Biological fate, functional properties, and design strategies for oral delivery systems for cinnamaldehyde

Xiaolan Weng a, Chi-Tang Ho b and Muwen Lu *a
aGuangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China. E-mail: muwen90@scau.edu.cn; Tel: +18664527647
bDepartment of Food Science, Rutgers University, New Brunswick, NJ 08901, USA

Received 5th February 2024 , Accepted 8th May 2024

First published on 9th May 2024


Abstract

Cinnamaldehyde (CA) is the main bioactive component extracted from the internal bark of cinnamon trees with many health benefits. In this paper, the bioavailability and biological activities of cinnamaldehyde, and the underlying molecular mechanism are reviewed and discussed, including antioxidant, cardioprotective, anti-inflammatory, anti-obesity, anticancer, and antibacterial properties. Common delivery systems that could improve the stability and bioavailability of CA are also summarized and evaluated, such as micelles, microcapsules, liposomes, nanoparticles, and nanoemulsions. This work provides a comprehensive understanding of the beneficial functions and delivery strategies of CA, which is useful for the future application of CA in the functional food industry.


1. Introduction

Cinnamon is a popular spice around the world, which contains a variety of vitamins, minerals, and phytochemicals with many health benefits.1 Cinnamaldehyde (CA) is the major bioactive constituent extracted from the inner bark of various tree species within the Cinnamomum genus with concentrations as high as 90.5% in Cinnamomum verum and 85.3% in Cinnamomum cassia.2 The biosynthetic pathway leading to CA synthesis begins in the leaves and bark tissues of the plant.3 The photosynthetic process facilitates the generation of the precursor molecule phenylalanine, which subsequently undergoes a complicated biosynthetic pathway, leading to the formation of cinnamic acid.4 The cinnamic acid is then transported to the bark tissue and reduced to CA through a catalytic reaction.5

CA has been reported to exhibit diverse pharmacological properties, including antioxidant,6 cardioprotective,7,8 anti-inflammatory,9,10 anti-obesity,11,12 antitumor,13,14 and antibacterial activities15–17 (as shown in Fig. 1). However, due to the low water solubility and susceptibility to oxygen, light and high temperature, the stability and bioavailability of CA are negatively affected.18 Consequently, much effort has been made in recent decades to develop delivery systems for CA to enhance its biological efficacy. In this review, the bioavailability, pharmacological properties and underlying molecular mechanisms of CA are reviewed and discussed. Furthermore, various delivery systems for improving the bioavailability of CA are also summarized.


image file: d4fo00614c-f1.tif
Fig. 1 A summary of the biological efficacies of CA.

2. Bioavailability of cinnamaldehyde

A variety of studies had been conducted to evaluate the oral bioavailability of CA in the aspect of absorption, tissue distribution, metabolism, and excretion.19–21 Zhu et al. reported that after oral administration, CA was partially metabolized into cinnamic acid in the stomach and small intestine and was almost completely converted into cinnamic acid in the livers of rats.22 Sapienza et al. studied the primary metabolic pathway of CA in rats and reported that CA was firstly oxidized into benzoic acid by β-oxidation, which then reacted with glycine to form hippuric acid, and was excreted in urine. The major urinary metabolite was hippuric acid.1,23

Yong et al. studied the pharmacokinetics of CA after oral administration using male SD rats and found that the area under the blood concentration-time curve was 48[thin space (1/6-em)]648.38 ± 482.32 (mg min) L−1.24 The peak concentration of 301.61 ± 67.91 mg L−1 was reached at 20 minutes after oral administration. Ji et al. reported that the half-life for CA reached 8.7 ± 0.7 h after oral administration in rats.25 It was found that CA in rat tissues was mainly distributed in the gastrointestinal tract, livers, and kidneys in male Fischer 344 rats after the oral administration of 14C-labelled CA.20,23 According to Zhao et al., CA could not be detected after 24 hours of oral administration, indicating that CA was completely metabolized within one day.26

3. Biological efficacy of cinnamaldehyde

3.1 Antioxidant effect

The antioxidant properties of CA had been examined in numerous studies, which are summarized in Table 1. Tanaka et al. reported that CA had an effective antioxidant effect in the ultraviolet radiation B-induced keratinocytes by enhancing the expression of heme oxygenase 1 (HMOX1) (an enzyme responsible for oxidative degradation of the heme group).27 Uchi et al. discovered that CA effectively inhibited the nuclear translocation of aryl hydrocarbon receptor (AHR) induced by benzo(α)pyrene in human immortalized keratinocyte (HaCaT) cells, thereby inhibiting the overproduction of reactive oxygen species (ROS).28 CA had also been found to significantly inhibit ROS production in peripheral blood mononuclear cells of patients with rheumatoid arthritis, mouse skin tissue, and young mouse hepatocytes,27,29,30 suggesting great potential in the treatment of oxidative stress-induced diseases. Mitamura et al. claimed that CA suppressed the expression of periostin (a multifunctional matricellular protein in inflammatory microenvironments) through transforming growth factor (TGF)-β1 and the interleukin (IL)-13 signaling pathway by activating nuclear factor erythroid-derived 2-like 2 (Nrf2).31 Another study using rats fed a high-fat diet (HFD) revealed that CA significantly reduced the HFD-induced oxidative stress by restoring changes in the concentration of nitric oxide metabolites (NOx) in the serum and cerebellum.32 Therefore, CA has great potential to be used as a promising dietary supplement to prevent oxidation.
Table 1 Antioxidant effect of CA and the underlying mechanisms
In vitro/in vivo model Observations Ref.
Ultraviolet radiation b-induced keratinocytes Enhance induction of HMOX1 expression 27
Mouse skin tissue Downregulate the expression of MDA 27
Decrease lipid peroxidation
Decrease ROS
HaCaT cells Inhibit nuclear translocation of AHR 28
Decrease ROS
Rheumatoid arthritis patient peripheral blood mononuclear cells Reduce ROS 30
Young mouse hepatocytes Reduce ROS 29
Dermal fibroblasts Decrease POSTN 31
Rats fed a high-fat diet Decrease MDA in the serum and brain 32
Restore the concentration of NOx
Downregulate lipid peroxidation levels
Diminish weight gain
Albino Wistar rats Inhibit the activity of superoxide dismutase (SOD) 91
Decrease the expression of CAT
Fat-sucrose diet/streptozotocin (STZ) rat model Enhance reduced glutathione (GSH) and ascorbate of placental content 92
Suppress MDA and total non-enzymatic antioxidant power
Reduce flavonoids and total ascorbate
Monosex Nile tilapia fingerlings (Oreochromis niloticus) Decrease muscle MDA 93
Activate the activity of glutathione reductase
Cynoglossus semilaevis Reduce the accumulation of MDA 94
Increase the activities of antioxidant enzymes including superoxidase dismutase, CAT, total antioxidant capacity and glutathione peroxidase
Myocardial ischemia/reperfusion injury rat model Increase the levels of GSH and SOD 95
Inhibit the activity of MDA


3.2 Cardioprotective effect

Researchers had reported that CA could protect against cardiovascular disorders in various cell and animal models.33–35 Li et al. found that CA inhibited the proliferation, migration and inflammation of the oxidized low-density lipoprotein-induced vascular smooth muscle cells (VSMC), and foam cell formation by reducing the overexpression of MMP-2 and lectin-like oxidized low density lipoprotein receptor-1, upregulating the expression of HMOX1.33 According to Zheng et al., CA ameliorated abnormal myocardial morphology including edema, unclear striations, and some areas of necrosis and apoptosis in myocardial ischemia/hypoxia model through activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway.36 Many studies had reported the vasodilatory effect of CA by inhibiting calcium influx and release.35,37,38 According to a study using an adult male white rabbit model of subarachnoid hemorrhage, CA increased the cross-sectional areas of the basilar artery and decreased the arterial wall thickness via multiple pathways, such as transient receptor potential ankyrin-1 (TRPA1) agonism, resulting in the release of calcitonin gene-related peptides, indicating the neuroprotective and cerebral vasospasm-preventing properties of CA.38 Therefore, CA exerts effective cardioprotective properties by activation of the TRPA1 channel and regulating the expression levels of HMOX1 and MMP-2 via the PI3K/AKT signaling pathway (as summarized in Fig. 2 and Table 2).
image file: d4fo00614c-f2.tif
Fig. 2 The cardioprotective effect and mechanisms of CA.
Table 2 Cardioprotective effect of CA and the underlying mechanisms
In vitro/in vivo model Observations Ref.
Fructose-exposed H9c2 cells Restore fructose-induced changes in TGF-β, p-Smad2/3 and Smad4 protein levels; 96
Reduce nicotinamide adenine dinucleotide phosphate oxidase and xanthine oxidase activities;
Attenuate ox-ldl-induced ROS overproduction, hioredoxin-interacting protein overexpression and CD36 upregulation;
Neonatal rat cardiac myocytes and adult mouse cardiac myocytes Inhibit the expression of vasohibin 1, small vasohibin binding protein and tubulin tyrosine ligase and α-tubulin detyrosination; 97
enhance calcineurin activation caused by phenylephrine;
reduce store-operated Ca2+ entry and stromal interaction molecule-1/orai1 translocation;
protect T-tubule structure, calcium handling, and sarcomere contractility;
Human umbilical vein endothelial cells (HUVEC) Activate the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways; 98
enhance the secretion of vascular endothelial growth factor and HUVEC tube formation;
reduce HUVEC tube damage
The mouse Matrigel plug assay Form more capillary-like structures and neovessels, and thicken the vascular wall;
increase vascular endothelial growth factor protein around the damaged tissues
The adult male white rabbit model of subarachnoid hemorrhage Decrease the level of TXA2, an important regulator of vascular tension; 38
activate TRPA1, resulting in the release of the calcitonin gene-related peptide
VSMC Suppress the migration of VSMC induced by human oxidized low-density lipoprotein; 33
upregulate the expression of HMOX1;
block the cell cycle of VSMC in the S phase;
suppress the overexpression of MMP-2, p38, JNK/MAPK and NF-κB signaling pathways
Thoracic aortas of male Sprague-Dawley rats Activate the TRPA1 pathway; 37
release the calcitonin gene-related peptide;
inhibit calcium influx and release
Rabbits on a high cholesterol diet Reduce atherosclerotic lipid deposition, myeloperoxidase activity and high-cholesterol diet aortic intima/media ratio; 99
increase NOx levels;
decrease expression of cholesteryl ester transfer protein and myeloperoxidase
Thoracic aorta of male Wistar rats Reduce the exaggerated contraction of vascular and the formation of advanced glycation end products (AGEs); 8
stimulate nitric oxide(NO) production;
Myocardial ischemia/reperfusion injury rat model Reverse the decrease of left ventricular ejection fraction, left ventricular fractional shortening and stroke volume; 95
Reverse the increase of left ventricular internal diameter at end-systole and left ventricular internal diameter at end-diastole;
inhibit the elevations of cardiac troponin I, creatine kinase-MB, lactate dehydrogenase, and aspartate aminotransferase;
suppress the increase of mRNA and protein expression levels of gasdermin (GSDMD);
decrease the expression levels of IL-6, necrosis factor-alpha (TNF-α), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), pro-caspase-1, caspase-1, and apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC)
Zucker diabetic fatty rats Inhibit platelet derived growth factor-induced VSMC proliferation; 100
enhance the level of glutamate-cysteine ligase catalytic subunit and peroxiredoxin 1
Mice subjected to subcutaneous administration of phenylephrine Inhibit the elevation of hypertrophic genes, including Nppa, Nppb and Mhy7; 101
prevent the increase of the interventricular septal thickness at both systole and diastole, as well as the increase of the phosphorylation of calcium/calmodulin-dependent protein kinase II and extracellular signal-related kinase


3.3 Anti-inflammatory effect

Multiple studies had indicated the potential application of CA as an anti-inflammatory agent as shown in Fig. 3 and Table 3.39–42 According to Kim et al., CA effectively suppressed U937 monocytic cells adhesion to human umbilical vein endothelial cells by reducing the expression of vascular cell adhesion protein 1 (VCAM-1).42 Zhu et al. discovered that CA improved the immune function in helminth-infected rodents by suppressing the expression of toll-like receptor (TLR) and regulating T-cell populations in mesenteric lymph nodes.9trans-Cinnamaldehyde (TCA) had been found to reduce the proliferation of pro-inflammatory cytokines in C2C12 mouse skeletal muscle cells treated with lipopolysaccharide (LPS) by suppressing the expression levels of TLR-4 and inhibiting the NF-κB signaling pathway, as well as downregulating the expression of nitric oxide (NO) and prostaglandin E2 (PGE2), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2).39,43 According to Li et al., CA could alleviate cartilage destruction in the C28/I2 human chondrocyte cell line via decreasing the mRNA expression levels of MMP-1, MMP-3 and MMP-13 as well as reducing the levels of p-p38 and p-JNK, demonstrating an anti-inflammatory effect in vitro and a protective effect on chondrocytes in vivo.10 Mateen et al. discovered that CA exerted an anti-inflammatory effect in peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis by effectively inhibiting the secretion of pro-inflammatory cytokines TNF-α and IL-6 and regulating the equilibrium of cytokines secreted by Th1 and Th2 cells.30 Another study stated that CA alleviated collagen-induced swollen paw volume in rats with arthritis by inhibiting the phosphorylation of janus kinase 2 (JAK2) and decreasing the expression of p-signal transducer and activator of transcription 1 (STAT1) and p-STAT3.44 Therefore, CA has great potential to be used as an anti-inflammatory agent by suppressing the pro-inflammatory mediators and cytokines, such as TNF-α, IL-6, IL-8 IL-10, IL-17 and IL-1β.
image file: d4fo00614c-f3.tif
Fig. 3 The anti-inflammatory effect and mechanisms of CA.
Table 3 Anti-inflammatory effect of CA and the underlying mechanisms
In vitro/in vivo model Observations Ref.
U937 Reduce the expression of VCAM-1; 42
C2C12 mouse skeletal muscle cells Inhibit the expression of common pro-inflammatory mediators such as NO and PGE2 by suppressing the protein and mRNA expression of iNOS and COX-2; 39
suppress the expression levels of TLR-4;
inhibit the NF-κB signaling pathway
C28/I2 cells Alleviate cartilage destruction; 10
Reduce the mRNA expression levels of MMP-1, MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5
PBMC Inhibit the secretion of pro-inflammatory cytokines 30
Regulate the equilibrium of cytokines secreted by Th1 and Th2 cells
MH7A Inhibit the phosphorylation of JAK2; 44
decrease the expression of STAT1 and p-STAT3;
alleviate the collagen-induced arthritis by decreasing in paw swelling and significant reduction in histologic changes;
reduce the serum levels of pro-inflammatory cytokines IL-1β and IL-6
BV-2 microglial cells Inhibit the activation of extracellular-regulated kinase, JNK, p38 MAPK, and NF-κB; 102
decrease microglia-mediated neuroblastoma cell death
RAW 264.7 murine macrophage cells Inhibit the expression of Porphyromonas gingivalis (Pg) supernatant-induced IL-6, TNF-α and IL-1β; 103
attenuate the elevation of ROS;
inhibit the activation of the NF-κB signaling pathway
Human periodontal ligament cells Suppress the expression of Pg supernatant-induced IL-6, IL-8, TNF-α and IL-1β;
inhibit the elevation of monocyte chemoattractant protein 1, intercellular adhesion molecule 1 and VCAM-1 induced by the Pg supernatant;
attenuate the elevation of ROS;
THP-1 cells Inhibit the release of TNF-a and IL-1β; 104
suppress the phosphorylation of JNK, p38, and NF-κB;
increase the expression of absent in melanoma 1, ASC, procaspase-1 and pro-IL-1β
Human keratinocytes Activate the Nrf2 pathway; 105
increase HMOX1;
enhance the protein level of NAD(P)H quinone oxidoreductase 1
Female C57BL/6 mice Downregulate inflammation-related pathways in both healthy and helminth-infected rodents; 9
alter immune-related genes and NRF2-related xenobiotic-metabolizing pathways
Raw 264.7 murine macrophage cells Suppress the protein and mRNA expression of iNOS; 43
decrease the mRNA expression level and secretion of IL-1β, IL-6 and TNF-α
Endotoxin-induced mice Reverse endotoxin-induced body weight loss and the enlargement of lymphoid organ; 106
decrease endotoxin-induced levels of peripheral nitrate/nitrite;
downregulate IL-1β, IL-18, TNF-α, interferon-γ, and high-mobility group box 1 protein;
inhibit the activation of NF-κB and caspase-1;
inhibit the expression of caspase-recruitment domain and NLRP3;
enhance the expression of TLR4, myeloid differentiation protein 2, and myeloid differentiation primary response gene 88
Male Wistar rats fed with HFD Reduce the anti-atherogenic index 107
Overactive bladder-related murine model Inhibit overexpression of macrophage migration inhibitory factor and TLR4 108
Complete Freund's adjuvant-induced arthritis in mice Downregulate the expressions of TNF-α, NF-κB and COX-2 109
Reduce the levels of IL-1β, IL-6, IL-23 and IL-17
ApoE/ mice diminish atherosclerotic lesion areas; 40
reduce the perceptible atherosclerotic plaque formation and intima damage;
Female Wistar rats Decrease the spleen index; 41
decrease the arthritic score;
reduce paw volume of arthritic rats


3.4 Anti-obesity effect

CA had been reported to have an anti-obesity effect by reducing body weight and fat accumulation, as well as preventing obesity-related metabolism disorders, as summarized in Table 4.45–49 Neto et al. claimed that CA treatment reduced the size of white adipose tissue (WAT) adipocytes by decreasing the expression of peroxisome proliferator-activated receptor gamma (PPARγ).46 In another rat model of early obesity, CA was found to decrease the synthesis of lipid in the liver possibly through attenuating the increments of the mRNA expressions of sterol regulatory element-binding protein (SREBP1c) and acetyl-CoA carboxylase 1 (ACC1).47 Hoi et al. found that CA facilitated the release of serotonin via the TRPA1 pathway in differentiated Caco-2 cells, thereby alleviating the reduction of fatty acid uptake.50 CA treatment could also lead to a reduction in triglyceride accumulation (an indicator of fat content) in 3T3-L1 cells via the activation of TRPA1 channels.51 Abdelmageed et al. stated that CA improved lipid metabolism disorders by attenuating the levels of triacylglycerols, total cholesterol and very-low-density lipoprotein cholesterol.49 Therefore, CA treatment could be an effective approach for treating obesity and related metabolic disorders.
Table 4 Anti-obesity effect of CA and the mechanisms
In vitro/in vivo model Observations Ref.
Caco-2 cells Alleviate the reduction of fatty acid uptake; 50
induce serotonin release;
3T3-L1 cells Activate of TRPA1 channels; 51 and 110
reduce in triglyceride accumulation;
decrease the content of microRNA (miR)320;
increase the content of miR26-b;
downregulate the expression levels of key lipogenic transcription factors PPARγ, C/EBP-α, C/EBP-β, and lipogenic markers FAS gene and protein levels
Primary human omental preadipocytes Enhance insulin-induced activation of Akt2 and glucose uptake; 111
Alpha mouse liver 12 cells increase the expression of methyltransferase 3; 11
upregulate the levels of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid;
increase CYP4F40 expression;
alleviate steatosis
Male C57BL/6J rat model fed an HFD Decrease HFD-induced body weight gain; 45
diminish plasma free fatty acid and leptin levels;
inhibit the elevation of serum total cholesterol, triglyceride, and low-density lipoprotein cholesterol level;
enhance the expression of the peroxisome PPARγ, PR domain-containing 16 and PPARγ coactivator 1α proteins
HepG2 cells Decrease the activity of G6Pase; 12
inhibit glucose metabolism of α-enolase;
enhance gluconeogenesis;
increase the phosphorylation level of AMP-activated protein kinase
STZ-induced T2D rat model Decrease serum alanine aminotransferase and aspartate aminotransferase activity, serum AGEs and its receptors in the aorta; 49
decrease hepatic MDA;
increase hepatic and aortic glutathione and SOD;
inhibit steatosis and inflammation in the liver tissue
Male rat model of early obesity Reduce Srebf1c and Acaca expression; 46 and 47
diminish WAT and brown adipose tissue adipocyte;
reduce expression of lipogenesis-related genes like PPARγ and Dgat2;
increase BAT thermogenesis markers such as PPARα, Fgf21 and Ucp1;
reduce lipogenesis marker expression such as PPARγ and lipoprotein lipase
Male Wistar rats fed an HFD Decrease the NOx level of HFD rats; 48
reduce NO-induced insulin secretion;
inhibit iNOS activity of HFD rats
Male db/db mice Decrease the level of GHbA1c; 12
decrease glycerophosphocholine levels;
diminish long-chain fatty acids, such as myristoleic acid and oleic acid;
upregulate 1-stearoyl-2-oleoyl-sn-glycerol 3-phosphocholine


3.5 Anti-cancer effect

Cancer is one of the leading causes of death worldwide, and its prevention could be aided by the supplementation of various dietary phytochemicals.52 CA exerted anti-cancer effects in various cancer cells through promoting cell apoptosis and inhibiting cell proliferation, migration, and invasion, as shown in Fig. 4 and Table 5.53–55 Chen et al. discovered that CA treatment suppressed cell proliferation in A549, NCIH1650, SK-MES-1, and NCI-H226 cells by elevation of suppressors of cytokine signaling 1, BTG anti-proliferation factor 2 and Bruton tyrosine kinase via the JAK/STAT signaling pathway.55 CA suppressed the cell viability of the MDA-MB-231 human breast cancer cell line by reducing the elevated expression of proliferation-related proteins mammalian target of rapamycin, PI3K, and proliferating cell nuclear antigen (PCNA), indicating the potential of CA against breast cancer.52 Mei et al. discovered that CA treatment attenuated the inhibition of T cells mediated by cancer-associated fibroblasts (CAFs) by altering the expression levels of TLR4 pathway-related proteins such as phospho-c-Jun N-terminal kinase (p-JNK), JNK, p-TAK1, TAK1, and p-c-Jun, thus activating the TLR4 pathway.56 Kim et al. reported that CA mediated autophagy in NCI-N87 and MKN-74 cells by downregulating p62 expression and upregulating ATG5, Beclin-1, and LC3-II expression, thereby inhibiting the growth of gastric cancer cells.57 In a visfatin-induced proliferation xenograft animal model, tumor volume and weight decreased in mice treated with CA via downregulation of the expression of PCNA.52 Therefore, CA has great potential in the prevention and treatment of cancers, including breast cancer, gastric cancer, lung cancer, prostate cancer, colorectal cancer, bladder cancer, and ovarian cancer.58–60
image file: d4fo00614c-f4.tif
Fig. 4 The anti-cancer effect and mechanisms of CA.
Table 5 Anti-tumor effect of CA using different models and the underlying mechanisms
Cancer model Cell model Effect and mechanism Ref.
Breast cancer MDA-MB-231 cells Suppress cell proliferation, invasion, and migration; 52 and 53
induce apoptosis;
downregulate the levels of key proteins such as PPARA, PPARD, BDNF and NCOA2;
Upregulate the expression of TLR4;
Visfatin-induced proliferation xenograft animal model decrease tumor volume and weight were in mice;
diminish the expression of PCNA protein, intracellular and extracellular nicotinamide phosphoribosyl transferase protein
Gastric cancer NCI-N87 cells Induce autophagic cell death and accelerate calcium release; 57
upregulate ATG5, Beclin-1, LC3B, GRP78, p-PERK, p-eIF2α and CHOP;
MKN-74 cells Increase caspase 3 and 9 cleavage;
downregulae Bcl-2 and p62 expression;
Lung cancer A549 cells Decrease the relative cell activity; 54 and 55
arrest cell cycle;
increase the number of apoptotic cells;
NSCLC cells Induce cell apoptosis and suppress cell proliferation; 55
inhibit cell invasion and migration;
enhance the expression levels of cytokine signaling 1, CREB3 regulatory factor, MAX dimerization protein 1, BTG anti-proliferation factor 2, Bruton tyrosine kinase, lncRNAsLINC01504, LUCAT1, LINC01484, THUMPD3-AS1, and LINC01783;
decrease the phosphorylation levels of JAK, STAT3, NF-κB and p65
Subcutaneous tumor implantation model Decrease the volume and weight of tumors;
Prostate cancer CAFs Alter the expression levels of TLR4 pathway-related proteins such as phospho-c-Jun N-terminal kinase (p-JNK), JNK, p-TAK1, TAK1, and p-c-Jun; 56
relieve CAF-mediated T cell inhibition;
Colorectal cancer Xenograft mouse model Decrease tumor volume and weight were in mice; 59
downregulate Bcl-2;
upregulate Bax, pro-apoptotic proteins such as cleaved caspase-3 and cleaved PARP
Human CRC cell lines HCT116 and SW480 Induce cell apoptosis and inhibit proliferation;
upregulate pro-apoptotic proteins such as cleaved caspase-3 and cleaved PARP;
downregulate β-catenin, c-Myc, Cyclin-D1, p-GSK3β and nuclear β-catenin;
Ovarian cancer A2780 and SKOV3 cells Inhibit proliferation and invasion, and phosphorylation levels of mTOR, PI3K, and AKT; 60
increase the expression of mito-PARP and mito-caspase-3;
induce cell apoptosis
Subcutaneous xenograft model of the A2780 cells in nude mice Decrease tumor weight in mice;
suppress the expression levels of Ki67, MP9 and EGFR


3.6 Antibacterial effect

Many studies had shown that CA exerted antibacterial activity by inhibiting the growth of infectious microorganisms.61–65 He et al. reported that CA inhibited the growth of Streptococcus mutans by decreasing bacterial aggregation and metabolic activity, and increasing surface hydrophobicity.65 CA had also been reported to inhibit the proliferation of Escherichia coli (E. coli.) in the type 2 human epithelial cell model by reducing the aggregation and adhesion of E. coli.64 Similarly, CA exerted an anti-adhesive effect on Salmonella in human colon carcinoma cells via suppressing the type I fimbriae.66 Yu et al. discovered that the intervention of CA decreased the structural integrity of cells by reducing the concentration of extracellular polymer proteins in Campylobacter, thereby inhibiting its biofilm formation.62 Usai et al. discovered that CA had a synergistic effect with antibiotics against a wide range of Gram-negative and Gram-positive bacteria, particularly drug-resistant strains and superbugs, as determined by measuring the fractional inhibitory concentration index.61 Therefore, CA showed antibacterial activity by inhibiting the growth of microorganisms, destabilizing bacterial biofilms, reducing the aggregation and adhesion of bacterial cells, and functioning as a synergistic agent with antibiotics.

4. Novel delivery systems for cinnamaldehyde

Due to the poor water solubility and sensitivity to oxygen, light, and high temperature, the biological efficacy of CA was greatly limited.67 To enhance its bioavailability, various delivery systems for CA had been designed, including micelles, microcapsules, liposomes, nanoparticles and nanoemulsions, as depicted in Fig. 5.68–70 In this section, the novel delivery systems for CA were summarized and discussed.
image file: d4fo00614c-f5.tif
Fig. 5 Common delivery systems for CA with enhanced bioavailability.

4.1 Micelles

Micelles had been developed as nanocarriers for hydrophobic nutraceuticals, consisting of spherical, self-assembled amphiphilic block copolymers with diameters between 10 and 100 nanometers.71 Cartaya et al. encapsulated CA into poly(lactic-co-glycolic acid)-poly(siloxane) pluronic micelles using a direct dissolution method to prepare antioxidant response-activated nanospheres, providing complete drug integrity protection and selective targeting of cells, effectively inhibiting the proliferation and migration of vascular smooth muscle cells.72 CA-loaded micelles significantly increased the content of GSH compared to free unformulated CA. Raffai et al. reported that CA-loaded micelles were synthesized by the Michael addition reaction.73 Those CA-loaded micelles possessed vasodilator properties, shown to relieve coronary vasospasm and inhibit the Ca2+ influx in porcine coronary arteries. Deng et al. developed a pH-sensitive charge-conversion CA polymeric prodrug micelle using a reversible addition–fragmentation chain transfer polymerization method.74 The CA-loaded micelles had been proven to have a reduced particle size of 227 nm and enhanced anti-tumor effects on 143B osteosarcoma cells compared with free CA, indicating that micelles had great potential to reduce particle sizes and enhance the bioavailability of CA.

4.2 Microcapsules

Microcapsules have been widely used to protect bioactive compounds from oxidation and volatilization, effectively improving the drug stability.21,75,76 Li et al. prepared a three-matrix system of methyl cellulose/carboxymethyl chitosan/sodium alginate using a spray drying method to encapsulate CA with a 50% encapsulation rate and a 4% loading capacity.77 Physicochemical and biological studies showed that CA-loaded microcapsules exhibited enhanced resistance to oxidation, hydrolysis, and thermal decomposition, with prolonged storage and improved bioavailability. Xiao et al. claimed that the encapsulation of CA using β-cyclodextrin significantly elevated the plasma CA concentration while reducing the levels of its metabolites in male C57/BL6 mice.21 Notable distinctions in richness and diversity were observed in the fecal microbiota compared to the CA group, indicating that the CA microcapsules were effective in enhancing CA absorption with a pronounced modulatory effect on gut microbiota. Chen et al. prepared CA-loaded microcapsules using tannic acid with an encapsulation efficiency of 92.53 ± 5.20%.75 Biological studies showed that the microcapsules effectively improved the antifungal activity of CA against Aspergillus brasiliensis. Wong et al. stated that the sodium alginate–chitosan at a mass ratio of 150[thin space (1/6-em)]:[thin space (1/6-em)]1 had an encapsulation rate of 95.25% and a loading capacity of 81.42% for CA.78 Physiochemical characterization had proved that the sodium alginate and chitosan-wrapped CA had a prolonged release and improved absorption.

4.3 Liposomes

Liposomes were spherical vesicles composed of dispersed amphipathic lipids, featuring a hydrophilic head and a hydrophobic tail within an aqueous phase, which were considered ideal delivery systems for nutraceuticals due to their high drug loading rate and low biological toxicity.79 Xue et al. developed inulin-modified liposomes using the thin-film hydration method, achieving a particle size of 72.52 ± 0.71 nm and an encapsulation efficiency of 70.71 ± 0.53%.79 The inulin-modified liposomes inhibited particle aggregation, resulting in the prevention of CA leakage as well as increased storage stability and antioxidant activity. Sang et al. prepared a polymyxin B-modified liposomal system loaded with CA (P-CA-Lipo) using the thin film evaporation method, with a particle size of 150 nm, an encapsulation efficiency of 31.93 ± 0.6%, and a drug loading of 14.99 ± 0.28%.80 Compared to unformulated samples, the CA release from P-CA-Lipo was more stable and durable, exhibiting higher water solubility and stability, and improved antibacterial activity through enhanced bacterial targeting and penetration. Makwana et al. found that polydiacetylene N-hydroxysuccinimide liposomes loaded with CA could fuse with the bacterial cell membranes and release CA directly into the cells, thereby enhancing the antibacterial effect.81

4.4 Nanoparticles

Nanoparticles were tiny materials with particle sizes ranging from 1 to 100 nanometers, which had been widely used as nanocarriers in drug delivery.82–84 Compared with large molecules, nanoparticles were more easily absorbed by cells, thereby enhancing the pharmacological and therapeutic properties of drugs. Liu et al. developed CA-loaded nanoparticles (NPs-C) using a thermally induced gelation method, with a particle size of approximately 185 nm, an encapsulation efficiency of 76.57%, and a loading capacity of 19.02%.84 Compared with free CA, the NPs-C were more stable in harsh environments (extreme pH, high ionic strength, and elevated temperatures), with extended storage time and sustained antimicrobial activity. Li et al. discovered that solid-lipid nanoparticles containing CA could reduce the toxic metabolite malonaldehyde in strawberry cells, enhance the activity of antioxidant enzymes, and prevent cell damage.83 Physicochemical and biological studies had demonstrated that nanoparticles effectively enhanced the sustained release and mitigated the toxic effects of high CA concentrations on strawberry cells. Gursu et al. found that CA-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles had an enhanced stability, with a particle size of 130.4 nm, an encapsulation efficiency of 93%, and zeta potential values ranging from −3.54 to −3.86 mV.82 CA-PLGA nanoparticles demonstrated stronger antifungal and antibiofilm properties, achieving higher sterilization effects with significantly lower amounts of CA. Therefore, nanoparticles could enhance the stability and retention for CA, with sustained release and improved bio-efficacy.

4.5 Nanoemulsions

Nanoemulsions were emulsions with a droplet size ranging from 10 to 1000 nm, which could effectively enhance the solubility of bioactive compounds due to high surface area and dispersibility.18 Hojati et al. prepared the CA-loaded nanoemulsion with a zeta potential of −0.60 mV and a droplet size of 146.1 nm.85 The CA-loaded nanodroplets demonstrated a reduced minimum inhibitory concentration and minimum bactericidal concentrations against S. aureus, E. coli, and C. perfringens, suggesting increased antimicrobial activity. Liu et al. used Tween 80 to encapsulate CA within a water-in-oil emulsifier, fabricating a CA nanoemulsion with an average particle size of 94.37 ± 2.12 nm and a polydispersity index (PDI) of 0.227 ± 0.008.86 The CA nanoemulsion reduced the volatility of CA and provided sustained release, effectively reducing loss in meat exudate and extending the shelf life of frozen pork. Otoni et al. prepared a CA-loaded oil-in-water nanoemulsion with particle sizes ranging from 41.32 to 271.95 nm and PDI ranging from 0.221 to 0.301.87 Microbiological assessment showed that the permeability of CA through microbial cells was enhanced due to the increased surface area of the nanoemulsion, thereby effectively enhancing the antibacterial activity.

5. Summary

As a natural aromatic aldehyde, CA has wide applications in the essence and aroma industry, as well as the pharmaceutical industry because of its diverse biological activities, including antioxidant, cardioprotective, anti-inflammatory, anti-obesity, and anti-tumor. After oral administration, CA could be rapidly absorbed in the stomach and proximal small intestine, which was metabolized, and finally excreted in the urine. Studies have investigated the safety of CA.88–90 The toxicity study using animal models indicated that the acute oral lethal dose (LD50) value of CA was 3.4 g kg−1 in white rats, white mongrel mice, and guinea pigs, indicating that CA exerted a low level of toxicity.1,90 Common delivery technologies to enhance the stability and bioavailability of CA were also summarized, including micelles, microcapsules, liposomes, nanoparticles, and nanoemulsions, which exhibited good load capacity and encapsulation capability. Currently, these delivery systems face limitations in human applications since an in vitro model could not completely mimic the physiological conditions of human organs. Therefore, future studies are needed to apply more in vivo models to evaluate the bioefficacy of the abovementioned delivery systems, which could better explore the specific mechanisms underlying the enhanced bioavailability of CA. This study could improve our understanding of the biological functions and molecular mechanisms of CA, providing the scientific reference for the future application of CA in the functional food industry.

Abbreviations

ADAMTSA disintegrin and metalloproteinase with thrombospondin motifs
AGEsAdvanced glycation end products
AHRAryl hydrocarbon receptor
AKTProtein kinase B
ASCApoptosis-associated speck-like protein containing a carboxy-terminal CARD
BTG2BTG anti-proliferation factor 2
BTKBruton tyrosine kinase
C/EBPCCAAT/enhancer binding protein
CACinnamaldehyde
CAFsCancer-related fibroblasts
CATCatalase
COX-2Cyclooxygenase-2
FASFatty acid synthase
GPx-1Glutathione peroxidase-1
GSDMDGasdermin
GSHReduced glutathione
HaCaTHuman immortalized keratinocytes
HFDHigh-fat diet
HMOX1Heme oxygenase 1
HUVECHuman umbilical vein endothelial cells
ILInterleukin
iNOSinducible NO synthase
JAK2Janus kinase 2
JNKC-Jun-amino terminal kinase
MAPKMitogen-activated protein kinases
MDAMalondialdehyde
miRMicroRNA
MMPMatrix metalloproteinases
NF-κBNuclear factor kappa-B
NLRP3Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3
NONitric oxide
NOxNitric oxide metabolites
NPs-CCA-loaded nanoparticles
Nrf2Nuclear factor erythroid-derived 2-like 2
PBMCPeripheral blood mononuclear cell
P-CA-LipoPolymyxin B-modified liposomal system loaded with CA
PCNAProliferating cell nuclear antigen
PDIPolydispersity index
PgPorphyromonas gingivalis
PGE2Prostaglandin E2
PI3KPhosphatidylinositol 3-kinase
p-JNKPhospho-c-Jun N-terminal kinase
PLGAPoly(DL-lactide-co-glycolide)
PPARProliferator-activated receptor
SOCS1Cytokine signaling 1
SODSuperoxide dismutase
STATTranscription
STZStreptozotocin
TCA trans-Cinnamaldehyde
TGFTransforming growth factor
TLRToll-like receptor
TNF-αTumor necrosis factor-α
TRPA1Transient receptor potential ankyrin-1
VCAM-1Vascular cell adhesion protein 1
VSMCVascular smooth muscle cell
WATWhite adipose tissue

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

This work was financially supported by the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (Grant No. 2019ZT08N291), the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A1515012124), and the Science and Technology Program of Guangzhou, China (Grant No. 2023A04J0760). The creation of Fig. 5 was supported by BioRender.com.

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