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
First published on 9th May 2024
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.
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.
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 48648.38 ± 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
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 |
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 |
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 |
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 |
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 |
ADAMTS | A disintegrin and metalloproteinase with thrombospondin motifs |
AGEs | Advanced glycation end products |
AHR | Aryl hydrocarbon receptor |
AKT | Protein kinase B |
ASC | Apoptosis-associated speck-like protein containing a carboxy-terminal CARD |
BTG2 | BTG anti-proliferation factor 2 |
BTK | Bruton tyrosine kinase |
C/EBP | CCAAT/enhancer binding protein |
CA | Cinnamaldehyde |
CAFs | Cancer-related fibroblasts |
CAT | Catalase |
COX-2 | Cyclooxygenase-2 |
FAS | Fatty acid synthase |
GPx-1 | Glutathione peroxidase-1 |
GSDMD | Gasdermin |
GSH | Reduced glutathione |
HaCaT | Human immortalized keratinocytes |
HFD | High-fat diet |
HMOX1 | Heme oxygenase 1 |
HUVEC | Human umbilical vein endothelial cells |
IL | Interleukin |
iNOS | inducible NO synthase |
JAK2 | Janus kinase 2 |
JNK | C-Jun-amino terminal kinase |
MAPK | Mitogen-activated protein kinases |
MDA | Malondialdehyde |
miR | MicroRNA |
MMP | Matrix metalloproteinases |
NF-κB | Nuclear factor kappa-B |
NLRP3 | Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 |
NO | Nitric oxide |
NOx | Nitric oxide metabolites |
NPs-C | CA-loaded nanoparticles |
Nrf2 | Nuclear factor erythroid-derived 2-like 2 |
PBMC | Peripheral blood mononuclear cell |
P-CA-Lipo | Polymyxin B-modified liposomal system loaded with CA |
PCNA | Proliferating cell nuclear antigen |
PDI | Polydispersity index |
Pg | Porphyromonas gingivalis |
PGE2 | Prostaglandin E2 |
PI3K | Phosphatidylinositol 3-kinase |
p-JNK | Phospho-c-Jun N-terminal kinase |
PLGA | Poly(DL-lactide-co-glycolide) |
PPAR | Proliferator-activated receptor |
SOCS1 | Cytokine signaling 1 |
SOD | Superoxide dismutase |
STAT | Transcription |
STZ | Streptozotocin |
TCA | trans-Cinnamaldehyde |
TGF | Transforming growth factor |
TLR | Toll-like receptor |
TNF-α | Tumor necrosis factor-α |
TRPA1 | Transient receptor potential ankyrin-1 |
VCAM-1 | Vascular cell adhesion protein 1 |
VSMC | Vascular smooth muscle cell |
WAT | White adipose tissue |
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