function against chronic cerebral hypoperfusion in rats [93]. In another attempt to understand the mechanism of action of pinocembrin, it increased ADP/O, glutathione, state 3 respiration state, neuronal survival rates, and oxidative phosphorylation rate in NADH/FADH2 and decreased LDH release, reactive oxygen species, nitric oxide, neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and 4 respiration state (V4) in NADH. Moreover, pinocembrin enhanced ATP content in brain mitochondria in SH-SY5Y cells; DNA laddering and caspase-3 are downregulated and increased PARP degradation [89, 94] and resulted in the alleviation of brain injury in the global cerebral ischemia/reperfusion (GCI/R) rats [94]. Furthermore, pinocembrin decreased neurological score and reduced brain edema induced by GCI/R. Pinocembrin also lessened the concentrations of Evan’s blue (EB) and fluorescein sodium (NaF) in brain tissue of the GCI/R rats and alleviated the ultrastructural changes of cerebral microvessels, astrocyte end-feet, and neurons and improved cerebral blood flow (CBF) in the GCI/R rats. In addition, pinocembrin increased the viability and mitochondrial membrane potential of cultured rat cerebral microvascular endothelial cells (RCMECs) induced by oxygen-glucose deprivation/reoxygenation (OGD/R) [95]. Therefore, pinocembrin may be a novel therapeutic strategy to reduce cerebral ischemia [89, 94].

4. Conclusions and Future Perspectives

This review suggests that pinocembrin is a good pharmacological drug with potential antioxidative, anti-inflammatory, antitumor, and antimicrobial properties. Several research results demonstrated the potential applications of pinocembrin both in vitro and in vivo. Pinocembrin is a natural product with a small molecular weight and is a biologically active constituent of honey, an edible nutrient, which ensures safety of pinocembrin during long-term administration, combined with its cost and future therapeutic potential, making it an ideal therapeutic agent. Pinocembrin analogues with improved pharmacokinetic and pharmacodynamics may also encourage further advances. Many studies have shown that pinocembrin induces apoptosis of many types of cancer cells, but mechanisms of actions have not been fully elucidated. This review suggests that pinocembrin may establish direct medicinal application as a pharmaceutical agent or may serve as chemical templates for the design, synthesis, and semisynthesis of new substances for the treatment of human diseases. Additional studies and clinical trials are required to determine its specific intracellular sites of action and derivative targets in order to fully understand the mechanisms of its anti-inflammatory, anticancer, and apoptotic effects to further validate this compound in medical applications and to make clear the potential role of pinocembrin as a medicinal agent in the prevention and treatment of various diseases.

Acknowledgments

This work was supported by Ministry of Science and Technology (no. 2010DFA31430), Ministry of Education of China (NCET-10-0316; 10SSXT147), Jilin Provincial Science & Technology Department (20130521010JH, YYZX201241, 20070719, and 200905116), Changchun Science & Technology Department (no. 2011114-11GH29) and National Natural Science Foundation of China (no. 30871301).

References

A. Gurib-Fakim, “Medicinal plants: traditions of yesterday and drugs of tomorrow,” Molecular Aspects of Medicine, vol. 27, no. 1, pp. 1–93, 2006.

D. J. Newman, G. M. Cragg, and K. M. Snader, “The influence of natural products upon drug discovery,” Natural Product Reports, vol. 17, no. 3, pp. 215–234, 2000.

A. L. Harvey, “Natural products in drug discovery,” Drug Discovery Today, vol. 13, no. 19-20, pp. 894–901, 2008.

D. J. Newman, G. M. Cragg, and K. M. Snader, “Natural products as sources of new drugs over the period 1981–2002,” Journal of Natural Products, vol. 66, no. 7, pp. 1022–1037, 2003.

M. J. Balunas and A. D. Kinghorn, “Drug discovery from medicinal plants,” Life Sciences, vol. 78, no. 5, pp. 431–441, 2005.

Y.-W. Chin, M. J. Balunas, H. B. Chai, and A. D. Kinghorn, “Drug discovery from natural sources,” AAPS Journal, vol. 8, no. 2, article 28, pp. E239–E253, 2006.

F. E. Koehn and G. T. Carter, “The evolving role of natural products in drug discovery,” Nature Reviews Drug Discovery, vol. 4, no. 3, pp. 206–220, 2005.

D. J. Newman and G. M. Cragg, “Natural products as sources of new drugs over the last 25 years,” Journal of Natural Products, vol. 70, no. 3, pp. 461–477, 2007.

I. Paterson and E. A. Anderson, “The renaissance of natural products as drug candidates,” Science, vol. 310, no. 5747, pp. 451–453, 2005.

M. S. Butler, “Natural products to drugs: natural product derived compounds in clinical trials,” Natural Product Reports, vol. 22, no. 2, pp. 162–195, 2005.

N. R. Farnsworth, O. Akerele, and A. S. Bingel, “Medicinal plants in therapy,” Bulletin of the World Health Organization, vol. 63, no. 6, pp. 965–981, 1985.

N. F. Balandrin, A. D. Kinghorn, and N. R. Farnsworth, “Plant-derived natural products in drug discovery and development: an overview,” in Human Medicinal Agents from Plants, A. D. Kinghorn and M. F. Balandrin, Eds., vol. 534 of ACS Symposium Series, pp. 2–12, 1993.

R. Arvigo and M. Balick, Rainforest Remedies, Lotus Press, Twin Lakes, Colo, USA, 1993.

F. Grifo, D. J. Newman, A. S. Fairfield, B. Bhattacharya, and J. T. Grupenhoff, The Origin of Prescription Drugs, F. Grifo, and J. Rosenthal, Eds., Island Press, Washington, DC, USA, 1997.

B. Patwardhan, “Ethnopharmacology and drug discovery,” Journal of Ethnopharmacology, vol. 100, no. 1-2, pp. 50–52, 2005.

D.-X. Kong, X.-J. Li, and H.-Y. Zhang, “Where is the hope for drug discovery? Let history tell the future,” Drug Discovery Today, vol. 14, no. 3-4, pp. 115–119, 2009.

X. Su, L. Kong, X. Lei, L. Hu, M. Ye, and H. Zou, “Biological fingerprinting analysis of traditional Chinese medicines with targeting ADME/Tox property for screening of bioactive compounds by chromatographic and MS methods,” Mini-Reviews in Medicinal Chemistry, vol. 7, no. 1, pp. 87–98, 2007.

T. Y. K. Chan, J. C. N. Chan, B. Tomlinson, and J. A. J. H. Critchley, “Chinese herbal medicines revisited: a Hong Kong perspective,” Lancet, vol. 342, no. 8886-8887, pp. 1532–1534, 1993.

T.-H. Tsai, “Analytical approaches for traditional Chinese medicines exhibiting antineoplastic activity,” Journal of Chromatography B, vol. 764, no. 1-2, pp. 27–48, 2001.

M. B. Sporn and D. L. Newton, “Chemoprevention of cancer with retinoids,” Federation Proceedings, vol. 38, no. 11, pp. 2528–2534, 1979.

L. Chen, “Polyphenols from leaves of Euphorbia hirta L,” Journal of Chinese Medicinal Materials, vol. 16, no. 1, pp. 38–64, 1991.

A. G. Hegazi, F. K. Abd El Hady, and F. A. M. Abd Allah, “Chemical composition and antimicrobial activity of European propolis,” Zeitschrift für Naturforschung C, vol. 55, no. 1-2, pp. 70–75, 2000.

J.-P. Rauha, S. Remes, M. Heinonen et al., “Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds,” International Journal of Food Microbiology, vol. 56, no. 1, pp. 3–12, 2000.

M. A. S. Kumar, M. Nair, P. S. Hema, J. Mohan, and T. R. Santhoshkumar, “Pinocembrin triggers Bax-dependent mitochondrial apoptosis in colon cancer cells,” Molecular Carcinogenesis, vol. 46, no. 3, pp. 231–241, 2007.

C. Punvittayagul, R. Wongpoomchai, S. Taya, and W. Pompimon, “Effect of pinocembrin isolated from Boesenbergia pandurata on xenobiotic-metabolizing enzymes in rat liver,” Drug Metabolism Letters, vol. 5, no. 1, pp. 1–5, 2011.

L. Estevinho, A. P. Pereira, L. Moreira, L. G. Dias, and E. Pereira, “Antioxidant and antimicrobial effects of phenolic compounds extracts of Northeast Portugal honey,” Food and Chemical Toxicology, vol. 46, no. 12, pp. 3774–3779, 2008.

A. Šarić, T. Balog, S. Sobočanec et al., “Antioxidant effects of flavonoid from Croatian Cystus incanus L. rich bee pollen,” Food and Chemical Toxicology, vol. 47, no. 3, pp. 547–554, 2009.

A. Sala, M. C. Recio, G. R. Schinella et al., “Assessment of the anti-inflammatory activity and free radical scavenger activity of tiliroside,” European Journal of Pharmacology, vol. 461, no. 1, pp. 53–61, 2003.

L. W. Soromou, X. Chu, L. Jiang et al., “In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses,” International Immunopharmacology, vol. 14, no. 1, pp. 66–74, 2012.

A. López, S. M. Dong, and G. H. N. Towers, “Antifungal activity of benzoic acid derivatives from Piper lanceaefolium,” Journal of Natural Products, vol. 65, no. 1, pp. 62–64, 2002.

J. A. Ramirez, A. G. McIntosh, R. Strehlow, V. A. Lawrence, D. J. Parekh, and R. S. Svatek, “Definition, incidence, risk factors, and prevention of paralytic ileus following radical cystectomy: a systematic review,” European Urology, 2012.

R. Feng, Z. K. Guo, C. M. Yan, E. G. Li, R. X. Tan, and H. M. Ge, “Anti-inflammatory flavonoids from Cryptocarya chingii,” Phytochemistry, vol. 76, pp. 98–105, 2012.

A. P. Danelutte, J. H. G. Lago, M. C. M. Young, and M. J. Kato, “Antifungal flavanones and prenylated hydroquinones from Piper crassinervium Kunth,” Phytochemistry, vol. 64, no. 2, pp. 555–559, 2003.

G. N. Diaz Napal, M. C. Carpinella, and S. M. Palacios, “Antifeedant activity of ethanolic extract from Flourensia oolepis and isolation of pinocembrin as its active principle compound,” Bioresource Technology, vol. 100, no. 14, pp. 3669–3673, 2009.

M. Mandal and S. K. Jaganathan, “Antiproliferative effects of honey and of its polyphenols: a review,” Journal of Biomedicine and Biotechnology, vol. 2009, Article ID 830616, 13 pages, 2009.

H. Jiang and J. A. Morgan, “Optimization of an in vivo plant P450 monooxygenase system in Saccharomyces cerevisiae,” Biotechnology and Bioengineering, vol. 85, no. 2, pp. 130–137, 2004.

I. Miyahisa, N. Funa, Y. Ohnishi, S. Martens, T. Moriguchi, and S. Horinouchi, “Combinatorial biosynthesis of flavones and flavonols in Escherichia coli,” Applied Microbiology and Biotechnology, vol. 71, no. 1, pp. 53–58, 2006.

J. A. Manthey, N. Guthrie, and K. Grohmann, “Biological properties of citrus flavonoids pertaining to cancer and inflammation,” Current Medicinal Chemistry, vol. 8, no. 2, pp. 135–153, 2001.

Y. S. Touil, A. Fellous, D. Scherman, and G. G. Chabot, “Flavonoid-induced morphological modifications of endothelial cells through microtubule stabilization,” Nutrition and Cancer, vol. 61, no. 3, pp. 310–321, 2009.

I. Jantan, S. M. Raweh, H. M. Sirat et al., “Inhibitory effect of compounds from Zingiberaceae species on human platelet aggregation,” Phytomedicine, vol. 15, no. 4, pp. 306–309, 2008.

N. A. Mustahil, M. A. Sukari, A. B. Abdul, N. A. Ali, and G. E. Lian, “Evaluation of biological activities of Alpinia mutica Roxb. and its chemical constituents,” Pakistan Journal of Pharmaceutical Sciences, vol. 26, no. 2, pp. 391–395, 2013.

X. Xu, H. Xie, J. Hao, Y. Jiang, and X. Wei, “Flavonoid glycosides from the seeds of litchi chinensis,” Journal of Agricultural and Food Chemistry, vol. 59, no. 4, pp. 1205–1209, 2011.

Y. Rufino-González, M. Ponce-Macotela, A. GonzÁlez-Maciel et al., “In vitro activity of the F-6 fraction of oregano against Giardia intestinalis,” Parasitology, vol. 139, no. 4, pp. 434–440, 2012.

E. E. Stashenko, J. R. Martínez, C. A. Ruíz et al., “Lippia origanoides chemotype differentiation based on essential oil GC-MS and principal component analysis,” Journal of Separation Science, vol. 33, no. 1, pp. 93–103, 2010.

D. R. Oliveira, G. G. Leitão, S. S. Santos et al., “Ethnopharmacological study of two Lippia species from Oriximiná, Brazil,” Journal of Ethnopharmacology, vol. 108, no. 1, pp. 103–108, 2006.

M. A. Peralta, M. Calise, M. C. Fornari et al., “A prenylated flavanone from Dalea elegans inhibits rhodamine 6 G efflux and reverses fluconazole-resistance in Candida albicans,” Planta Medica, vol. 78, no. 10, pp. 981–987, 2012.

S.-Y. Yao, Y.-B. Ma, Y. Tang, J.-J. Chen, and X.-M. Zhang, “Chemical constituents of Oxytropis falcate,” Zhongguo Zhongyao Zazhi, vol. 33, no. 12, pp. 1418–1421, 2008.

W.-H. Chen, R. Wang, and Y.-P. Shi, “Flavonoids in the poisonous plant Oxytropis falcata,” Journal of Natural Products, vol. 73, no. 8, pp. 1398–1403, 2010.

M. P. Yuldashev, E. K. Batirov, A. D. Vdovin, and N. D. Abdullaev, “Structural study of glabrisoflavone, a novel isoflavone from Glycyrrhiza glabra L,” Bioorganicheskaya Khimiya, vol. 26, no. 11, pp. 873–876, 2000.

Y.-M. Cui, M.-Z. Ao, W. Li, and L.-J. Yu, “Effect of glabridin from Glycyrrhiza glabra on learning and memory in mice,” Planta Medica, vol. 74, no. 4, pp. 377–380, 2008.

F. D. N. Costa and G. G. Leitão, “Evaluation of different solvent systems for the isolation of sparattosperma leucanthum flavonoids by counter-current chromatography,” Journal of Chromatography A, vol. 1218, no. 36, pp. 6200–6205, 2011.

M. I. Aboushoer, H. M. Fathy, M. S. Abdel-Kader, G. Goetz, and A. A. Omar, “Terpenes and flavonoids from an Egyptian collection of Cleome droserifolia,” Natural Product Research, vol. 24, no. 7, pp. 687–696, 2010.

M. J. Salvador, F. T. Sartori, A. C. B. C. Sacilotto, E. M. F. Pral, S. C. Alfieri, and W. Vichnewski, “Bioactivity of flavonoids isolated from Lychnophora markgravii against Leishmania amazonensis amastigotes,” Zeitschrift fur Naturforschung C, vol. 64, no. 7-8, pp. 509–512, 2009.

S. E. Drewes and S. F. van Vuuren, “Antimicrobial acylphloroglucinols and dibenzyloxy flavonoids from flowers of Helichrysum gymnocomum,” Phytochemistry, vol. 69, no. 8, pp. 1745–1749, 2008.

M. J. Simirgiotis, S. Adachi, S. To et al., “Cytotoxic chalcones and antioxidants from the fruits of Syzygium samarangense (Wax Jambu),” Food Chemistry, vol. 107, no. 2, pp. 813–819, 2008.

E. Harlev, E. Nevo, E. P. Lansky, S. Lansky, and A. Bishayee, “Anticancer attributes of desert plants: a review,” Anti-Cancer Drugs, vol. 23, no. 3, pp. 255–271, 2012.

J. Zhao, A. K. Dasmahapatra, S. I. Khan, and I. A. Khan, “Anti-aromatase activity of the constituents from damiana (Turnera diffusa),” Journal of Ethnopharmacology, vol. 120, no. 3, pp. 387–393, 2008.

Y.-L. Liu, D. K. Ho, J. M. Cassady, V. M. Cook, and W. M. Baird, “Isolation of potential cancer chemopreventive agents from Eriodictyon californicum,” Journal of Natural Products, vol. 55, no. 3, pp. 357–363, 1992.

S. Horinouchi, “Combinatorial biosynthesis of non-bacterial and unnatural flavonoids, stilbenoids and curcuminoids by microorganisms,” Journal of Antibiotics, vol. 61, no. 12, pp. 709–728, 2008.

E. I. Hwang, M. Kaneko, Y. Ohnishi, and S. Horinouchi, “Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster,” Applied and Environmental Microbiology, vol. 69, no. 5, pp. 2699–2706, 2003.

I. Miyahisa, M. Kaneko, N. Funa et al., “Efficient production of (2S)-flavanones by Escherichia coli containing an artificial biosynthetic gene cluster,” Applied Microbiology and Biotechnology, vol. 68, no. 4, pp. 498–504, 2005.

P. S. Ruddock, M. Charland, S. Ramirez et al., “Antimicrobial activity of flavonoids from Piper lanceaefolium and other Colombian medicinal plants against antibiotic susceptible and resistant strains of Neisseria gonorrhoeae,” Sexually Transmitted Diseases, vol. 38, no. 2, pp. 82–88, 2011.

M. K. Urban, “COX-2 specific inhibitors offer improved advantages over traditional NSAIDs,” Orthopedics, vol. 23, no. 7, pp. s761–s764, 2000.

L. W. Soromou, L. Jiang, M. Wei et al., “Protection of mice against lipopolysaccharide-induced endotoxic shock by pinocembrin is correlated with regulation of cytokine secretion,” Journal of Immunotoxicology, 2013.

S. Arslan, H. Ozbilge, E. G. Kaya, and O. Er, “In vitro antimicrobial activity of propolis, BioPure MTAD, sodium hypochlorite, and chlorhexidine on Enterococcus faecalis and Candida albicans,” Saudi Medical Journal, vol. 32, no. 5, pp. 479–483, 2011.

J. Metzner, H. Bekemeier, E. M. Schneidewind, and U. Wenzel, “Pharmacokinetic studies of the propolis constituent pinocembrin in the rat,” Pharmazie, vol. 34, no. 3, pp. 185–187, 1979.

J. Metzner and E. M. Schneidewind, “Studies on the question of potentiating effects of propolis constituents,” Pharmazie, vol. 33, no. 7, p. 465, 1978.

Y. K. Park, M. H. Koo, J. A. S. Abreu, M. Ikegaki, J. A. Cury, and P. L. Rosalen, “Antimicrobial activity of propolis on oral microorganisms,” Current Microbiology, vol. 36, no. 1, pp. 24–28, 1998.

A. S. Tsao, E. S. Kim, and W. K. Hong, “Chemoprevention of cancer,” Ca-A Cancer Journal for Clinicians, vol. 54, no. 3, pp. 150–180, 2004.

S. Elmore, “Apoptosis: a review of programmed cell death,” Toxicologic Pathology, vol. 35, no. 4, pp. 495–516, 2007.

M. O. Hengartner, “The biochemistry of apoptosis,” Nature, vol. 407, no. 6805, pp. 770–776, 2000.

G. I. Evan and K. H. Vousden, “Proliferation, cell cycle and apoptosis in cancer,” Nature, vol. 411, no. 6835, pp. 342–348, 2001.

D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.

S. Fulda, “Evasion of apoptosis as a cellular stress response in cancer,” International Journal of Cell Biology, vol. 2010, Article ID 370835, 6 pages, 2010.

A. Lawen, “Apoptosis—an introduction,” BioEssays, vol. 25, no. 9, pp. 888–896, 2003.

J. C. Reed, “Apoptosis-based therapies,” Nature Reviews Drug Discovery, vol. 1, no. 2, pp. 111–121, 2002.

A. Rasul, R. Bao, M. Malhi et al., “Induction of apoptosis by costunolide in bladder cancer cells is mediated through ros generation and mitochondrial dysfunction,” Molecules, vol. 18, no. 2, pp. 1418–1433, 2013.

A. Rasul, C. Ding, X. Li et al., “Dracorhodin perchlorate inhibits PI3K/Akt and NF-kappaB activation, up-regulates the expression of p53, and enhances apoptosis,” Apoptosis, vol. 17, no. 10, pp. 1104–1119, 2012.

A. Rasul, M. Khan, B. Yu, T. Ma, and H. Yang, “Xanthoxyletin, a coumarin induces S phase arrest and apoptosis in human gastric adenocarcinoma SGC-7901 cells,” Asian Pacific Journal of Cancer Prevention, vol. 12, no. 5, pp. 1219–1223, 2011.

A. Rasul, R. Song, W. Wei et al., “Tubeimoside-1 inhibits growth via the induction of cell cycle arrest and apoptosis in human melanoma A375 cells,” Bangladesh Journal of Pharmacology, vol. 7, pp. 150–156, 2012.

A. Rasul, B. Yu, M. Khan et al., “Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways,” International Journal of Oncology, vol. 40, no. 4, pp. 1153–1161, 2012.

A. Rasul, B. Yu, L.-F. Yang et al., “Induction of mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells by kuraridin and nor-kurarinone isolated from sophora flavescens,” Asian Pacific Journal of Cancer Prevention, vol. 12, no. 10, pp. 2499–2504, 2011.

A. Rasul, B. Yu, L. Zhong, M. Khan, H. Yang, and T. Ma, “Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy,” Oncology Reports, vol. 27, no. 5, pp. 1481–1487, 2012.

Y. Shi, Y. L. Bao, Y. Wu et al., “Alantolactone inhibits cell proliferation by interrupting the interaction between Cripto-1 and activin receptor type II A in activin signaling pathway,” Journal of Biomolecular Screening, vol. 16, no. 5, pp. 525–535, 2011.

C. Punvittayagul, W. Pompimon, H. Wanibuchi, S. Fukushima, and R. Wongpoomchai, “Effects of pinocembrin on the initiation and promotion stages of rat hepatocarcinogenesis,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 5, pp. 2257–2261, 2012.

M. M. Essa, R. K. Vijayan, G. Castellano-Gonzalez, M. A. Memon, N. Braidy, and G. J. Guillemin, “Neuroprotective effect of natural products against Alzheimer's disease,” Neurochemical Research, vol. 37, no. 9, pp. 1829–1842, 2012.

J. Almaliti, S. E. Nada, B. Carter, Z. A. Shah, and L. M. Tillekeratne, “Natural products inspired synthesis of neuroprotective agents against H₂O₂-induced cell death,” Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 5, pp. 1232–1237, 2013.

M. Weigl, G. Tenze, B. Steinlechner et al., “A systematic review of currently available pharmacological neuroprotective agents as a sole intervention before anticipated or induced cardiac arrest,” Resuscitation, vol. 65, no. 1, pp. 21–39, 2005.

L.-L. Shi, G.-F. Qiang, M. Gao et al., “Effect of pinocembrin on brain mitochondrial respiratory function,” Yaoxue Xuebao, vol. 46, no. 6, pp. 642–649, 2011.

M. Gao, R. Liu, S.-Y. Zhu, and G.-H. Du, “Acute neurovascular unit protective action of pinocembrin against permanent cerebral ischemia in rats,” Journal of Asian Natural Products Research, vol. 10, no. 6, pp. 551–558, 2008.

M. Gao, S.-Y. Zhu, C.-B. Tan, B. Xu, W.-C. Zhang, and G.-H. Du, “Pinocembrin protects the neurovascular unit by reducing inflammation and extracellular proteolysis in MCAO rats,” Journal of Asian Natural Products Research, vol. 12, no. 5, pp. 407–418, 2010.

R. Liu, M. Gao, Z.-H. Yang, and G.-H. Du, “Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro,” Brain Research, vol. 1216, pp. 104–115, 2008.

H.-M. Guang and G.-H. Du, “Protections of pinocembrin on brain mitochondria contribute to cognitive improvement in chronic cerebral hypoperfused rats,” European Journal of Pharmacology, vol. 542, no. 1-3, pp. 77–83, 2006.

L.-L. Shi, B.-N. Chen, M. Gao et al., “The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats,” Life Sciences, vol. 88, no. 11-12, pp. 521–528, 2011.

F. Meng, R. Liu, M. Gao et al., “Pinocembrin attenuates blood-brain barrier injury induced by global cerebral ischemia-reperfusion in rats,” Brain Research, vol. 1391, pp. 93–101, 2011.

B. Gröblacher, O. Kunert, and F. Bucar, “Compounds of Alpinia katsumadai as potential efflux inhibitors in Mycobacterium smegmatis,” Bioorganic and Medicinal Chemistry, vol. 20, no. 8, pp. 2701–2706, 2012.

M.-Y. Lee, C.-S. Seo, J.-A. Lee et al., “Alpinia katsumadai HAYATA seed extract inhibit LPS-induced inflammation by induction of heme oxygenase-1 in RAW264.7 Cells,” Inflammation, vol. 35, no. 2, pp. 746–757, 2011.

J. Tang, N. Li, H. Dai, and K. Wang, “Chemical constituents from seeds of Aplinia katsumadai, inhibition on NF-κB activation and anti-tumor effect,” Zhongguo Zhongyao Zazhi, vol. 35, no. 13, pp. 1710–1714, 2010.

X.-Q. Wang, X.-J. Yang, and J.-S. Li, “Studies on chemical constituents of Alpinia katsumadai,” Journal of Chinese Medicinal Materials, vol. 31, no. 6, pp. 853–855, 2008.

C.-L. Hsu, Y.-S. Yu, and G.-C. Yen, “Anticancer effects of Alpinia pricei Hayata roots,” Journal of Agricultural and Food Chemistry, vol. 58, no. 4, pp. 2201–2208, 2010.

Y. S. Yu, C.-L. Hsu, and Y. Gow-Chin, “Anti-inflammatory Effects of the Roots of Alpinia pricei Hayata and Its Phenolic Compounds,” Journal of Agricultural and Food Chemistry, vol. 57, no. 17, pp. 7673–7680, 2009.

H. Mohamad, F. Abas, D. Permana et al., “DPPH free radical scavenger components from the fruits of Alpinia rafflesiana Wall. ex. Bak. (Zingiberaceae),” Zeitschrift fur Naturforschung C, vol. 59, no. 11-12, pp. 811–815, 2004.

P. Tuchinda, V. Reutrakul, P. Claeson et al., “Anti-inflammatory cyclohexenyl chalcone derivatives in Boesenbergia pandurata,” Phytochemistry, vol. 59, no. 2, pp. 169–173, 2002.

S. Charoensin, C. Punvittayagul, W. Pompimon, U. Mevateeand, and R. Wongpoomchai, “Toxicological and clastogenic evaluation of pinocembrin and pinostrobin isolated from Boesenbergia pandurata in Wistar rats,” Thai Journal of Toxicology, vol. 25, no. 1, pp. 29–40, 2010.

D. R. Katerere, A. I. Gray, R. J. Nash, and R. D. Waigh, “Phytochemical and antimicrobial investigations of stilbenoids and flavonoids isolated from three species of Combretaceae,” Fitoterapia, vol. 83, no. 5, pp. 932–940, 2012.

T.-H. Chou, J.-J. Chen, C.-F. Peng, M.-J. Cheng, and I.-S. Chen, “New flavanones from the leaves of cryptocarya chinensis and their antituberculosis activity,” Chemistry and Biodiversity, vol. 8, no. 11, pp. 2015–2024, 2011.

F. Kurniadewi, L. D. Juliawaty, Y. M. Syah et al., “Phenolic compounds from Cryptocarya konishii: their cytotoxic and tyrosine kinase inhibitory properties,” Journal of Natural Medicines, vol. 64, no. 2, pp. 121–125, 2010.

H. Alvarez-Ospina, I. Rivero Cruz, G. Duarte, R. Bye, and R. Mata, “HPLC determination of the major active flavonoids and GC-MS analysis of volatile components of Dysphania graveolens (Amaranthaceae),” Phytochemical Analysis, vol. 24, no. 3, pp. 248–254, 2012.

Y. Wu, W. Qu, D. Geng, J.-Y. Liang, and Y.-L. Luo, “Phenols and flavonoids from the aerial part of Euphorbia hirta,” Chinese Journal of Natural Medicines, vol. 10, no. 1, pp. 40–42, 2012.

J. H. Lago, A. T. Ito, C. M. Fernandes, M. C. Young, and M. J. Kato, “Secondary metabolites isolated from Piper chimonantifolium and their antifungal activity,” Natural Product Research, vol. 26, no. 8, pp. 770–773, 2012.

L. Pan, S. Matthew, D. D. Lantvit et al., “Bioassay-guided isolation of constituents of Piper sarmentosum using a mitochondrial transmembrane potential assay,” Journal of Natural Products, vol. 74, no. 10, pp. 2193–2199, 2011.

J. B. Zižić, N. L. Vuković, M. B. Jadranin et al., “Chemical composition, cytotoxic and antioxidative activities of ethanolic extracts of propolis on HCT-116 cell line,” Journal of the Science of Food and Agriculture, 2013.

H. M. Salahdeen and B. A. Murtala, “Vasorelaxant effects of aqueous leaf extract of Tridax procumbens on aortic smooth muscle isolated from the rat,” Journal of Smooth Muscle Research, vol. 48, no. 2-3, pp. 37–45, 2012.