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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">New Paradigm Shift for the Green Synthesis of Antibacterial Silver Nanoparticles Utilizing Plant Extracts</title><author><name sortKey="Park, Youmie" sort="Park, Youmie" uniqKey="Park Y" first="Youmie" last="Park">Youmie Park</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25343010</idno><idno type="pmc">4206743</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206743</idno><idno type="RBID">PMC:4206743</idno><idno type="doi">10.5487/TR.2014.30.3.169</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001412</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">New Paradigm Shift for the Green Synthesis of Antibacterial Silver Nanoparticles Utilizing Plant Extracts</title><author><name sortKey="Park, Youmie" sort="Park, Youmie" uniqKey="Park Y" first="Youmie" last="Park">Youmie Park</name></author></analytic><series><title level="j">Toxicological Research</title><idno type="ISSN">1976-8257</idno><idno type="eISSN">2234-2753</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>This review covers general information regarding the green synthesis of antibacterial silver nanoparticles. Owing to their antibacterial properties, silver nanoparticles are widely used in many areas, especially biomedical applications. In green synthesis practices, the chemical reducing agents are eliminated, and biological entities are utilized to convert silver ions to silver nanoparticles. Among the various biological entities, natural plant extracts have emerged as green reducing agents, providing eco-friendly routes for the preparation of silver nanomaterials. The most obvious merits of green synthesis are the increased biocompatibility of the resulting silver nanoparticles and the ease with which the reaction can be carried out. This review summarizes some of the plant extracts that are used to produce antibacterial silver nanoparticles. Additionally, background information regarding the green synthesis and antibacterial activity of silver nanoparticles is provided. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Toxicol Res</journal-id><journal-id journal-id-type="iso-abbrev">Toxicol Res</journal-id><journal-id journal-id-type="publisher-id">ksot</journal-id><journal-title-group><journal-title>Toxicological Research</journal-title></journal-title-group><issn pub-type="ppub">1976-8257</issn><issn pub-type="epub">2234-2753</issn><publisher><publisher-name>The Korean Society Of Toxicology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25343010</article-id><article-id pub-id-type="pmc">4206743</article-id><article-id pub-id-type="publisher-id">toxicr-30-169</article-id><article-id pub-id-type="doi">10.5487/TR.2014.30.3.169</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>New Paradigm Shift for the Green Synthesis of Antibacterial Silver Nanoparticles Utilizing Plant Extracts</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Park</surname><given-names>Youmie</given-names></name></contrib></contrib-group><aff>College of Pharmacy, Inje University, Gimhae, Korea</aff><author-notes><corresp id="cor1">Correspondence to: Youmie Park, College of Pharmacy, Inje University, 197 Inje-ro, Gimhae, Gyeongnam 621-749, Korea E-mail: <email>youmiep@inje.ac.kr</email></corresp></author-notes><pub-date pub-type="ppub"><month>9</month><year>2014</year></pub-date><volume>30</volume><issue>3</issue><fpage>169</fpage><lpage>178</lpage><history><date date-type="received"><day>03</day><month>9</month><year>2014</year></date><date date-type="rev-recd"><day>23</day><month>9</month><year>2014</year></date><date date-type="accepted"><day>25</day><month>9</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014, The Korean Society Of Toxicology</copyright-statement><copyright-year>2014</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>This review covers general information regarding the green synthesis of antibacterial silver nanoparticles. Owing to their antibacterial properties, silver nanoparticles are widely used in many areas, especially biomedical applications. In green synthesis practices, the chemical reducing agents are eliminated, and biological entities are utilized to convert silver ions to silver nanoparticles. Among the various biological entities, natural plant extracts have emerged as green reducing agents, providing eco-friendly routes for the preparation of silver nanomaterials. The most obvious merits of green synthesis are the increased biocompatibility of the resulting silver nanoparticles and the ease with which the reaction can be carried out. This review summarizes some of the plant extracts that are used to produce antibacterial silver nanoparticles. Additionally, background information regarding the green synthesis and antibacterial activity of silver nanoparticles is provided. Finally, the toxicological aspects of silver nanoparticles are briefly mentioned.</p></abstract><kwd-group kwd-group-type="author"><kwd>Plant extracts</kwd><kwd>Green synthesis</kwd><kwd>Silver nanoparticles</kwd><kwd>Antibacterial activity</kwd></kwd-group></article-meta></front><body><sec sec-type="intro"><title>INTRODUCTION</title><p>As an important aspect of nanotechnology, nanoparticles (NPs, less than 100 nm in one dimension) have been developed for a variety of applications, especially in the area of nanomedicine <xref rid="B001" ref-type="bibr">(1)</xref>. NPs possess characteristic properties that differ from those of their bulk counterparts. In the area of nanomedicine, NPs are commonly employed as drug delivery vehicles. Recently, NPs have been employed in therapeutic applications to target specific sites, such as lung tissue, as well as in cancer therapy and vaccinations <xref rid="B001" ref-type="bibr">(1)</xref>. Additionally, the use of NPs continues to increase in microbial applications due to the potential of NPs to circumvent microbial resistance while satisfying the current need for novel antibiotics <xref rid="B002" ref-type="bibr">(2</xref>-<xref rid="B004" ref-type="bibr">4)</xref>. The number of infections and outbreaks associated with multi-drug-resistant (MDR) bacteria has increased, threatening public health. The NPs used to overcome microbial resistance include nitric oxide-releasing NPs, chitosan NPs and metallic NPs <xref rid="B003" ref-type="bibr">(3)</xref>. Among the metallic NPs, the medicinal potentials of gold NPs (AuNPs) and silver NPs (AgNPs) have been extensively discussed elsewhere <xref rid="B005" ref-type="bibr">(5)</xref>. AgNPs possess excellent antibacterial, antiviral and antifungal activities <xref rid="B006" ref-type="bibr">(6)</xref>. Metallic NPs are commonly synthesized by traditional chemical and physical methods <xref rid="B007" ref-type="bibr">(7)</xref>. However, current sustainability issues have led to explorations of eco-friendly synthesis and green synthesis for the production of metallic NPs based on diverse biological entities <xref rid="B007" ref-type="bibr">(7)</xref>. This review is not meant to be inclusive of all plant extracts utilized for the green synthesis of AgNPs. There are extensive reviews that address this area <xref rid="B008" ref-type="bibr">(8</xref>-<xref rid="B012" ref-type="bibr">12)</xref>. Instead, this review focuses on the preparation of antibacterial AgNPs by using plant extracts as reducing agents.</p></sec><sec><title>GREEN SYNTHESIS OF AgNPs</title><p><italic><bold>Advantages and applications.</bold></italic> The chemical synthesis of AgNPs employs chemical reducing agents to convert Ag ions to AgNPs. One of the most widely used chemical reducing agents is sodium borohydride. This process involves the undesired use of hazardous chemicals, and the biocompatibility of the resulting AgNPs is too low for application in biological systems. Relative to this traditional chemical method, methods of green synthesis that use environmentally friendly or eco-friendly compounds as reducing agents are emerging (13-19). The biological entities used for green synthesis include bacteria, fungi, plants, pure compounds from plants, algae, carbohydrates, microorganisms, etc. The process of green synthesis requires the use of water as an environmentally friendly solvent; of note is the fact that water is more biocompatible than organic solvents.</p><p>Green synthesis possesses the following advantages over traditional chemical methods. (1) green synthesis is simple and usually involves a one-pot reaction; (2) it is amenable to scale up; (3) the toxicity-associated hazardous chemicals are eliminated, increasing the biocompatibility of the resulting product with normal tissues for <italic>in vivo</italic> applications; and (4) green biological entities can be used as reducing agents and capping agents, providing AgNPs with enhanced colloidal stability. Colloidal stability is an important factor when making claims regarding the biological activity of AgNPs. (5) Finally, the process is cost-effective. These advantages are not limited to AgNPs. Other metallic NPs can be greensynthesized and have many uses in biomedical and industrial applications. There are extensive reviews elsewhere regarding the applications of green-synthesized metallic NPs <xref rid="B020" ref-type="bibr">(20</xref>,<xref rid="B021" ref-type="bibr">21)</xref>. The applications of metallic NPs include (1) biomedical applications, such as antimicrobial applications, drug delivery vehicles, medical imaging and diagnostics; (2) environmental remediation applications, such as the catalytic degradation of pollutants; and (3) industrial applications, such as energy-related applications and catalysis in organic synthesis <xref rid="B020" ref-type="bibr">(20)</xref>. Borase <italic>et al</italic>. have extensively reviewed AgNPs in a variety of applications, including anticancer, catalysis, biosensor, drug delivery, textiles and cosmetics, antituberculosis, antiviral, insect management and water purification <xref rid="B012" ref-type="bibr">(12)</xref>.</p><p><italic><bold>Procedures and characterization.</bold></italic> We utilized various biological entities, including plant extracts (<italic>Leonurus japonicus</italic>, <italic>Artemisia capillaris</italic>, <italic>Polygala tenuifolia</italic>, and <italic>Caesalpinia sappan</italic>), a pure compound from plants (chlorogenic acid), polysaccharides (chondroitin sulfate and acharan sulfate), an oligosaccharide (sialyllactose) and invertebrate extracts (an African giant snail <italic>Achatina fulica</italic> and an earthworm <italic>Eisenia andrei</italic>), for the green synthesis of AgNPs <xref rid="B022" ref-type="bibr">(22</xref>-<xref rid="B029" ref-type="bibr">29)</xref>. The green synthesis of AgNPs is a simple and facile approach that is carried out by mixing silver nitrate (the Ag ion source) with a biological entity (the reducing agent). A schematic representation of the synthesis process is depicted in <xref ref-type="fig" rid="F0001">Fig. 1</xref>. In our experiment, an external source of energy, for example, oven incubation, is used to facilitate the reaction. The applications that we evaluated were mainly antibacterial (minimum inhibitory concentration, MIC) and <italic>in vivo</italic> wound-healing activities. Remarkably, AgNPs synthesized with the extract of <italic>Leonurus japonicus</italic> exhibited enhanced antibacterial activities (approximately 127-fold increase) against <italic>Pseudomonas aeruginosa</italic>, <italic>Escherichia coli</italic> and <italic>Enterobacter cloacae</italic><xref rid="B022" ref-type="bibr">(22)</xref>. The aerial portion of <italic>Leonurus japonicus</italic> was utilized. In the case of AgNPs synthesized with the root extract of <italic>Polygala tenuifolia</italic>, the strain of <italic>Escherichia coli</italic> DC2 was shown to be the most effective when treated with AgNPs (approximately 16-fold increase) <xref rid="B024" ref-type="bibr">(24)</xref>. The aerial portion of <italic>Artemisia capillaris</italic> was also used as a reducing agent for the synthesis of AgNPs and AgNPs enhance the antibacterial activity against <italic>Pseudomonas aeruginosa</italic>, <italic>Escherichia coli</italic>, <italic>Enterobacter cloacae</italic>, <italic>Klebsiella oxytoca</italic> and <italic>Klebsiella areogenes</italic><xref rid="B023" ref-type="bibr">(23)</xref>. In each case, MIC values are compared with values recorded for the original plant extract alone. Generally, AgNPs synthesized with the three plant extracts mentioned above show more effective antibacterial activities against Gram-negative than Gram-positive bacteria.</p><fig id="F0001" orientation="portrait" position="float"><label>Fig. 1.</label><caption><title>A schematic of the procedure followed to synthesize AgNPs by using plant extracts as reducing agents.</title></caption><graphic xlink:href="toxicr-30-169-g0001"></graphic></fig><p>The formation of AgNPs is generally characterized with spectroscopic and microscopic methods, including UV-visible spectrophotometry, Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and zeta potential measurements. The formation of AgNPs is initially judged based on the color change of the solution, using the naked eye. The characteristic absorbance is observed in the range of 380~450 nm (yellow color), in which predominantly spherical AgNPs are synthesized. When the synthesis is completed, the size, shape and dispersion state of AgNPs are commonly visualized and measured by microscopic methods, such as TEM, AFM and SEM. Next, the crystalline nature of AgNPs is confirmed by XRD analysis. FT-IR spectra provide information regarding the functional groups of the reducing agents that are involved in the reduction of Ag<sup>+</sup> to AgNPs. Further, zeta potential measurements give information regarding the surface charges of AgNPs, which affect their colloidal stability. The reaction yield is measured by using both ultracentrifugation and inductively coupled plasma mass spectrometry (ICP-MS). After performing ultracentrifugation, AgNPs settle to the bottom of the tube. The colorless supernatant solution containing the unreacted Ag<sup>+</sup> is pooled and analyzed by ICP-MS. Then, the yield can be calculated by measuring the concentrations of both the total Ag in the solution of AgNPs and the unreacted Ag in the supernatant.</p><sec><title>PLANT EXTRACTS AS REDUCING AGENTS FOR THE GREEN SYNTHESIS OF AgNPs</title><p>Following various sustainability initiatives, plant extracts are emerging as potential reducing agents for the green synthesis of AgNPs. Various categories of plant extracts further act as stabilizing agents. Approximately 321,212 species of plants are known on earth, according to the Botanic Gardens Conservation International, indicating that researchers have access to a significant variety of natural plant material <xref rid="B012" ref-type="bibr">(12)</xref>. The author extensively reviewed the green synthesis of AuNPs and AgNPs using polysaccharides and phytochemicals as reducing agents <xref rid="B013" ref-type="bibr">(13)</xref>. Phytochemicals and plant-derived polysaccharides, such as cellulose, starch, dextran, and alginic acid, play dual roles as reducing and stabilizing agents. The oxidation of the hydroxyl groups of polysaccharides to carbonyl groups is most likely involved in the reduction of metal ions to produce metallic NPs <xref rid="B013" ref-type="bibr">(13)</xref>.</p><p>Researchers have reported that four factors—pH, temperature, reaction time and the ratio of plant extracts to silver nitrate—affect the synthesis of AgNPs based on plant extracts <xref rid="B008" ref-type="bibr">(8</xref>,<xref rid="B012" ref-type="bibr">12)</xref>. (1) By changing the pH, the charges of the biomolecules in extracts are altered. Because the Ag ion is a cation, the charge of the biomolecules also affects the synthesis of AgNPs. (2) Generally, increasing the reaction temperature leads to a higher reaction rate. In high-temperature reactions, thermo-stable compounds can play a major role in obtaining higher yields. (3) Additionally, by increasing the reaction time, the reaction rate generally increases. (4) Finally, the ratio of plant extract to silver nitrate is a very important factor for obtaining AgNPs with various sizes and shapes.</p><table-wrap id="T0001" orientation="portrait" position="float"><label>Table 1.</label><caption><title>Plant extracts used for the green synthesis of antibacterial AgNPs</title></caption><table frame="hsides" rules="groups"><tbody><tr><th colspan="4" rowspan="1" align="center">Antibacterial AgNPs</th></tr><tr><td colspan="4" rowspan="1"><hr></hr></td></tr><tr><th align="left" rowspan="1" colspan="1">Scientific name</th><th align="left" rowspan="1" colspan="1">Intrinsic biological activities of plants</th><th align="center" rowspan="1" colspan="1">Plant part used for the green synthesis of AgNPs</th><th align="center" rowspan="1" colspan="1">Refs.</th></tr><tr><td colspan="6" rowspan="1"><hr></hr></td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Azadirachta indica</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory and antinociceptive activities</td><td colspan="1" rowspan="3" align="center">leaves</td><td colspan="1" rowspan="3" align="center"><xref rid="B040" ref-type="bibr">(40)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antioxidant and antiproliferative activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) cytotoxic and melanogenesis-inhibitory activity</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Boswellia ovalifoliolata</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant activity</td><td colspan="1" rowspan="1" align="center">stem barks</td><td colspan="1" rowspan="1" align="center"><xref rid="B041" ref-type="bibr">(41)</xref></td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Caesalpinia sappan</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory activity</td><td colspan="1" rowspan="2" align="center">heartwoods</td><td colspan="1" rowspan="2" align="center"><xref rid="B025" ref-type="bibr">(25)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) vasorelaxant activity</td></tr><tr><td colspan="1" rowspan="6" align="left"><italic>Camellia sinensis</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant activity</td><td colspan="1" rowspan="6" align="center">leaves</td><td colspan="1" rowspan="6" align="center"><xref rid="B042" ref-type="bibr">(42)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) blood anticoagulation and antiplatelet activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) neuroprotective effect</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antimicrobial activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) hypoglycaemic and hypolipidemic activities</td></tr><tr><td colspan="1" rowspan="1" align="left">6) wound healing activity</td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Carica papaya</italic></td><td colspan="1" rowspan="1" align="left">1) antiplasmodial activity</td><td colspan="1" rowspan="3" align="center">fruits</td><td colspan="1" rowspan="3" align="center"><xref rid="B043" ref-type="bibr">(43)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antioxidant activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) anxiolytic and sedative effects</td></tr><tr><td colspan="1" rowspan="5" align="left"><italic>Catharanthus roseus</italic></td><td colspan="1" rowspan="1" align="left">1) larvicidal efficacy</td><td colspan="1" rowspan="5" align="center">leaves</td><td colspan="1" rowspan="5" align="center"><xref rid="B044" ref-type="bibr">(44)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antidiabetic and antioxidant activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) hypoglycemic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) hypolipidemic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) AchE inhibitory activity</td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Chrysanthemum morifolium</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory activity</td><td colspan="1" rowspan="3" align="center">flower</td><td colspan="1" rowspan="3" align="center"><xref rid="B045" ref-type="bibr">(45)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) anti HIV activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antitumor activity</td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Cinnamon zeylanicum</italic></td><td colspan="1" rowspan="1" align="left">1) improves insulin sensitivity in the brain</td><td colspan="1" rowspan="3" align="center">bark</td><td colspan="1" rowspan="3" align="center"><xref rid="B046" ref-type="bibr">(46)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antihypertension effect</td></tr><tr><td colspan="1" rowspan="1" align="left">3) effects neurodegenerative diseases and its potent antineuroinflammatory capacity</td></tr><tr><td colspan="1" rowspan="5" align="left"><italic>Citrullus colocynthis</italic></td><td colspan="1" rowspan="1" align="left">1) antimicrobial potentials</td><td colspan="1" rowspan="5" align="center">leaves</td><td colspan="1" rowspan="5" align="center"><xref rid="B047" ref-type="bibr">(47)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) analgesic and antiinflammatory activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antibacterial activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antioxidant activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antitumor activity</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Citrus sinensis</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant and antifungal activities</td><td colspan="1" rowspan="1" align="center">peel</td><td colspan="1" rowspan="1" align="center"><xref rid="B048" ref-type="bibr">(48)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Cochlospermum gossypium</italic></td><td colspan="1" rowspan="1" align="left">none</td><td colspan="1" rowspan="1" align="center">gum</td><td colspan="1" rowspan="1" align="center"><xref rid="B049" ref-type="bibr">(49)</xref></td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Coleus aromaticus</italic></td><td colspan="1" rowspan="1" align="left">1) wound healing activity</td><td colspan="1" rowspan="2" align="center">leaves</td><td colspan="1" rowspan="2" align="center"><xref rid="B050" ref-type="bibr">(50)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) diuretic activity</td></tr><tr><td colspan="1" rowspan="4" align="left"><italic>Coleus forskohlii</italic></td><td colspan="1" rowspan="1" align="left">1) wound healing activity</td><td colspan="1" rowspan="4" align="center">root</td><td colspan="1" rowspan="4" align="center"><xref rid="B051" ref-type="bibr">(51)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) anti HIV activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) diuretic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antifungal activity</td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Curcuma longa</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant, antiinflammatory and chemosensitizer activities</td><td colspan="1" rowspan="2" align="center">tuber</td><td colspan="1" rowspan="2" align="center"><xref rid="B052" ref-type="bibr">(52)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) hepatoprotective effect</td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Desmodium triflorum</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant and antiproliferative activities</td><td colspan="1" rowspan="2" align="center">whole plant</td><td colspan="1" rowspan="2" align="center"><xref rid="B053" ref-type="bibr">(53)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) analgesic and antiinflammatory activities</td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Dioscorea batatas</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory activity</td><td colspan="1" rowspan="2" align="center">rhizome</td><td colspan="1" rowspan="2" align="center"><xref rid="B054" ref-type="bibr">(54)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antioxidant activity</td></tr><tr><td colspan="1" rowspan="4" align="left"><italic>Dioscorea bulbifera</italic></td><td colspan="1" rowspan="1" align="left">1) antibacterial activity</td><td colspan="1" rowspan="4" align="center">tuber</td><td colspan="1" rowspan="4" align="center"><xref rid="B055" ref-type="bibr">(55)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antitumor activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antidiabetic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) analgesic and antiinflammatory</td></tr><tr><td colspan="1" rowspan="5" align="left"><italic>Eucalyptus citriodora</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory activity</td><td colspan="1" rowspan="5" align="center">leaves</td><td colspan="1" rowspan="5" align="center"><xref rid="B056" ref-type="bibr">(56)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) analgesic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antiproliferative effect</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antituberculosis</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antibacterial activity</td></tr><tr><td colspan="1" rowspan="8" align="left"><italic>Euphorbia hirta</italic></td><td colspan="1" rowspan="1" align="left">1) antimicrobial activity</td><td colspan="1" rowspan="8" align="center">leaves</td><td colspan="1" rowspan="8" align="center"><xref rid="B057" ref-type="bibr">(57</xref>,<xref rid="B058" ref-type="bibr">58)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) mosquito larvicidal and pupicidal activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antidiabetic and antioxidant potentials</td></tr><tr><td colspan="1" rowspan="1" align="left">4) immunomodulatory activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antianaphylactic effect</td></tr><tr><td colspan="1" rowspan="1" align="left">6) burn-wound healing activity</td></tr><tr><td colspan="1" rowspan="1" align="left">7) antidiarrhoeic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">8) analgesic, antipyretic and antiinflammatory properties</td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Euphorbia nivulia</italic></td><td colspan="1" rowspan="1" align="left">1) wound healing activity</td><td colspan="1" rowspan="3" align="center">latex</td><td colspan="1" rowspan="3" align="center"><xref rid="B059" ref-type="bibr">(59)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) haemostatic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antibacterial activity</td></tr><tr><td colspan="1" rowspan="6" align="left"><italic>Ficus benghalensis</italic></td><td colspan="1" rowspan="1" align="left">1) antimicrobial activity</td><td colspan="1" rowspan="6" align="center">leaves</td><td colspan="1" rowspan="6" align="center"><xref rid="B060" ref-type="bibr">(60)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antiinflammatory activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antidiabetic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antiatherogenic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antioxidant activity</td></tr><tr><td colspan="1" rowspan="1" align="left">6) antiinflammatory and analgesic activities</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Fissidens minutus</italic></td><td colspan="1" rowspan="1" align="left">none</td><td colspan="1" rowspan="1" align="center">mosses</td><td colspan="1" rowspan="1" align="center"><xref rid="B061" ref-type="bibr">(61)</xref></td></tr><tr><td colspan="1" rowspan="8" align="left"><italic>Garcinia mangostana</italic></td><td colspan="1" rowspan="1" align="left">1) neuroprotective effect</td><td colspan="1" rowspan="8" align="center">leaves</td><td colspan="1" rowspan="8" align="center"><xref rid="B062" ref-type="bibr">(62)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antiinflammatory effect</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antioxidant and antitumor activities</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antimicrobial and antiprotozoal activities</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antiangiogenic effect</td></tr><tr><td colspan="1" rowspan="1" align="left">6) antihyperglycemic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">7) analgesic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">8) antiviral activity</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Gliricidia sepium</italic></td><td colspan="1" rowspan="1" align="left">1) larvicidal, ovicidal and pupicidal activities</td><td colspan="1" rowspan="1" align="center">leaves</td><td colspan="1" rowspan="1" align="center"><xref rid="B063" ref-type="bibr">(63)</xref></td></tr><tr><td colspan="1" rowspan="7" align="left"><italic>Hibiscus sabdariffa</italic></td><td colspan="1" rowspan="1" align="left">1) nephroprotective effect</td><td colspan="1" rowspan="7" align="center">leaves, stems</td><td colspan="1" rowspan="7" align="center"><xref rid="B064" ref-type="bibr">(64)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antimicrobial effect</td></tr><tr><td colspan="1" rowspan="1" align="left">3) hypolipidemic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) wound healing activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antidiabetic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">6) diuretic effect</td></tr><tr><td colspan="1" rowspan="1" align="left">7) antioxidant activity</td></tr><tr><td colspan="1" rowspan="5" align="left"><italic>Leonurus japonicus</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant activity</td><td colspan="1" rowspan="5" align="center">aerial parts</td><td colspan="1" rowspan="5" align="center"><xref rid="B022" ref-type="bibr">(22)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) anticancer activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) cardioprotective effect</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antibacterial activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antiinflammatory activity</td></tr><tr><td colspan="1" rowspan="4" align="left"><italic>Mangifera indica</italic></td><td colspan="1" rowspan="1" align="left">1) ameliorates diabetes and decrease in high density lipoprotein</td><td colspan="1" rowspan="4" align="center">peel</td><td colspan="1" rowspan="4" align="center"><xref rid="B065" ref-type="bibr">(65)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) inhibitory effects of mango leaves against <italic>S. typhi</italic></td></tr><tr><td colspan="1" rowspan="1" align="left">3) chemopreventive activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antiphotoaging activity in UVB-irradiated hairless mice</td></tr><tr><td colspan="1" rowspan="6" align="left"><italic>Mentha piperita</italic></td><td colspan="1" rowspan="1" align="left">1) prevents chemotherapy-induced nausea and vomiting</td><td colspan="1" rowspan="6" align="center">leaves</td><td colspan="1" rowspan="6" align="center"><xref rid="B066" ref-type="bibr">(66)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antifungal activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antioxidant and free radical scavenging activities</td></tr><tr><td colspan="1" rowspan="1" align="left">4) a potential source of natural antimicrobial products</td></tr><tr><td colspan="1" rowspan="1" align="left">5) analgesic effect</td></tr><tr><td colspan="1" rowspan="1" align="left">6) antispasmodic activity on rat trachea</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Mimusops elengi</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant activity</td><td colspan="1" rowspan="1" align="center">fruits</td><td colspan="1" rowspan="1" align="center"><xref rid="B067" ref-type="bibr">(67)</xref></td></tr><tr><td colspan="1" rowspan="9" align="left"><italic>Moringa oleifera</italic></td><td colspan="1" rowspan="1" align="left">1) antimicrobial, anticancer, antiinflammatory, antidiabetic, and antioxidant effects</td><td colspan="1" rowspan="9" align="center">leaves</td><td colspan="1" rowspan="9" align="center"><xref rid="B068" ref-type="bibr">(68)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antidiabetic and antioxidant activities</td></tr><tr><td colspan="1" rowspan="1" align="left">3) antiinflammatory activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) hypoglycemia and hypolipidemia activities</td></tr><tr><td colspan="1" rowspan="1" align="left">5) antioxidant capacity and antimicrobial activities</td></tr><tr><td colspan="1" rowspan="1" align="left">6) antifungal activity</td></tr><tr><td colspan="1" rowspan="1" align="left">7) recovery from hepatic damage</td></tr><tr><td colspan="1" rowspan="1" align="left">8) antispasmodic, antiinflammatory and diuretic activities</td></tr><tr><td colspan="1" rowspan="1" align="left">9) induces apoptosis</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Musa paradisiaca</italic></td><td colspan="1" rowspan="1" align="left">1) antioxidant, antimutagenic, anticarcinogenic, and cytoprotective activities</td><td colspan="1" rowspan="1" align="center">peel</td><td colspan="1" rowspan="1" align="center"><xref rid="B069" ref-type="bibr">(69)</xref></td></tr><tr><td colspan="1" rowspan="4" align="left"><italic>Nerium indicum</italic></td><td colspan="1" rowspan="1" align="left">1) antifungal activity</td><td colspan="1" rowspan="4" align="center">leaves</td><td colspan="1" rowspan="4" align="center"><xref rid="B058" ref-type="bibr">(58)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antioxidant activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) anticancer effects</td></tr><tr><td colspan="1" rowspan="1" align="left">4) antidiabetic activity</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Nicotiana tobaccum</italic></td><td colspan="1" rowspan="1" align="left">none</td><td colspan="1" rowspan="1" align="center">leaves</td><td colspan="1" rowspan="1" align="center"><xref rid="B070" ref-type="bibr">(70)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Ocimum tenuiflorum</italic></td><td colspan="1" rowspan="1" align="left">1) antihyperglycemic activity</td><td colspan="1" rowspan="1" align="center">leaves</td><td colspan="1" rowspan="1" align="center"><xref rid="B071" ref-type="bibr">(71)</xref></td></tr><tr><td colspan="1" rowspan="6" align="left"><italic>Opuntia ficus-indica</italic></td><td colspan="1" rowspan="1" align="left">1) activity of the coagulants</td><td colspan="1" rowspan="6" align="left">leaves</td><td colspan="1" rowspan="6" align="left"><xref rid="B072" ref-type="bibr">(72)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antibacterial activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) inhibits the ulcerogenic activity</td></tr><tr><td colspan="1" rowspan="1" align="left">4) wound healing activity</td></tr><tr><td colspan="1" rowspan="1" align="left">5) reduces hangover symptoms and inhibites the production of inflammatory mediators</td></tr><tr><td colspan="1" rowspan="1" align="left">6) hepatoprotective effect</td></tr><tr><td colspan="1" rowspan="3" align="left"><italic>Polygala tenuifolia</italic></td><td colspan="1" rowspan="1" align="left">1) antiinflammatory activity</td><td colspan="1" rowspan="3" align="center">roots</td><td colspan="1" rowspan="3" align="center"><xref rid="B024" ref-type="bibr">(24)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) antitumor activity</td></tr><tr><td colspan="1" rowspan="1" align="left">3) anxiolytic activity</td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Sesuvium portulacastrum</italic></td><td colspan="1" rowspan="1" align="left">1) potential antimicrobial agent</td><td colspan="1" rowspan="2" align="center">leaves, callus</td><td colspan="1" rowspan="2" align="center"><xref rid="B073" ref-type="bibr">(73)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) cholinesterase inhibitory activity</td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Shorea tumbuggaia</italic></td><td colspan="1" rowspan="1" align="left">1) decreases cholesterol and triglycerides</td><td colspan="1" rowspan="1" align="center">stem barks</td><td colspan="1" rowspan="1" align="center"><xref rid="B041" ref-type="bibr">(41)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left"><italic>Svensonia hyderabadensis</italic></td><td colspan="1" rowspan="1" align="left">none</td><td colspan="1" rowspan="1" align="center">leaves</td><td colspan="1" rowspan="1" align="center"><xref rid="B074" ref-type="bibr">(74)</xref></td></tr><tr><td colspan="1" rowspan="7" align="left"><italic>Tribulus terrestris</italic></td><td colspan="1" rowspan="1" align="left">1) antitumor and antiangiogenic activities</td><td colspan="1" rowspan="7" align="center">fruits</td><td colspan="1" rowspan="7" align="center"><xref rid="B075" ref-type="bibr">(75)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) large gains in strength and lean muscle mass</td></tr><tr><td colspan="1" rowspan="1" align="left">3) inhibits oxidative stress</td></tr><tr><td colspan="1" rowspan="1" align="left">4) reduces Cd load</td></tr><tr><td colspan="1" rowspan="1" align="left">5) conventional analgesic drugs</td></tr><tr><td colspan="1" rowspan="1" align="left">6) antihypertensive effect both systolic and diastolic</td></tr><tr><td colspan="1" rowspan="1" align="left">7) antidepressive effect</td></tr><tr><td colspan="1" rowspan="2" align="left"><italic>Vitex negundo</italic></td><td colspan="1" rowspan="1" align="left">1) treats various inflammatory disorders</td><td colspan="1" rowspan="2" align="center">leaves</td><td colspan="1" rowspan="2" align="center"><xref rid="B076" ref-type="bibr">(76)</xref></td></tr><tr><td colspan="1" rowspan="1" align="left">2) analgesic and antiinflammatory activities</td></tr></tbody></table></table-wrap></sec></sec><sec><title>ANTIBACTERIAL ACTIVITIES OF AgNPs</title><p><italic><bold>MDR bacteria.</bold></italic> One of the most remarkable properties of AgNPs is their antibacterial activity. For 7,000 years, mankind has used Ag metal in coins, cutlery, textiles, cosmetics and medical implants. Ag has also been used as an antibacterial agent in the form of ions, NPs and bulk metal <xref rid="B030" ref-type="bibr">(30)</xref>. Currently, the increased use of AgNPs in medicine is closely associated with the antibacterial potential of AgNPs. The emergence of MDR bacteria requires novel antibiotics with improved antibacterial activities. In most respects, AgNPs have appeared as prospective alternatives for overcoming antibiotic resistance problems because AgNPs utilize multivalent or polyvalent mechanisms to exert their antibacterial activities. Additionally, the high surface-areato-volume ratio and the specific physical and chemical characteristics of AgNPs make them effective antibacterial agents against MDR bacteria, which includes methicillinresistant <italic>Staphylococcus aureus</italic> (MRSA), methicillin-sensitive <italic>Staphylococcus aureus</italic> (MSSA), <italic>methicillin-resistant Staphylococcus epidermis</italic> (MRSE), ampicillin-resistant <italic>Escherichia coli</italic>, vancomycin-resistant <italic>Staphylococcus aureus</italic> (VRSA), erythromycin-resistant <italic>Streptococcus pyogenes</italic> and multidrug-resistant <italic>Pseudomonas aeruginosa</italic><xref rid="B031" ref-type="bibr">(31)</xref>.</p><p><italic><bold>Mechanisms.</bold></italic> The antibacterial mechanisms of AgNPs are not yet fully understood; however, the research community has put forward several hypotheses, which follow <xref rid="B031" ref-type="bibr">(31)</xref>. (1) AgNPs penetrate the cell wall of Gram-negative bacteria, leading to increased cell permeability followed by cell death; (2) the formation of free radicals by AgNPs is attributed to membrane damage; and (3) the strong binding capacity of Ag<sup>+</sup> with thiol groups and phosphorous-containing bases, such as vital enzymes and DNA bases, causes the inhibition of bacterial growth and death. Key factors, such as size and shape, affect the antibacterial activity of AgNPs <xref rid="B031" ref-type="bibr">(31)</xref>. With decreasing size, the surface-area-to-volume ratio increases. The large surface area provides many opportunities for interactions with bacteria; thus, the small particle size is effective as an antibacterial agent. Pal et al. reported that triangular AgNPs are more active than spherical and rod-shaped AgNPs against <italic>Escherichia coli</italic>, suggesting that the shape of AgNPs should be considered to develop highly efficient antibacterial agents <xref rid="B032" ref-type="bibr">(32)</xref>.</p><p><italic><bold>Stabilizers.</bold></italic> For antibacterial applications of AgNPs, the colloidal stability is a major consideration. Thus, stabilizers are commonly employed to increase the stability of AgNPs. The most widely used stabilizers are anionic, cationic, and nonionic surfactants and polymers. Carmona-Ribeiro and de Melo Carrasco have reported that cationic compounds, especially compounds with quaternary ammonium groups, are promising candidates for the development of antimicrobial agents <xref rid="B033" ref-type="bibr">(33)</xref>. One cationic surfactant, cetyltrimethylammonium bromide (CTAB), has been employed as a stabilizing agent during the synthesis of AgNPs. The mechanism of CTAB adsorption onto the AgNPs is not clearly understood; however, the formation of a CTAB bilayer is a possibility <xref rid="B034" ref-type="bibr">(34)</xref>. As shown in <xref ref-type="fig" rid="F0002">Fig. 2</xref>A, the cationic head group of CTAB binds to the surface of AgNPs, with the hydrophilic group of the surfactant attaching to the AgNPs. Then, the outward hydrophobic tail binds to the hydrophobic tail of another CTAB molecule to form a bilayer structure. Consequently, due to the bilayer formation, the hydrophilic head group of CTAB is directed outward, contributing to the overall positive charge of CTAB-stabilized AgNPs (<xref ref-type="fig" rid="F0002">Fig. 2</xref>B). We performed a green synthesis reaction for AgNPs by using extract of <italic>Caesalpinia sappan</italic> in both the absence and presence of stabilizers. The stabilizers used were a nonionic polymer (PVP) and cationic (CTAB), anionic (SDS, NaDDSS) and nonionic (Tween 20 and 80) surfactants <xref rid="B025" ref-type="bibr">(25)</xref>. Among the tested stabilizers, CTAB-stabilized AgNPs were found to be the most potent antibacterial agents against 19 strains of MRSA <xref rid="B025" ref-type="bibr">(25)</xref>. The bilayer shell of CTAB provides improved colloidal stability to the AgNPs, which is closely connected to their enhanced antibacterial activity against MRSA. The overall positive charge of the CTAB-stabilized AgNPs offers many opportunities for the NPs to interact with the negatively charged bacterial cell wall.</p><fig id="F0002" orientation="portrait" position="float"><label>Fig. 2.</label><caption><title>The binding of CTAB on the AgNP surface. (A) The bilayer formation of CTAB, and (B) CTAB-stabilized AgNPs with overall positive charges <xref rid="B034" ref-type="bibr">(34)</xref>.</title></caption><graphic xlink:href="toxicr-30-169-g0002"></graphic></fig></sec><sec><title>PERSPECTIVES</title><p>Currently, AgNPs-based consumer products are widespread in medical devices, clothing, industry, household goods, healthcare products and cosmetics <xref rid="B035" ref-type="bibr">(35)</xref>. The potent antimicrobial activity of AgNPs is a key feature being utilized in the development of nanosilver products. Additionally, as a result of the increasing interest in the use of AgNPs in medical applications, the number of scientific publications on this subject has risen 41-fold since the last decade (2000~2011) <xref rid="B035" ref-type="bibr">(35)</xref>. Whereas there were only four related publications in 2000, the number of publication increased to 164 in 2011 when a PubMed database search was performed using the keyword ‘nanosilver’ <xref rid="B035" ref-type="bibr">(35)</xref>. In spite of the broad range of AgNP therapeutic applications, the limited information has been reported regarding the toxicity of AgNPs. One mechanism of AgNPs-induced toxicity is cellular apoptosis, which decreases cell viability <xref rid="B006" ref-type="bibr">(6)</xref>. Safety issues concerning the environment should also be considered because AgNPs from consumer products enter ecosystems. However, understanding the toxicity and fate of AgNPs in ecosytems requires further investigation <xref rid="B006" ref-type="bibr">(6)</xref>. The green synthetic strategy of AgNPs based on plant extracts, as reported in the current review, contributes to the protection of the ecosystem and our health by decreasing the use of toxicity-associated hazardous chemicals. 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