Chemistry, Antimicrobial Mechanisms, and Antibiotic Activities of

Review pubs.acs.org/JAFC

Chemistry, Antimicrobial Mechanisms, and Antibiotic Activities of Cinnamaldehyde against Pathogenic Bacteria in Animal Feeds and Human Foods Mendel Friedman* Healthy Processed Foods Research, Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Albany, California 94710, United States ABSTRACT: Cinnamaldehyde is a major constituent of cinnamon essential oils produced by aromatic cinnamon plants. This compound has been reported to exhibit antimicrobial properties in vitro in laboratory media and in animal feeds and human foods contaminated with disease-causing bacteria including Bacillus cereus, Campylobacter jejuni, Clostridium perf ringens, Escherichia coli, Listeria monocytogenes, and Salmonella enterica. This integrated review surveys and interprets our current knowledge of the chemistry, analysis, safety, mechanism of action, and antibiotic activities of cinnamaldehyde in food animal (cattle, lambs, calves, pigs, poultry) diets and in widely consumed liquid (apple, carrot, tomato, and watermelon juices, milk) and solid foods. Solid foods include various fruits (bayberries, blueberries, raspberries, and strawberries), vegetables (carrots, celery, lettuce, spinach, cucumbers, and tomatoes), meats (beef, ham, pork, and frankfurters), poultry (chickens and turkeys), seafood (oysters and shrimp), bread, cheese, eggs, infant formula, and peanut paste. The described findings are not only of fundamental interest but also have practical implications for food safety, nutrition, and animal and human health. The collated information and suggested research needs will hopefully facilitate and guide further studies needed to optimize the use of cinnamaldehyde alone and in combination with other natural antimicrobials and medicinal antibiotics to help prevent and treat food animal and human diseases. KEYWORDS: cinnamaldehyde, chemistry, analysis, biochemistry, metabolism, browning prevention, antibiotic properties, antibiotic resistance, pathogenic bacteria, infectious diseases, antifungal effects, spoilage microorganisms, microbial food safety, food animal diets, human diets, nutrition, liquid foods, fruits, vegetables, meat products, poultry products, seafood, infant formula, research needs

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INTRODUCTION

and sensory properties. The results of this active worldwide research effort suggest that cinnamaldehyde is a useful antimicrobial that can protect against multiple pathogenic bacteria in different feed and food milieus.

Foodborne diseases result from ingesting food animal diets and human foods that are contaminated with either infectious microorganisms or toxins produced by microorganisms. The antibiotic resistance of some pathogens is a major concern.1 Bacteria can exert adverse effects in tissues of animals and human by adhesion to and disruption of cell membranes, chemical modification of essential protein and other molecules, and penetration into cells with release of cellular toxins. There has been interest in developing new types of effective and nontoxic antimicrobial compounds. Some promising natural antimicrobials include tea catechins and theaflavins,2 chitosans,3 essential oil compounds,4−6 winery byproducts,7 and mushroom polysaccharides.8 This review is largely limited to summarizing and evaluating studies on the inhibition of foodborne pathogens in animal feed and human food by the natural antimicrobial cinnamaldehyde, a major component of plant-derived cinnamon oils that can also be produced synthetically, as well as describing the complex chemistry and antimicrobial mechanisms of cinnamaldehyde that might offer insight into the antimicrobial activity and providing suggestions for further research. The ultimate goal of such studies is to devise practical feed and food formulations that use active and safe food-compatible compounds such as cinnamaldehyde to reduce pathogens in foods, feeds, and possibly also in animals and humans after consumption. Studies with foods might require the assessment of safety, practicality, This article not subject to U.S. Copyright. Published 2017 by the American Chemical Society

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CHEMICAL PROPERTIES AND ANALYSIS OF CINNAMALDEHYDE AND ITS DERIVATIVES Natural and Synthetic Cinnamaldehydes: Occurrence and Production. trans-Cinnamaldehyde (cinnamic aldehyde; (E)-3-phenylprop-2-enal; mol. wt. 132.16, a yellowish oily liquid prepared by extraction from cinnamon oils and synthetically by condensation of benzaldehyde and acetaldehyde or by oxidation of cinnamyl alcohol; 1 mL is soluble in ∼700 mL of water and miscible with ethanol.9,10 Figure 1 illustrates the biosynthesis of cinnamaldehyde, and Figure 2 depicts the structure of cinnamaldehyde and selected derivatives, some of which have also been evaluated for antimicrobial and other health benefits. Cinnamaldehyde is an important bioactive compound found in the genus Cinnamonum, which consists of several hundred species. More than 89 compounds have been isolated from Received: Revised: Accepted: Published: 10406

September 25, 2017 November 7, 2017 November 12, 2017 November 20, 2017 DOI: 10.1021/acs.jafc.7b04344 J. Agric. Food Chem. 2017, 65, 10406−10423

Journal of Agricultural and Food Chemistry

Review

Bang et al.14 engineered Escherichia coli as a biological platform for the production of cinnamaldehyde from its biosynthetic precursors at concentrations of up to 75 mg/L. The engineered molecule had a nematocidal activity against Bursaphelenchus xylophilus similar to that of commercial cinnamaldehyde, suggesting that the described approach could serve as another source of cinnamaldehyde. A related study by Gottardi et al.15 describes the biosynthesis of bioactive trans-cinnamic acid derivatives in Saccharomyces cerevisiae. In this review, “cinnamaldehyde” refers to the trans and not the cis isomer. Analysis of Cinnamaldehyde. Using methyl benzoate as an internal standard, Friedman et al.16 developed a gas chromatography-mass spectrometric method for the analysis of components of commercial foods that have the name “cinnamaldehyde” on the label. The results indicate that the cinnamaldehyde content of 20 widely consumed foods varied widely, ranging from trace amounts in orange juice to 12.2 mg/ 100 g (122 ppm) in apple cinnamon cereals and 31.1 mg/100 g (311 ppm) for cinnamon swirl bread. Additional studies showed that, starting at ∼60 °C, pure cinnamaldehyde undergoes a temperature-dependent transformation to benzaldehyde, possibly by the mechanism illustrated in Figure 3.

Figure 1. Biosynthesis of cinnamaldehyde from phenylalanine.197,198 The plant enzymes catalyzing the indicated transformations are not shown.

Figure 3. Heat-induced transformation of cinnamaldehyde to benzaldehyde (adapted from Friedman et al.16).

Eugenol, both pure and in cinnamon oil, protects cinnamaldehyde against thermal destruction, even at 200 °C. JiménezSalcedo and Tena17 developed a GC/MS assay for microencapsulated cinnamaldehyde, carvacrol, and thymol in feedstuff that can be applied for quality control and stability studies. Raffo et al.18 found a low variability of cinnamaldehyde content in 70 commercial samples of cola-flavored soft drinks. Lafeuille et al.19 evaluated 106 dried pure cinnamon samples and reported that some samples were contaminated with up to 524 μ/g of styrene, apparently the result of natural exposure to fungal (mold) species. Using principal component analysis of eight Cinnamon cassia components including cinnamaldehyde, Chen et al.20 developed chemical fingerprints that can be used to identify cinnamon herbs for quality control. Using HPLC, Woehrlin et al.21 observed high variation in cinnamaldehyde content of 47 cassia bark samples from the German market and authentic samples from Indonesia. Although cinnamaldehyde is reported to undergo a large number of metabolic transformations in vivo, as illustrated in Figure 4, Zhao et al.22 found, using GC/MS, that there was no long-term accumulation of cinnamaldehyde in rat tissues.

Figure 2. Structures of natural and synthetic cinnamaldehyde and derivatives (adapted from Narasimhan et al.,199 Sova,200 Heleno et al.,201 Cui et al.,202 Guzman,203 Gunawardena et al.,204 Hong et al.,205 Wang et al.,54 Yang et al.,206 and Nunes et al.207).

different parts of the cinnamon plant with cinnamaldehyde as a major component.11,12 Volatile cinnamon oils isolated by hydrodistillation and supercritical fluid extraction are used as food flavors and spices, in cosmetics, and in medicine.10,13 10407

DOI: 10.1021/acs.jafc.7b04344 J. Agric. Food Chem. 2017, 65, 10406−10423


Review

For example, using whole-genome transcriptional profiling, Visvalingam et al. 23 found that a 2 h exposure to cinnamaldehyde resulted in the induction of oxidative stress, reduced DNA replication, and synthesis of proteins, Oantigens, and fimbriae by the downregulation of the respective functional genes in E. coli. After 4 h, E. coli was able to convert bioactive cinnamaldehyde to inactive cinnamic alcohol through the use of a dehydrogenase enzyme, which suggests that the aldehyde moiety of cinnamaldehyde is essential for its antimicrobial activity. In addition, a study by Mousavi et al.24 showed that cinnamaldehyde induced the dose-dependent formation of numerous metabolites in E. coli by chemically interacting with membrane and other proteins, nucleic acids, lipids, and carbohydrates, suggesting that the antimicrobial acts as an antioxidative stress agent against the pathogen. Low levels of cinnamaldehyde seem to interact with cell membrane components, and higher levels diffuse inside the cell and modify cytoplasm enzymes in the transcriptome, leading to cell death. A kinetic study by Wang et al.25 revealed that cinnamaldehyde inhibited the hydrolytic enzyme β-galactosidase with an IC50 value of 3.46 × 10−4 mol L−1 by changing the surface morphology and causing molecular aggregation of the enzyme. The cited in vitro studies and additional observations on mechanistic aspects mentioned below indicate that the antibiotic properties of cinnamaldehyde seem to result from the modification of bioactive compounds in E. coli. Such modifications probably occur by both nucleophilic additions of microbial components concurrently and independently to two reactive sites: the conjugated double bond and aldehyde group. We do not know if exposure of other pathogens to cinnamaldehyde would induce similar changes in microbial compounds or to what extent, if any, analogous functional groups in food with added cinnamaldehyde would competitively interact with cinnamaldehyde in vitro and in vivo after consumption. Two such competitive interactions could, in principle, arise from biological alkylations of (a) the heat-induced food ingredient acrylamide (CH2CH−CONH2) that exerts numerous adverse effect via the nucleophilic addition of NH2 and/or SH functional groups present in protein and DNA to the acrylamide-conjugated system of double bonds26,27 and (b) the heat- and alkali-induced formation of dehydroalanine [CH2CH(NH2)-COOH] derived from the elimination of H2S from cysteine and H2O from serine that can also react with the ε-NH2 group of lysine and the SH group of cysteine in addition reactions to form lysinoalanine and lanthionine, respectively, affecting the nutritional quality and safety of food proteins.28,29 See also Friedman30,31 for a detailed discussion of mechanisms of nucleophilic and free radical reactions of protein functional groups with electrophilic compounds such as cinnamaldehyde. Safety of Cinnamaldehyde. The following information released by regulatory agencies cited by Cocchiara et al.32 indicates that cinnamaldehyde (cinnamic aldehyde CAS Registry Number 104-55-2) is a safe food and flavor compound: • The United States Food and Drug Administration (FDA) approved cinnamaldehyde as Generally Recognized as Safe (GRAS, 21 CFR 182, 60).

Figure 4. Metabolism of cinnamaldehyde (adapted from Bickers et al.208).

Nucleophilic Addition Reactions of Cinnamaldehyde. The cinnamaldehyde molecule has two electrophilic reactive sites, the conjugated double bond and the aldehyde group, that can react with nucleophilic molecules. Theoretically possible reactions are schematically illustrated in eqs 1−3 and in Figure 5. Potential participants in these concurrent and consecutive

Figure 5. A possible mechanism for the in vivo inactivation of the enzyme cytochrome CYP2A6 by cinnamaldehyde via nucleophilic addition of an SH group of a cysteine residue to the α,β-conjugated double bond system to form a cysteine adduct (conjugate) and of an εNH2 group of a lysine side chain to the aldehyde group to form an aldimine (Schiff base) derivative (adapted from Chan et al.209).

reactions of cinnamaldehyde in vitro and in vivo include α-NH2 groups or lysine ε-NH2 or SH groups of amino acids, peptides, proteins, as well as nucleic acid (DNA) side chains shown in eq 1. Reactive nucleophilic compounds include SH-containing cysteine, reduced glutathione, and structural and bioactive enzymes. The participation of cinnamaldehyde in such reactions is supported by various molecular, genetic, and cellular studies. 10408



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• Cinnamaldehyde was included by the Council of Europe in the list of substances granted A status−may be used in foodstuffs (Code No 102). • Flavor and Extract Manufacturer’s Association (FEMA) states that cinnamaldehyde is GRAS as a flavor ingredient− GRAS 3 (2286). According to Kiwamoto et al.,33 unlike many α,β-unsaturated aldehydes, cinnamaldehyde is not genotoxic or carcinogenic in vivo. These authors compared DNA-adduct formation (eq 1) of cinnamaldehyde and 18 foodborne α,β-unsaturated aldehydes using physiologically based kinetic/dynamic (PBK/D) modeling in rats. The results suggest that cinnamaldehyde was predicted to induce higher DNA adduct levels than 6 of the 18 aldehydes. Overall, the data confirm that cinnamaldehyde seems to be safe at the highest exposure level (4,100 ppm) as also indicated by a 2-year rat feeding study.34

the membrane resulting in alteration of its external structure. This change could facilitate the cellular incorporation of cinnamaldehyde or even other interstitial compounds. This mechanism of facilitating entry into the cell could explain the synergism sometimes seen when using multiple antimicrobials. Proteomic analysis indicated that the mode of antibacterial action of cinnamaldehyde against Cronobacter sakazakii seems to involve multiple mechanisms, including disruption of amino acid, carbohydrate, and lipid metabolism, resulting in the inhibition of cellular defenses against oxidative stress that attenuates virulence.40 The observation that cinnamaldehyde was effective in significantly reducing the virulence factors of L. monocytogenes by downregulating the transcription of the virulence factors of the pathogen is consistent with this suggestion.41 A study by Nowotarska et al.6 using model membranes describes the creation of quantitative parameters that indicate that the antimicrobial compounds such as cinnamaldehyde could modify the lipid monolayer structure by forming aggregates of antimicrobials and lipids. Nowotarska et al.5 also reported that several natural compounds including cinnamaldehyde cause time-and concentration-dependent leakage of phosphate ions from Mycobacterium avium subsp. paratuberculosis (Map) cells; the extent of leakage did not parallel the relative antimicrobial activities of the test compounds. It seems that cinnamaldehyde kills the cells by inducing release of phosphate ions. Andrade-Ochoa et al.42 developed quantitative structure−activity relationships (QSAR) that correlated predicted versus actual antimicrobial activities of multiple antimicrobials including cinnamaldehyde against two mycobacteria to provide insights into the mechanisms of action. The authors suggest that molecules with high antibacterial activity and low cytotoxicity for macrophages might be candidates for further in vivo evaluation. Montagu et al.43 showed that carvacrol but not cinnamaldehyde lipid nanocapsules penetrated the Acetobacter baumanii bacterial membrane. Smith et al.44 showed that a combination of a bioengineered nisin derivative with cinnamaldehyde was effective in eradicating L. monocytogenes biofilms, suggesting that the antibacterial properties of some antibiotics could be enhanced by cinnamaldehyde and that combinations could be useful in the treatment of resistant biofilms in contaminated foods. In a collaborative study, we utilized several techniques to study the membrane integrity of E. coli C600 in the presence of nonlethal concentrations of carvacrol using autofluorescence, membrane potential, and ATP flux techniques.45 The data showed that autofluorescence techniques were more sensitive than membrane potential or ATP flux methods, measuring membrane leakage at much lower concentrations. It might be of interest to apply this approach to cinnamaldehyde. The cited results indicate that many mechanisms seem to govern the antimicrobial activities of cinnamaldehyde, and mechanisms associated with a specific pathogen might not be the same as those associated with other pathogens for the following reasons. Because of differences in susceptibilities to inactivation, the mechanisms for each pathogen and different strains of the same pathogen merits separate study. For example, Cox et al.46 noted that, although the minimum inhibitory concentration (MIC) values for tea tree oil against E. coli and S. aureus were similar, S. aureus was initially slower in responding, suggesting that the oil diffused through the membrane more slowly. Cristani et al.47 found that the Gram-positive S. aureus was more susceptible to membrane

C6H5‐CH=CH‐CH=O + H 2N‐DNA trans‐cinnamaldehyde

→ C6C5‐CH(NH‐DNA)‐CH 2‐CH=O cinnamaldehyde DNA‐adduct

(1)

C6H5‐CH=CH‐CH=O + R′‐NH 2 or R′‐SH trans‐cinnamaldehyde

→ C6H5‐CH(NHR′)‐CH 2‐CH=O amine adduct

+ C6H5‐CH(SR′)‐CH 2‐CHO thiol adduct

(2)

C6H5‐CH=CH‐CH=O + R‐NH 2 or R‐SH trans‐cinnamaldehyde

→ C6H5‐CH=CH‐CH=NHR aldimine (Schiff base)

+ C6H5‐CH=CH‐CH(OH)‐SR thiohemiketal

+ C6H5‐CH=CH‐CH(OH) − (SR)2 + H 2O thioketal

(3)

where C6H5 = benzene ring and R = amino acid, peptide, protein.

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MECHANISMS OF THE ANTIMICROBIAL ACTION OF CINNAMALDEHYDE There are many reported mechanisms of action for cinnamaldehyde’s antimicrobial activity, some of which overlap. Here, we summarize some of these findings in chronological order. Helander et al.35 investigated the mechanism of cinnamaldehyde along with other natural antimicrobials. They found that, whereas both carvacrol and thymol disintegrated the cell membrane in the Gram-negative bacterium Salmonella Typhimurium, cinnamaldehyde did not. Studies of the mechanism of bactericidal action of cinnamaldehyde against L. monocytogenes and E. coli by Gill and Holley36−38 suggest an interaction with the cell membrane induces rapid inhibition of energy metabolism. The disruption of the proton motive forces results in leakage of small ions without the leakage of larger components such as ATP accompanied by the inhibition of ATP generation and inhibition of membrane-bound adenosine triphosphatase (ATPase) activity. In support of the results of Helander et al.,35 Di Pasqua et al.39 found that cinnamaldehyde did not cause the collapse of the cell membrane, although it did cause a profound change in the composition of the fatty acids in 10409



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groups of glutathione (GSH) affecting oxidative stress in vivo.57,58 Overall, the cited studies suggest that cinnamaldehyde in food and in vivo could, in principle, participate in nucleophilic addition reactions with amino acid, peptide, protein, and DNA functional groups. Additional Health Benefits of Cinnamaldehyde. In addition to its antimicrobial properties, cinnamaldehyde is reported to have other health-promoting bioactivities. These include anti-Alzheimer disease,59 anticancer,60 antidiabetes,61 antidepression,62 anti-inflammatory,63 antiobesity,64 antioxidant,65 and antioral bacteria66,67 properties. Further discussion of these health-promoting properties is beyond the scope of this paper.

damage by the more hydrophilic thymol, whereas the Gramnegative E. coli was more susceptible to the lipophilic carvacrol. They speculated that the compound-specific antimicrobial effect is influenced by both the net surface charge of the membrane and the hydrophobicity of the monoterpene. In our studies, we found that S. enterica, but not E. coli, had very different responses to essential oils added to clarified vs unfiltered apple juice.48 We do not know whether this is a difference in the mechanism or a difference in the sensitivity to the media. Susceptibility is also influenced by the growth stage of the cells. Stationary-phase cells were found to be less susceptible to terpenes than were exponential-phase cells, possibly reflecting a decrease in the incorporation of these molecules.49,50 Different strains of the same bacterium might also not be equally susceptible to inhibition. For example, Ravishankar et al.51 compared the susceptibility of antibiotic-resistant vs -sensitive isolates of Salmonella enterica to carvacrol and cinnamaldehyde. The highly resistant Salmonella Newport showed different susceptibilities to carvacrol and cinnamaldehyde than those of the other strains. With this background on the chemistry, biochemistry, and antimicrobial mechanisms, we will present brief overviews of the impact of cinnamaldehyde on the microbial safety of animal feeds and human foods. Bioactive Cinnamaldehyde Derivatives. Wei et al.52 evaluated the antimicrobial properties of a series of cinnamaldehyde adducts with the NH2 group of amino acids. Both cinnamaldehyde and the adducts were more active against B. subtilis than against E. coli. Because the adducts are more soluble owing to the presence of carboxyl groups and one of the adducts was active against E. coli in fish meat and nontoxic in mice, the authors suggest that cinnamaldehyde adducts with amino acids provide alternative antimicrobials in food to avoid the strong flavors of cinnamaldehyde. Two related studies further support the potential benefits of cinnamaldehyde derivatives. Liu et al.53 note that, because essential oil components have strong odors and are immiscible with water, they prepared Schiff bases from cinnamaldehyde and salicylaldehyde with γ-aminobutyric acid and evaluated the beneficial properties of the adducts. The adducts exhibited antioxidative properties as well as antimicrobial and antibrowning activities in vitro and on mushrooms. The antibacterial effects were enhanced by forming complexes with Cu2+ and Zn2+ ions. The authors suggest that multifunctional properties of the adducts merit further study for their preservative properties in food. Wang et al.54 describe the synthesis and characterization of 24 Schiff bases by reacting three cinnamaldehyde derivatives and eight amino acids. All of the compounds exhibited antimicrobial and antifungal properties. The authors discuss structure−activity aspects of the novel antimicrobials. Biodegradable films prepared from Schiff bases of the corn protein zein with cinnamaldehyde and other aldehydes exhibited antibacterial properties against multiple Gram-negative and -positive pathogenic bacteria, suggesting the potential use of the novel films in packaging and medicine.55 It should be noted, however, that it would have to be shown that the bioactive derivatives are safe to be used as food additives. Cysteine and Glutathione Adducts of Cinnamaldehyde. Sadofsky et al.56 found that cinnamaldehyde activated the nociceptor TRPA1 via covalent nucleophilic addition, suggesting that the method could be used to sense environmental compounds in vivo. Similar biochemical changes seem to be based on analogous nucleophilic additions of the SH

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INHIBITION OF ENZYMATIC BROWNING REACTIONS IN FOOD BY CINNAMALDEHYDE As briefly mentioned above, cinnamaldehyde can also have an additional beneficial effect on food items. As noted elsewhere,68 enzymatic and nonenzymatic (Maillard) browning reactions of amino acids, peptides, and proteins with carbohydrates and oxidized lipids and phenolic compounds cause discoloration (browning) and nutritional damage to foods. Fujita et al.69 found that the immersion of cut lettuce into a solution of cinnamaldehyde inhibits undesirable enzymatic browning in cut lettuce by inhibiting the enzyme phenylalanine ammonia-lyase (PAL) that catalyzes the browning reaction. In a related study, Tanaka et al.70 found that both cinnamaldehyde and mild heat treatment inhibited the induction of PAL in cut lettuce and that, after 12 days, the microbial content of cinnamaldehydetreated lettuce was lower than that of the heat-treated samples. Related studies reported that fumigation with cinnamaldehyde inhibited enzymatic browning in button mushrooms (Agaricus bisporus).71

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THE IMPACT OF CINNAMALDEHYDE IN FARM ANIMAL FEED There are many studies that have reported on the effects of cinnamaldehyde-supplemented animal feeds, indicating their antimicrobial and other beneficial properties. Poultry-Related Salmonella and Salmonellosis. Salmonella is an ongoing issue in farmed poultry. A review by Cosby et al.72 on the significance of Salmonella in broilers notes the following relevant aspects: • S. enterica is a zoonotic pathogen that passes from chickens to humans through the consumption of contaminated food. • In the United States, it is estimated that ∼42,000 cases of reported and more than 1 million unreported nontyphoid foodborne salmonellosis cases occur annually with an estimated total loss to the economy of ∼14 billion dollars per year. • The emergence of antibiotic-resistant Salmonella further aggravates the adverse effects of Salmonella on human health. • Symptoms of salmonellas include diarrhea, abdominal pain, nausea, and vomiting. • Although salmonellosis is a self-limiting disease, immunecompromised children, infants, and elderly usually require antibiotic treatment. • Antibiotics can lose efficacy resulting in antimicrobial multidrug resistance (MDR) and limiting treatment options. These considerations suggest the need to develop replacements for medicinal antibiotics by natural antimicrobials, including cinnamaldehyde, the focus here. 10410



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Reduction of Layer-Chicken Egg-Borne Transmission of S. enterica. The following general information on eggs as a source of potentially lethal Salmonella infection in humans was adapted from Upadhyaya et al.73 This aspect is also discussed by Gantois et al.,74 Moffatt et al.,75 and Osimani et al.76 • Of the 90 billion eggs produced, 67.5 billion are consumed annually in the United States. • Chickens act as asymptomatic carriers of S. Enteritidis. • Humans are infected via consumption of contaminated, raw, and undercooked eggs. • Despite pre- and postharvest control measures, epidemiological studies confirm the association between human salmonellosis and egg consumption. • Because eggs are the primary source of salmonellosis, there is a need for alternative approaches to control the spread of Salmonella. • The cecum is the primary site of colonization of the pathogen in chickens, resulting in contamination of the ovaries via a trans-ovarian rout followed by dissemination into the yolk, albumen, and eggshell membranes before oviposition. Baron et al.77 note that Salmonella bacteria colonize the egg yolk and egg white components (lysozyme, ovotransferrin, polysaccharides). Traditional antibiotics inhibit the growth of Salmonella and other pathogens possibly through chelation to the bacterial membrane forming pores in the bacterial cell wall. It seems that the antimicrobial activity of these antimicrobials is insufficient to completely overcome contamination by Salmonella. Reduction of Salmonella Contamination of Eggs. The continued threat of Salmonella infection from eggs induced Upadhyaya et al.73,78 to evaluate the efficacy of cinnamaldehyde feed supplementation in reducing Salmonella colonization, spread, and contamination of eggs in layer chickens. They found that supplementation with cinnamaldehyde reduced S. Enteritidis contamination of yolk and shell without adversely affecting feed intake, body weight, and egg production or consumer acceptability of eggs from treated birds. In addition, they found that a 0.04% solution of cinnamaldehyde or eugenol in ethanol could be used as a fumigation treatment to reduce Salmonella on embryonated egg shells without any apparent differences in shell color or consistency compared to control eggs. They also used cell culture and gene expression analysis using real-time quantitative PCR (qPCR) to show that cinnamaldehyde decreased colonization of the oviduct epithelium and survival of chicken macrophages by downregulating virulence factors of virulence genes in the pathogen. Reduction in Salmonella Contamination of Broiler Chickens. In addition to investigating the issue of Salmonella infection exclusively from eggs, Upadhyaya et al.73 conducted a study that also involved the reproductive tract of layer or broiler chickens. It seems that feed-supplemented cinnamaldehyde at 1% or 1.5% (vol/wt) and fumigation as well as washing with cinnamaldehyde solutions have the potential to reduce the trans-ovarian route of transmission of Salmonella in layer chickens and/or inhibit the growth of the pathogens on egg shells. Some investigations have used a combination approach. An examination of the influence of xylanase supplementation and a blend of cinnamaldehyde and thymol on wheat and soybean meals on performance and Salmonella horizontal transmission in 2000 broiler chickens challenged with Salmonella showed that the additives improved body weight gain and feed efficiency and did not affect feed intake.79 These beneficial

effects were accompanied by a decrease in cecal content of Salmonella by 61 and 77% for the two diets, respectively. The authors suggest that the observed improvement in both nutrition and safety in the broiler chickens implies that both the xylanase enzyme and the combination of essential oil compounds could be used as part of an integrated program to control Salmonella levels in poultry production. In a related study, Cerisuelo et al.80 found that Salmonella contamination of the cecum of broiler chickens orally infected with S. Enteritidis was lower on a diet supplemented with a mixture of low doses of essential oil components and sodium butyrate compared to the control basal diet. The additives did not affect the growth performance of the broilers. Inhibition of Brachyspira intermedia in Broiler Breeder Hens. Because cecal enteritis caused by Brachyspira infection adversely affects laying hens and broiler breeder hens, Verlinden et al.81 evaluated the in vitro sensitivity of poultry B. intermedia to a series of essential oil components including cinnamaldehyde. The highly active cinnamaldehyde had the lowest MIC values (40−80 mg/L). The supplementation of coated cinnamaldehyde (500 mg/kg) to the feed of rearing pullets young hens (less than a year old) also reduced colonization of the ceca, suggesting the possibility for alternative control of avian intestinal spirochetosis. In a similar species, an vitro study by Vande Maele et al.82 found that Brachyspira hyodysenteriae, a causative organism of swine dysentery, was highly sensitive to cinnamaldehyde with an MIC value 1.7 log CFU/g without affecting germination.171 Bread and Cheese. Active food packaging of gliadin protein films with 1.5−5.0% cinnamaldehyde completely inhibited the food-spoilage fungi Penicillium expansum and Aspergillus niger in sliced bread and cheese spread during storage for 10 days at 23 °C and for 26 days during storage at 4 °C, demonstrating the potential of the films to extend the shelf life of foods.172 Eggs. A cinnamaldehyde antimicrobial wash in deionized water rapidly inactivated nalidixic-acid-resistant Salmonella Enteritidis on egg shells.78 The results indicate that the initial bacterial count on the eggs of 8.0 log CFU/mL was reduced by ∼6.0 log CFU/mL after washing, and there were no differences in shell color or consistency compared with control eggs,

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RESEARCH NEEDS AND OUTLOOK Although much progress has been made in the investigations described here on the use of cinnamaldehyde as a novel antimicrobial, there are areas for further research to facilitate its potential use. Future studies are needed to address the following food and medical aspects of the cinnamaldehyde: • Determine the longevity of its antimicrobial activity in the feed and food systems. • Define additive, synergistic, and antagonistic effects of cinnamaldehyde in combinations with other natural antimicrobials and medical antibiotics. Evaluate its effectiveness against antibiotic-resistant pathogens in human foods and animal feeds. The interest in 10416



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genic and antidiabetic properties, suggest that it has the potential to help alleviate other diseases. GRAS-listed cinnamaldehyde has been shown in many cases to be an effective antimicrobial in farm animal feeds and in/on food from many different food categories for its antimicrobial activities against bacterial foodborne pathogens as well as spoilage microorganisms in foods and feeds. The following summary shows that cinnamaldehyde is an effective antimicrobial in foods and farm animal feeds and in/on food different food categories. Cinnamaldehyde has been reported to inactivate susceptible strains of B. cereus, C. jejuni, C. perf ringens, E. coli O157:H7, L. monocytogenes, S. enterica, and S. aurous as well as antibioticresistant strains of some pathogens. Cinnamaldehyde has also been incorporated into edible films prepared from fruits, vegetables, food proteins, and chitosan and has inactivated foodborne pathogens in foods either from direct contact of the films or by released vapors from the films in closed containers. The antimicrobial films also reduced nonpathogenic spoilage organisms that impact food quality. Because cinnamaldehyde is a safe compound with a pleasant taste and odor and is already added to foods to enhance flavor, synthetic cinnamaldehyde has the potential to be an inexpensive source of a food-compatible, broad-spectrum antimicrobial for use against a broad range of infectious diseases of animal and humans. The future research areas and needs outlined above should help to optimize the potential use of cinnamaldehyde in animal feeds, on or in human food items, as well as in medicine to combat pathogen contamination and infection.

cinnamaldehyde as a possible antimicrobial against resistant bacteria is indicated by the following recent observations: (a) Narayanan et al.179 found that in-feed supplementation of cinnamaldehyde reduced urinary tract E. coli infections in mice, suggesting that this finding is significant given the increase in incidence of antibiotic-resistant urinary tract infections in humans, (b) Kot et al.180 reported that cinnamaldehyde might have therapeutic potential as an inhibitory agent for use in methicillin-resistant Staphylococcus aureus (MRSA) biofilmrelated infections, and (c) Utchariyakiat et al.181 suggested that cinnamaldehyde might offer an alternative treatment against the multidrug-resistant food spoilage microorganism Pseudomonas aeruginosa. The potential of cinnamaldehyde to inhibit resistant pathogens in foods and feeds merits study. • Determine if cinnamaldehyde-supplemented feeds will increase feed intake and growth performance of farm animals and poultry.90 • Determine whether molecular modeling/simulations of antimicrobial−pathogen cell membrane interactions can be used to predict antibiotic activities.182,183 • Develop methods to concurrently reduce both pathogens and carcinogenic heterocyclic amines and mycotoxins in processed meat and poultry products. • Determine the concurrent inactivation of both pathogens and virulent toxins and endotoxins produced by the pathogens.184−187 • Determine if consumption of the cinnamaldehyde-treated contaminated foods will lower the risk of infection and concurrently impart other health benefits to farm animals and humans. • Determine whether using cinnamaldehyde can protect food animals and humans against infections through stimulation of the immune system, as described in detail for other food-compatible formulations.188−192 • Determine whether molecular modeling the cinnamaldehyde structure−cell membrane interactions can be used to predict antibiotic activity of cinnamaldehyde and derivatives. • Determine whether cinnamaldehyde metabolites formed after absorption into the circulation by animals and humans exhibit antibiotic properties. On the basis of the results that a combination of condensed tannins with cinnamaldehyde synergistically inhibited Caenorhabditis elegans, an intestinal nematode of livestock,193 determine whether cinnamaldehyde will also inhibit diseasecausing human and animal Trichomonas protozoa.194,195 • Will consumption of cinnamaldehyde-containing food improve oral hygiene? • Finally, on the basis of our previous observations using amino acid analysis196 that the α,β-unsaturated compound methyl vinyl sulfone (CH2CH−SO2−CH3) also reacted with the -NH group of histidine residues in polyhistidine, bovine serum albumin (BSA), and wool to form histidine adducts, it would be of interest to determine if cinnamaldehyde might also participate in similar transformations. We also found that one or both Hs in the ε-NH2 groups of protein lysine side chains participated in the addition reactions to form mono- and bisadducts. This aspect also merits study with cinnamaldehyde. In summary, the investigations described here into the use of cinnamaldehyde as an antimicrobial agent to protect animal feed, farm animals and food from contamination are of general interest to farmers, consumers, and food and medical scientists. Indeed, cinnamaldehyde is not just potentially an antimicrobial agent; other health benefits reported, including anticarcino-

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AUTHOR INFORMATION

Corresponding Author

*Phone: (510) 559-5615; e-mail: [email protected]. gov. ORCID

Mendel Friedman: 0000-0003-2582-7517 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS I thank Dr. Christopher J. Silva and Carol Levin for creative contributions and my colleagues whose names are shown in the cited references for excellent scientific collaboration.

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REFERENCES

(1) Friedman, M. Antibiotic-resistant bacteria: prevalence in food and inactivation by food-compatible compounds and plant extracts. J. Agric. Food Chem. 2015, 63, 3805−3822. (2) Friedman, M. Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol. Nutr. Food Res. 2007, 51, 116−134. (3) Friedman, M.; Juneja, V. K. Review of antimicrobial and antioxidative activities of chitosans in food. J. Food Prot. 2010, 73, 1737−1761. (4) Friedman, M. Chemistry and multi-beneficial bioactivities of carvacrol (4-isopropyl-2-methylphenol), a component of essential oils produced by aromatic plants and spices. J. Agric. Food Chem. 2014, 62, 7652−7670. (5) Nowotarska, S. W.; Nowotarski, K.; Grant, I. R.; Elliott, C. T.; Friedman, M.; Situ, C. Mechanisms of antimicrobial action of cinnamon and oregano oils, cinnamaldehyde, carvacrol, 2,5-dihydroxybenzaldehyde, and 2-hydroxy-5-methoxybenzaldehyde against Mycobacterium avium subsp. paratuberculosis (Map). Foods 2017, 6, 72.

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carvacrol and thymol. Biochim. Biophys. Acta, Gen. Subj. 2017, 1861, 3189−3198. (26) Friedman, M.; Levin, C. E. Review of methods for the reduction of dietary content and toxicity of acrylamide. J. Agric. Food Chem. 2008, 56, 6113−6140. (27) Friedman, M. Acrylamide: inhibition of formation in processed food and mitigation of toxicity in cells, animals, and humans. Food Funct. 2015, 6, 1752−1772. (28) Friedman, M. Chemistry, biochemistry, nutrition, and microbiology of lysinoalanine, lanthionine, and histidinoalanine in food and other proteins. J. Agric. Food Chem. 1999, 47, 1295−1319. (29) Friedman, M. Lysinoalanine in food and antimicrobial proteins. In Impact of Processing on Food Safety; Springer: New York, NY, 1999; Vol. 459, pp 145−159. (30) Friedman, M. The Chemistry and Biochemistry of the Sulfhydryl Group in Amino Acids, Peptides, and Proteins; Pergamon Press: Oxford, England, 1973; p 499. (31) Friedman, M. Application of the S-pyridylethylation reaction to the elucidation of the structures and functions of proteins. J. Protein Chem. 2001, 20, 431−453. (32) Cocchiara, J.; Letizia, C. S.; Lalko, J.; Lapczynski, A.; Api, A. M. Fragrance material review on cinnamaldehyde. Food Chem. Toxicol. 2005, 43, 867−923. (33) Kiwamoto, R.; Ploeg, D.; Rietjens, I. M.; Punt, A. Dosedependent DNA adduct formation by cinnamaldehyde and other foodborne α,β-unsaturated aldehydes predicted by physiologically based in silico modelling. Toxicol. In Vitro 2016, 31, 114−125. (34) National Toxicology Program. NTP toxicology and carcinogenesis studies of trans-cinnamaldehyde (CAS No. 14371-10-9) in F344/N rats and B6C3F1 mice (feed studies). Natl. Toxicol. Program Technol. Rep. Ser. 2004, 1−281. (35) Helander, I. M.; Alakomi, H. L.; Latva-Kala, K.; MattilaSandholm, T.; Pol, I. E.; Smid, E. J.; Gorris, L. G. M.; von Wright, A. Characterization of the action of selected essential oil components on gram-negative bacteria. J. Agric. Food Chem. 1998, 46, 3590−3595. (36) Gill, A. O.; Holley, R. A. Mechanisms of bactericidal action of cinnamaldehyde against Listeria monocytogenes and of eugenol against L. monocytogenes and Lactobacillus sakei. Appl. Environ. Microbiol. 2004, 70, 5750−5755. (37) Gill, A. O.; Holley, R. A. Inhibition of membrane bound ATPases of Escherichia coli and Listeria monocytogenes by plant oil aromatics. Int. J. Food Microbiol. 2006, 111, 170−174. (38) Gill, A. O.; Holley, R. A. Disruption of Escherichia coli, Listeria monocytogenes and Lactobacillus sakei cellular membranes by plant oil aromatics. Int. J. Food Microbiol. 2006, 108, 1−9. (39) Di Pasqua, R.; Betts, G.; Hoskins, N.; Edwards, M.; Ercolini, D.; Mauriello, G. Membrane toxicity of antimicrobial compounds from essential oils. J. Agric. Food Chem. 2007, 55, 4863−4870. (40) Amalaradjou, M. A. R.; Venkitanarayanan, K. Proteomic analysis of the mode of antibacterial action of trans-cinnamaldehyde against Cronobacter sakazakii 415. Foodborne Pathog. Dis. 2011, 8, 1095−1102. (41) Upadhyay, A.; Johny, A. K.; Amalaradjou, M. A.; Ananda Baskaran, S.; Kim, K. S.; Venkitanarayanan, K. Plant-derived antimicrobials reduce Listeria monocytogenes virulence factors in vitro, and down-regulate expression of virulence genes. Int. J. Food Microbiol. 2012, 157, 88−94. (42) Andrade-Ochoa, S.; Nevarez-Moorillon, G. V.; Sanchez-Torres, L. E.; Villanueva-Garcia, M.; Sanchez-Ramirez, B. E.; RodriguezValdez, L. M.; Rivera-Chavira, B. E. Quantitative structure-activity relationship of molecules constituent of different essential oils with antimycobacterial activity against Mycobacterium tuberculosis and Mycobacterium bovis. BMC Complementary Altern. Med. 2015, 15, 332. (43) Montagu, A.; Joly-Guillou, M. L.; Guillet, C.; Bejaud, J.; Rossines, E.; Saulnier, P. Demonstration of the interactions between aromatic compound-loaded lipid nanocapsules and Acinetobacter baumannii bacterial membrane. Int. J. Pharm. 2016, 506, 280−288. (44) Smith, M. K.; Draper, L. A.; Hazelhoff, P. J.; Cotter, P. D.; Ross, R. P.; Hill, C. A bioengineered nisin derivative, M21A, in combination

(6) Nowotarska, S. W.; Nowotarski, K. I.; Friedman, M.; Situ, C. Effect of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers. Molecules 2014, 19, 7497−7515. (7) Friedman, M. Antibacterial, antiviral, and antifungal properties of wines and winery byproducts in relation to their flavonoid content. J. Agric. Food Chem. 2014, 62, 6025−6042. (8) Friedman, M. Mushroom polysaccharides: chemistry and antiobesity, antidiabetes, anticancer, and antibiotic properties in cells, rodents, and humans. Foods 2016, 5, 80. (9) O’Neil, M. J. The Merck Index, 15th ed.; Royal Society of Chemistry: Oxford, U.K., 2013. (10) Teuscher, E. Medicinal Spices - A Handbook of Culinary Herbs, Spices, Spice Mixtures and Their Essential Oils; Medpharm Scientific Publishers: Stuttgart, Germany, 2006; p 459. (11) Jayaprakasha, G. K.; Rao, L. J. Chemistry, biogenesis, and biological activities of Cinnamomum zeylanicum. Crit. Rev. Food Sci. Nutr. 2011, 51, 547−562. (12) Rao, P. V.; Gan, S. H. Cinnamon: a multifaceted medicinal plant. Evid. Based Complement. Alternat. Med. 2014, 2014, 642942. (13) McGee, H. On Food and Cooking - The Science and Lore of the Kitchen; Scribner: New York, NY, 2004; p 884. (14) Bang, H. B.; Lee, Y. H.; Kim, S. C.; Sung, C. K.; Jeong, K. J. Metabolic engineering of Escherichia coli for the production of cinnamaldehyde. Microb. Cell Fact. 2016, 15, 16. (15) Gottardi, M.; Knudsen, J. D.; Prado, L.; Oreb, M.; Branduardi, P.; Boles, E. De novo biosynthesis of trans-cinnamic acid derivatives in Saccharomyces cerevisiae. Appl. Microbiol. Biotechnol. 2017, 101, 4883− 4893. (16) Friedman, M.; Kozukue, N.; Harden, L. A. Cinnamaldehyde content in foods determined by gas chromatography-mass spectrometry. J. Agric. Food Chem. 2000, 48, 5702−5709. (17) Jimén ez-Salcedo, M.; Tena, M. T. Determination of cinnamaldehyde, carvacrol and thymol in feedstuff additives by pressurized liquid extraction followed by gas chromatography-mass spectrometry. J. Chromatogr. A 2017, 1487, 14−21. (18) Raffo, A.; D’Aloise, A.; Magri, A. L.; Leclercq, C. Quantitation of tr-cinnamaldehyde, safrole and myristicin in cola-flavoured soft drinks to improve the assessment of their dietary exposure. Food Chem. Toxicol. 2013, 59, 626−635. (19) Lafeuille, J. L.; Buniak, M. L.; Vioujas, M. C.; Lefevre, S. Natural formation of styrene by cinnamon mold flora. J. Food Sci. 2009, 74, M276−283. (20) Chen, P. Y.; Yu, J. W.; Lu, F. L.; Lin, M. C.; Cheng, H. F. Differentiating parts of Cinnamomum cassia using LC-qTOF-MS in conjunction with principal component analysis. Biomed. Chromatogr. 2016, 30, 1449−1457. (21) Woehrlin, F.; Fry, H.; Abraham, K.; Preiss-Weigert, A. Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from indonesia. J. Agric. Food Chem. 2010, 58, 10568−10575. (22) Zhao, H.; Yang, Q.; Xie, Y.; Sun, J.; Tu, H.; Cao, W.; Wang, S. Simultaneous determination of cinnamaldehyde and its metabolite in rat tissues by gas chromatography-mass spectrometry. Biomed. Chromatogr. 2015, 29, 182−187. (23) Visvalingam, J.; Hernandez-Doria, J. D.; Holley, R. A. Examination of the genome-wide transcriptional response of Escherichia coli O157:H7 to cinnamaldehyde exposure. Appl. Environ. Microbiol. 2013, 79, 942−950. (24) Mousavi, F.; Bojko, B.; Bessonneau, V.; Pawliszyn, J. Cinnamaldehyde characterization as an antibacterial agent toward E. coli metabolic profile using 96-blade solid-phase microextraction coupled to liquid chromatography-mass spectrometry. J. Proteome Res. 2016, 15, 963−975. (25) Wang, L. H.; Wang, M. S.; Zeng, X. A.; Gong, D. M.; Huang, Y. B. An in vitro investigation of the inhibitory mechanism of βgalactosidase by cinnamaldehyde alone and in combination with 10418



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with food grade additives eradicates biofilms of Listeria monocytogenes. Front. Microbiol. 2016, 7, 1939. (45) Friedman, M. Antibiotic activities of plant compounds against non-resistant and antibiotic-resistant foodborne human pathogens. ACS Symp. Ser. 2006, 931, 167−183. (46) Cox, S. D.; Mann, C. M.; Markham, J. L.; Bell, H. C.; Gustafson, J. E.; Warmington, J. R.; Wyllie, S. G. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (Tea tree oil). J. Appl. Microbiol. 2000, 88, 170−175. (47) Cristani, M.; D’Arrigo, M.; Mandalari, G.; Castelli, F.; Sarpietro, M. G.; Micieli, D.; Venuti, V.; Bisignano, G.; Saija, A.; Trombetta, D. Interaction of four monoterpenes contained in essential oils with model membranes: Implications for their antibacterial activity. J. Agric. Food Chem. 2007, 55, 6300−6308. (48) Friedman, M.; Henika, P. R.; Levin, C. E.; Mandrell, R. E. Antibacterial activities of plant essential oils and their components against Escherichia coli O157:H7 and Salmonella enterica in apple juice. J. Agric. Food Chem. 2004, 52, 6042−6048. (49) Gustafson, J. E.; Liew, Y. C.; Chew, S.; Markham, J.; Bell, H. C.; Wyllie, S. G.; Warmington, J. R. Effects of tea tree oil on Escherichia coli. Lett. Appl. Microbiol. 1998, 26, 194−198. (50) Kwiecinski, J.; Eick, S.; Wójcik, K. Effects of tea tree (Melaleuca alternifolia) oil on Staphylococcus aureus in biofilms and stationary growth phase. Int. J. Antimicrob. Agents 2009, 33, 343−347. (51) Ravishankar, S.; Zhu, L.; Reyna-Granados, J.; Law, B.; Joens, L.; Friedman, M. Carvacrol and cinnamaldehyde inactivate antibioticresistant Salmonella enterica in buffer and on celery and oysters. J. Food Prot. 2010, 73, 234−240. (52) Wei, Q. Y.; Xiong, J. J.; Jiang, H.; Zhang, C.; Wen, Y. The antimicrobial activities of the cinnamaldehyde adducts with amino acids. Int. J. Food Microbiol. 2011, 150, 164−170. (53) Liu, T. T.; Tseng, Y. W.; Yang, T. S. Functionalities of conjugated compounds of γ-aminobutyric acid with salicylaldehyde or cinnamaldehyde. Food Chem. 2016, 190, 1102−1108. (54) Wang, H.; Yuan, H.; Li, S.; Li, Z.; Jiang, M. Synthesis, antimicrobial activity of Schiff base compounds of cinnamaldehyde and amino acids. Bioorg. Med. Chem. Lett. 2016, 26, 809−813. (55) Soliman, E. A.; Khalil, A. A.; Deraz, S. F.; El-Fawal, G.; Elrahman, S. A. Synthesis, characterization and antibacterial activity of biodegradable films prepared from Schiff bases of zein. J. Food Sci. Technol. 2014, 51, 2425−2434. (56) Sadofsky, L. R.; Boa, A. N.; Maher, S. A.; Birrell, M. A.; Belvisi, M. G.; Morice, A. H. TRPA1 is activated by direct addition of cysteine residues to the N-hydroxysuccinyl esters of acrylic and cinnamic acids. Pharmacol. Res. 2011, 63, 30−36. (57) Glaab, V.; Collins, A. R.; Eisenbrand, G.; Janzowski, C. DNAdamaging potential and glutathione depletion of 2-cyclohexene-1-one in mammalian cells, compared to food relevant 2-alkenals. Mutat. Res., Genet. Toxicol. Environ. Mutagen. 2001, 497, 185−197. (58) Janzowski, C.; Glaab, V.; Mueller, C.; Straesser, U.; Kamp, H. G.; Eisenbrand, G. α,β-Unsaturated carbonyl compounds: induction of oxidative DNA damage in mammalian cells. Mutagenesis 2003, 18, 465−470. (59) George, R. C.; Lew, J.; Graves, D. J. Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer’s disease pathogenesis. J. Alzheimers Dis. 2013, 36, 21−40. (60) Wu, C.; Zhuang, Y.; Jiang, S.; Tian, F.; Teng, Y.; Chen, X.; Zheng, P.; Liu, S.; Zhou, J.; Wu, J.; Wang, R.; Zou, X. Cinnamaldehyde induces apoptosis and reverses epithelial-mesenchymal transition through inhibition of Wnt/β-catenin pathway in non-small cell lung cancer. Int. J. Biochem. Cell Biol. 2017, 84, 58−74. (61) Zhu, R.; Liu, H.; Liu, C.; Wang, L.; Ma, R.; Chen, B.; Li, L.; Niu, J.; Fu, M.; Zhang, D.; Gao, S. Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety. Pharmacol. Res. 2017, 122, 78−89. (62) Yao, Y.; Huang, H. Y.; Yang, Y. X.; Guo, J. Y. Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like

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