Cinnamon: an aromatic condiment applicable to chronic kidney disease

Laís de Souza Gouveia Moreira; Isabela de Souza da Costa Brum; Drielly C. M. de Vargas Reis; Liana Trugilho; Tuany R. Chermut; Marta Esgalhado; Ludmila F. M. F. Cardozo; Peter Stenvinkel; Paul G. Shiels; Denise Mafra

doi:10.23876/j.krcp.22.111

Kidney Res Clin Pract > Volume 42(1); 2023 > Article

Moreira, Brum, de Vargas Reis, Trugilho, Chermut, Esgalhado, Cardozo, Stenvinkel, Shiels, and Mafra: Cinnamon: an aromatic condiment applicable to chronic kidney disease

Review Article

Kidney Research and Clinical Practice 2023;42(1):4-26.

Published online: January 31, 2023

DOI: https://doi.org/10.23876/j.krcp.22.111

Cinnamon: an aromatic condiment applicable to chronic kidney disease

¹Graduate Program in Medical Sciences, Fluminense Federal University, Niterói, Brazil

²Graduate Program in Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

³Graduate Program in Nutrition Sciences, Fluminense Federal University, Niterói, Brazil

⁴Graduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Brazil

⁵Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

⁶Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

⁷Graduate Program in Biological Sciences – Physiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Correspondence: Peter Stenvinkel Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital M99, 141 86 Stockholm, Sweden. E-mail: Peter.Stenvinkel@ki.se

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited.

Abstract

Cinnamon, a member of the Lauraceae family, has been widely used as a spice and traditional herbal medicine for centuries and has shown beneficial effects in cardiovascular disease, obesity, and diabetes. However, its effectiveness as a therapeutic intervention for chronic kidney disease (CKD) remains unproven. The bioactive compounds within cinnamon, such as cinnamaldehyde, cinnamic acid, and cinnamate, can mitigate oxidative stress, inflammation, hyperglycemia, gut dysbiosis, and dyslipidemia, which are common complications in patients with CKD. In this narrative review, we assess the mechanisms by which cinnamon may alleviate complications observed in CKD and the possible role of this spice as an additional nutritional strategy for this patient group.

Keywords: Chronic renal insufficiency, Cinnamomum zeylanicum, Inflammation, Oxidative stress, Spices

Introduction

Cinnamon is a spice used for centuries as a culinary flavoring agent with organoleptic properties in different cultures worldwide. It has been used traditionally as a remedy for respiratory and gastrointestinal complications and has been widely studied because of its potential health-promoting properties [1]. These include antioxidant, anti-inflammatory, antimicrobial, antidiabetic, anticancer, and antilipemic properties [2–4].

The anti-inflammatory properties of cinnamon have been suggested to be derived via inhibition of nuclear factor kappa B (NF-κB) expression and consequently reduced production of proinflammatory cytokines, such as tumor necrosis factor (TNF), C-reactive protein (CRP), and interleukin (IL) 6 [5–7]. Cinnamon also promotes the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which upregulates a host of cytoprotective defenses and increases the synthesis of antioxidant enzymes such as catalase (CAT), heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx-1), and NAD(P)H dehydrogenase [quinone] 1 [6–9].

Patients with chronic diseases, including chronic kidney disease (CKD), commonly present with systemic inflammation and oxidative stress, dysregulated glucose and lipid metabolism, variations in blood pressure, and, consequently, a higher risk of cardiovascular disease (CVD) [10]. Furthermore, these patients may present with an altered composition of gut microbiota associated with increased uremic toxin levels in the circulation, exacerbating oxidative and inflammatory burdens [11].

The concept of food as medicine (nutrients and bioactive compounds are obtained from food) has been used to promote health and mitigate the chronic burden of lifestyle diseases [12]. Foods such as turmeric, propolis, Brazil nut, beetroot, berries, and cruciferous vegetables have documented benefits in patients with CKD, including control of inflammation, oxidative stress, and gut dysbiosis [13–19].

Few studies have been conducted on the effects of regular cinnamon consumption in patients with CKD. Therefore, in this narrative review, we summarize the beneficial effects of cinnamon and its possible role as a nonpharmacologic adjuvant therapy for complications associated with CVD, diabetes, obesity, and gut dysbiosis in patients with CKD to explore its medicinal benefits for these high-risk patient groups.

Cinnamon

Cinnamon is an indigenous spice obtained from the inner bark of trees belonging to the genera Cinnamomum from the Lauraceae family. It has been used since as early as 3,000 BC in Egypt. The name is of Greek origin (kinnámōmon), which translates as ‘sweet wood’ [20]. Today, it is used daily in various cuisines worldwide. Despite there being several varieties of cinnamon, only two, Ceylon cinnamon (also known as true cinnamon, which originates mainly from Sri Lanka) and cassia cinnamon (which originates from China, Vietnam, and Indonesia), are available in American and European food markets (Table 1) [2,21].

Cinnamon contains carbohydrates (52%), fibers (33%), protein (3.5%), and fat (4%). This spice is also a source of potassium (134.7 mg/g), magnesium (85.5 mg/g), calcium (83.8 mg/g), phosphorus (42.4 mg/g), manganese (20.1 mg/g), and iron (7.0 mg/g) [22]. The key components of cinnamon are essential oils of trans-cinnamaldehyde, cinnamyl acetate, and eugenol; a range of bioactive resinous compounds including cinnamaldehyde, cinnamic acid, and cinnamate; water-soluble polyphenols such as catechin, epicatechin, procyanidin, quercetin, and kaempferol; and polyphenolic polymers [23,24]. Eugenol is the main compound in the leaves, whereas cinnamaldehyde is predominant in the bark and camphor in the root [2,23,25]. The spicy flavor and fragrance characteristics of cinnamon are due to cinnamaldehyde (known as cinnamic aldehyde). In addition, the aging of cinnamon leads to color darkening due to higher levels of resinous compounds [25].

The daily intake of cinnamon can be considered safe if it does not exceed the tolerable daily intake of coumarin (0.1 mg/kg of body weight) [2], which is a phytochemical with anticoagulant, carcinogenic, and hepatotoxic properties [2,26]. However, coumarin concentration depends on the type of cinnamon, e.g., cassia cinnamon contains significant amounts of coumarin, whereas Ceylon cinnamon contains only trace quantities [2].

Different species of cinnamon may present an array of other oils with diverse characteristics, and their effects have been widely debated. Various studies have used different species and forms of cinnamon supplementation, leading to equivocal findings [1,27,28].

Cinnamon: antioxidant and anti-inflammatory actions

High production of reactive oxygen species (ROS) and reactive nitrogen species and reduced antioxidant capacity lead to oxidative stress, which promotes the pathogenesis of several chronic diseases, including diabetes, CKD, and CVD [29,30]. Therefore, modulating antioxidant enzyme production can reduce ROS formation and oxidative stress, slowing chronic disease progression [31]. Various cinnamon extracts, such as Cinnamomum zeylanicum Blume essential oil, ethanol extracts of cinnamon bark, cinnamon bark aqueous extract, and methanolic crude extract of Cinnamomum verum, display antioxidant activity, which indicates the potential for cinnamon to manage oxidative stress-related disorders [32]. Most cinnamon studies in vitro and in vivo (Table 2) [9,33–47] demonstrate significant antioxidant activity through multiple mechanisms, including reduction of malondialdehyde level (lipid peroxidation marker), activation of transcription factor Nrf2, and synthesis of antioxidant enzymes such as HO-1, superoxide dismutase, CAT, and GPx [48,49]. Twenty-two chemical ingredients have been isolated from cinnamon in addition to cinnamaldehyde analogues; of these, lignan pinoresinol (PRO) and the flavonol (–)-(2R,3R)-5,7-dimethoxy-3', 4'-methylenedioxy-flavan-3-ol (MFO) display antioxidant capacity [50].

The primary mechanism by which cinnamon (principally the cinnamaldehyde component) acts as an anti-inflammatory is via the downregulation of NF-κB [33,51] and diminution of inflammatory cytokine expression (e.g., TNF, CRP, and IL-6). Cinnamon also appears to reduce the levels of IL-1β and IL-18 by inhibiting the expression of NLR family pyrin domain containing 3 inflammasome and caspase-1 [34].

Additionally, cinnamaldehyde suppresses the expression of cyclooxygenase 2, nitric oxide synthase and prostaglandin E2 (PGE2) [52,53]. It has been implicated in the decreased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (p38 MAPKs) pathways [35]. The role of cinnamon as an antioxidant and anti-inflammatory agent is illustrated in Fig. 1.

A limited number of studies have described the anti-inflammatory effects of cinnamon in humans, but the results remain inconclusive. Supplementation of 1.5 g/day of Cinnamomum burmannii powder in women with rheumatoid arthritis for 8 weeks promoted a reduction in both visual and pain scales, reduced tender and swollen joint counts, and reduced serum CRP and TNF levels [5]. Similarly, cinnamon (1.8 g/day for 2 months) in patients with migraines reduced serum IL-6 and nitric oxide (NO) levels [54]. The frequency, severity, and duration of migraine attacks decreased, suggesting a reduction in the inflammatory process [54]. In contrast, Davari et al. [51] used 3 g/day of cinnamon for 8 weeks in patients with type 2 diabetes (T2D). They found no beneficial effects on NF-κB, sirtuin 1 (SIRT1), or other systemic inflammation markers, including IL-6 and high-sensitivity CRP. The reasons for this outcome disparity remain unclear and may be multifactorial, including differing cinnamon sources, purity, and experimental methodologies.

Diabetes and cinnamon

Diabetes is one of the leading causes of CKD, manifesting as diabetic kidney disease. Several studies (Table 3) [51,55–78] have proposed that cinnamon therapy can improve insulin action and glucose metabolism, with procyanidin type-A polymers and cinnamaldehyde being the primary components associated with the antidiabetic effects [79].

Procyanidin type-A polymers in cinnamon can mimic insulin action as they increase insulin receptor autophosphorylation of β-subunit tyrosine residues and reduce oxidative stress in pancreatic β-cells [80,81]. Moreover, cinnamon extract (C. zeylanicum) ameliorated glucose transporter 4 translocation via the adiponectin and intracellular 5' adenosine monophosphate-activated protein kinase (AMPK) signaling pathway [82,83] and through stimulation of liver kinase B1 mediated AMPK phosphorylation [84].

Additionally, inhibition of α-glucosidase and pancreatic α-amylase, which promote postprandial glycemic amelioration, has been attributed to the action of the cinnamon extract [85].

Cinnamon also induces the expression of the peroxisome proliferator-activated receptors (PPAR) alpha and gamma (PPAR-α and PPAR-γ) in vitro and in vivo. This is notable as these regulate adipogenesis and insulin resistance by regulating the expression of genes encoding proteins involved in adipokine synthesis, adipocyte differentiation, and lipid and carbohydrate metabolism [86]. Additionally, cinnamaldehyde may stimulate the expression of PPAR-γ and PPAR delta (PPAR-δ) in differentiated adipocytes, promoting insulin sensitivity and fatty acid β-oxidation in adipose tissue and skeletal muscle [87]. Another component of cinnamon extract, the B-type procyanidin C1, has been demonstrated to stimulate preadipocyte differentiation as well as act as a potential insulin sensitizer through the protein kinase B (AKT)/endothelial NO synthase (eNOS): AKT/eNOS pathway in mature adipocytes [88]. The phosphoinositide 3-kinase (PI3K)/AKT pathway participates in glucose uptake by skeletal muscles, adipose tissues, and liver. Cinnamaldehyde treatment (10 mg/kg) has been reported to increase the expression of insulin receptor substrate 1 (IRS-1), PI3K, and AKT2 in diabetic rats, promoting enhanced insulin signaling by the IRS1/PI3K/AKT pathway and reducing insulin resistance and promoting an antidiabetic effect [55].

Despite the salutogenic effects of cinnamon treatment in diabetes, other human-based studies have yielded equivocal results. In one systematic review, no significant benefits were found for cinnamon in reducing glucose and glycated hemoglobin (HbA1c) levels in patients with type 1 diabetes [89]. Conversely, a meta-analysis has reported that intake of whole cinnamon or cinnamon extract lowered fasting blood glucose (FBG) in T2D and prediabetes [90]. In a meta-analysis of 435 patients, Akilen et al. [91] reported that cinnamon doses ranging from 1 to 6 g/day ingested for between 40 days and 4 months reduced HbA1c and fasting glycemia levels. In 2013, a further meta-analysis including 543 patients reported that cinnamon supplementation (powdered cinnamon and aqueous extract) ranging from 120 mg to 6 g ingested for between 4 and 18 weeks reduced blood glucose, total cholesterol, and triglycerides but did not affect HbA1c level [92]. Costello et al. [80] have shown that cinnamon dietary supplements (doses ranging from 120 to 6,000 mg/day ingested for between 4 and 16 weeks) have clinically meaningful effects on glycemic control (FBG or HbA1c) in patients with T2D.

Additionally, a meta-analysis showed no effect of powdered cassia cinnamon intake (1–2 g) on fasting glucose, HbA1c, triglycerides, low-density lipoprotein (LDL), and total cholesterol levels in patients with T2D. On the other hand, a higher (at least 3 g) rather than a lower dose of cassia bark powder or cassia extract associated with lifestyle and diet protocols was more effective for glucose control in T2D [93].

Analyzing the impact of cinnamon on patients with diabetes is very complex as cinnamon contains several compounds, such as coumarin, cinnamic acid, cinnamaldehyde, cinnamic alcohol, and eugenol, with varied concentrations among species [94]. In addition, results are related to the quality of cinnamon, the type of branches, and manufacturing practices among species and formulations [95].

The effectiveness of cinnamon in glucose control may depend on how well the diabetes was controlled during the study. In addition, previous studies have used different parameters and periods [95]. Therefore, administering cinnamon can be a helpful add-on therapy in integrative medicine for managing T2D. Still, long-term trials are required to establish the efficacy and safety of cinnamon. In addition, the differing contributions of various microbiomes between subjects must be addressed [96].

Cinnamon: benefits in obesity

Obesity is a strong predictor of renal dysfunction and CKD [97]. Some physiological responses of the kidneys to obesity include increased glomerular filtration rate, tubular reabsorption of sodium, filtration fraction, and renal plasma flow [98]. Central obesity and abdominal fat are risk factors for metabolic syndrome, which is also associated with the development and progression of CKD and CVD [99].

Cinnamon has been studied as a potential nutritional strategy for managing obesity and its complications [9]. Cinnamon’s antiobesogenic effect may be related to its ability to induce thermogenesis in adipocytes as mediated by uncoupling protein 1 which is expressed in brown and beige tissues and improves metabolism to promote weight loss [100].

Moreover, cinnamaldehyde activates a classic thermogenesis pathway through protein kinase A signaling that phosphorylates p38 MAPK, inducing the transcription of thermogenic genes such as hormone-sensitive lipase and lipid droplet-associated protein perilipin 1 [52]. Additionally, as cinnamaldehyde is the primary natural agonist of the transient receptor potential ankyrin 1 (TRPA1), it may also indirectly influence food intake and weight gain, which can be expressed in gastrointestinal functions such as decreasing ghrelin secretion [101,102]. Other natural compounds present in cinnamon oil, such as cumin aldehyde (cumin), p-anisaldehyde (anise), and triglycaldehyde (onion/garlic), can activate human TRPA1 specifically but with lower affinity compared to cinnamaldehyde. Among these compounds, cumin aldehyde demonstrated glucose-dependent insulin secretagogue activity in diabetic rats by TRPA1 stimulation [102].

The AMPK pathway is also relevant to the study of obesity as it is a mediator of cellular energy production, which can improve insulin sensitivity in insulin-sensitive tissues, such as adipose tissue [103]. Cinnamon seems to exert beneficial effects via AMPK activation and enhanced adiponectin concentrations, as demonstrated by Kopp et al. [104]. They evaluated the Gi/Go-protein-coupled receptor 09A, which stimulates adiponectin secretion after binding trans-cinnamic acid from cinnamon.

Other protective effects ascribed to cinnamon appear to result from a reduction of hepatic expression of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and NF-κB, in conjunction with upregulation of PPAR-α, a cluster of differentiation 36 (CD36), fatty acid synthase, carnitine palmitoyltransferase I, and Nrf-2 [105]. Studies of obese rats with hepatic steatosis caused by a high-fat diet suggest enhancement of hepatic beta-oxidation and inhibition of hepatic lipogenesis, oxidative damage, and inflammation resulting from cinnamon intake.

Aqueous extract of Cinnamomum cassia bark has been linked to neurochemical and behavioral effects in rats by decreasing food intake through augmentation of 5-hydroxy tryptamine in the brain [106].

Only a few studies have reported a relationship between cinnamon and antiobesogenic effects in humans. Yazdanpanah et al. [107] have conducted a systematic review and meta-analysis to investigate the effects of cinnamon on fat and body mass, body mass index (BMI), waist circumference, and waist-hip ratio. In total, 21 randomized controlled trials (RCTs) with 1,480 participants were included, and it was reported that cinnamon supplementation decreased obesogenic parameters. In agreement with the studies discussed, a systematic review and dose-response meta-analysis suggested that cinnamon supplementation could improve obesity measures, particularly in obese subjects aged <50 years at dosages of ≥2 g/day for at least 12 weeks [108]. More recently, Keramati et al. [109] evaluated the effects of cinnamon on obesity rates in humans through an umbrella meta-analysis, which indicated that cinnamon supplementation reduced BMI. The effects of cinnamon were more pronounced at doses of ≥3 g/day and in patients with polycystic ovary syndrome. Table 4 [52,72,105,110–123] lists these associated experimental and clinical studies on the effects of cinnamon on obesity.

Cinnamon and cardiovascular disease

Patients with CKD have a high risk of developing premature CVD due to a combination of traditional risk factors, including diabetes, obesity, dyslipidemia, hypertension, and a toxic uremic milieu [124]. Cinnamon may benefit cardiovascular health; indeed, studies have shown hypotensive effects, control of dyslipidemia, and protection of the endothelium and vascular smooth muscle cells (VSMC). As already discussed, cinnamon has anti-inflammatory and antioxidant properties, which can reduce the progress of atherosclerosis [56]. However, postulated hypotensive effects ascribed to cinnamon remain inconclusive [125]. Ghavami et al. [126] evaluated the effects of cinnamon supplementation on blood pressure through a systematic review and meta-analysis of RCTs. Eight studies, including 582 participants, suggested that cinnamon supplementation had beneficial effects only on diastolic blood pressure.

Components of cinnamon, such as catechin, epicatechin, procyanidin B2, and phenolic polymers, can act as agonists of PPARs, inhibiting the formation of advanced glycation end products to reduce oxidative stress and increasing the bioavailability of vasodilator NO [108,125].

Furthermore, cinnamon improves the lipid profile and reduces lipid oxidation and the risk of vascular blockage, mitigating potential hypertensive conditions [127]. Flavonoids and phenolic acids found in cinnamon inhibit pancreatic lipase, which is necessary for forming chylomicrons [110]. Cinnamon ameliorates lipid profiling by suppressing the expression of transcription factor SREBP-1c and liver X receptor alpha enzymes, such as ATP-citrate lyase and NF-κB p65. Furthermore, it upregulates PPAR-α expression to enable modulation of lipid metabolism [9]. Additionally, cinnamon has been reported to inhibit the secretion of proatherogenic apolipoprotein B 48 CD36, and the class A macrophage scavenger receptor, as well as the uptake of acetylated LDL, again suggesting that cinnamon can act as a preventive medicine [128,129].

Despite these promising results, the evidence remains inconclusive. Krittanawong et al. [130] have systematically reviewed the literature and evaluated cinnamon consumption and cardiovascular risk. A meta-analysis that included 23 studies (1,070 subjects) concluded that there was no association between cinnamon consumption and differences in LDL-cholesterol, high-density lipoprotein cholesterol, and HbA1c levels. Studies on cinnamon in vitro, in animals, and in humans are listed in Table 5 [9,45,131–144]. Again, allowance for different exposome features, such as microbiota composition, may be pertinent here [145].

Does cinnamon benefit the gut microbiota?

Microbiota dysbiosis is a disruption to the normative microbial community driven by host-related exposome factors such as diet, resulting in perturbations to its composition and function [145,146]. Dysbiosis is associated with many chronic diseases, such as metabolic syndrome, inflammatory bowel disease, and CKD, which present a typical proinflammatory phenotype. Increased permeability in the gut with age and condition enables the entry of microbial metabolites, pathobionts, or endotoxins such as lipopolysaccharides (LPS) into the circulation [147,148]. It also presents a loss of symbiotic microbes.

Beyond typical treatments to mitigate dysbioses, such as pro-, pre-, or symbiotics, some bioactive compounds can be effective in modulating the gut microbiota [149,150]. Studies of the benefits of cinnamon in this capacity have been increasing [150,151].

Cinnamon compounds, such as polyphenols, reach the colon and serve as substrates for bacterial metabolism [152]. Normative gut microbiota is dominated by anaerobic bacteria from the Firmicutes and Bacteroidetes phyla. Dysbiosis is characterized by a loss of microbial diversity and symbionts and an increased representation of pathobionts [96,153]. Cinnamon effectively enriches gut microbiota by reducing Proteobacteria and increasing Bacteroidetes [154].

The essential oil in cinnamon contributes to the growth of salutogenic bacteria capable of short-chain fatty acid production. These can produce butyrate, acetate, and propionate, which not only serve as the substrate for the host cells but also regulate inflammation [154,155]. Cinnamon oil may improve microbiota diversity and downregulate inflammatory processes [154]. Moreover, cinnamon oil can protect against LPS-induced intestinal injury through upregulation of epidermal growth factor, claudin-1, occludin, alkaline phosphatase (ALP), and pregnane X receptor expression, improving gut barrier integrity [156]. The evidence supports cinnamon or cinnamon compounds as nutritional adjuvants for maintaining intestinal integrity [156,157].

An experimental study conducted with early-weaned rats, highly susceptible to intestinal stress and alterations, has shown that treatment with 100 or 200 mg/kg body weight/day cinnamaldehyde for 2 weeks improved the gut barrier and was accompanied by an increase in mucin production, reduced inflammation, and improved microbiome diversity [158]. These authors suggested that the beneficial effects were due to inhibition of NF-κB activation; upregulated expression of mucin 2, trefoil factor 3, and tight junction proteins; and reduced IL-6 and TNF-α expression, potentially mediated by increased in gut microbe diversity [158].

Another recent study has supported this assertion, indicating that the microbiota in ovariectomized mice displayed improved diversity after treatment with cinnamic acid. This result was accompanied by an elevation in transforming growth factor beta levels in bone marrow cells, which induced osteoblast differentiation and increased the expression of osteogenic markers [159].

Based on these data, cinnamon usage is encouraged not only to manage diseases influenced by microbiota, such as CKD but also for general health. The role of the microbiota in the health of the general population has recently been exemplified by a report linking poor renal function with accelerated aging and an imbalanced diet [160]. These data are pertinent to the treatment and management of CKD, as well as other diseases of aging.

Cinnamon: could it be of benefit in chronic kidney disease?

Although studies evaluating the effect of cinnamon on the kidneys are scarce, the salutogenic effects suggested by the literature (as shown in Fig. 2) suggest an overall benefit [161]. CKD is a significant cause of mortality globally, and its prevalence is growing in low-middle-income countries, where social deprivation amplifies its effects [145]. The reenvisioning of the Hippocratic concept of ‘food as medicine’ champions the use of natural bioactives as potential therapeutics to tackle the emerging diseasome of aging [12]. The use of cinnamon is merited for evaluation to be included in the physician’s and nutritionist’s armamentarium.

Common pathways underpin the salutogenic effects of cinnamon in CKD, including the inactivation of the ERK/JNK/p38 MAPK pathway leading to reduced renal interstitial fibroblast proliferation and hypertrophy [162]. Nrf2 pathway stimulation, promoting attenuation of renal damage and preservation of renal function, is also a key element in this mechanism [8,163–165]. Other reported benefits of cinnamon are the inhibition of peroxynitrite-induced nitration and lipid peroxidation and its influence on the production of NO and PGE2 [166,167].

Patients with CKD experience premature and accelerated aging [145], and cinnamon may also benefit in mitigating the effects of cellular aging. In support of this, it has been reported that cinnamaldehyde attenuates cellular senescence in the kidney through PI3K/AKT pathway-mediated autophagy via downregulation of microRNA-155 [168].

Cinnamon is a promising candidate in the dietetic management of CKD, as it can mitigate complications such as dyslipidemia and diabetes. Studies have suggested possible improvements in kidney function through dietetic approaches aimed at upregulating antioxidant and anti-inflammatory defenses [12,169]. However, despite the known properties of cinnamon, its effect on patients with CKD has not been explored, and most studies are experimental (Table 6) [65,168,170–173]. This highlights the need for further investigations.

Toxicity caused by cinnamon

Contrary to popular belief, herbal medicines are not entirely safe and may have adverse effects. The available data suggest that cinnamon is safe for use as a spice, and moderate ingestion has several health benefits, as previously reported. However, its use for medicinal purposes in high doses or over a long duration may lead to adverse effects, such as gastrointestinal disturbances and self-limiting allergic reactions that should be clinically monitored [174]. Yun et al. [175] have reported that cinnamon extract (2 g/kg body weight/day for 13 weeks) might result in nephrotoxicity and hepatotoxicity in rats due to high doses of coumarin. In animals, despite all the extracts tested showing possible antioxidant activity in vitro, they showed acute dose-dependent toxicity (1,000, 2,000, 3,000, 4,000, and 5,000 mg/kg body weight) in vivo, with increased levels of aspartate transaminase, alanine transaminase ALP, urea, and creatinine reported in animals treated with the highest dose [57].

In a systematic review of the adverse effects of cinnamon, the authors report that most studies did not identify the cinnamon species responsible for these effects. Knowing that different cinnamon species contain other components, such as coumarin, studies on herbal medicines should be standardized to include their exact identification, dose, and duration of treatment [174]. Recently, Gu et al. [176] evaluated the safety of cinnamon in humans through a study using relevant meta-analyses and systematic reviews of RCTs and concluded that there are no adverse effects caused by cinnamon.

There is no exact recommendation for the daily intake of cinnamon. Still, studies recommend approximately 1 to 4 g per day, and attention should be paid to the amount of coumarin in different types of cinnamon and symptoms such as diarrhea, nausea, and vomiting [161].

Conclusion

Cinnamon compounds have several beneficial effects for consideration for inclusion in a ‘food as medicine’ strategy to treat CKD. These reside in inherent antioxidant, anti-inflammatory, cardioprotective, antiobesogenic, and antidiabetic properties. Additionally, they may reside in the ability of cinnamon to influence the composition of the gut and microbiota. Though most reported studies are preclinical, they indicate that human clinical studies are merited. Therefore, different clinical trials need to be planned regarding the dose and period of supplementation, the types of cinnamon species, and other populations. This review highlights the need for further studies on patients with CKD who suffers from several comorbidities, in which the use of cinnamon supplementation has demonstrated potential advantages.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) number 200162/2020-9 and by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) number E-26/202.524/2019.

Data sharing statement

The data presented in this study are available on request from the corresponding author.

Authors’ contributions

Conceptualization: LSGM, ISCB, DCMVR, LT, TRC, ME, LFMFC, PS, DM

Funding acquisition, Methodology: DM

Supervision: PS, DM, PGS

Writing–original draft: LSGM, ISCB, DCMVR, LT, TRC, ME, LFMFC, DM

Writing–review & editing: LSGM, LFMFC, PS, PGS, DM

All authors read and approved the final manuscript.

Acknowledgments

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) support Denise Mafra.

Figure 1.

Antioxidant and anti-inflammatory actions of cinnamon in cells.

Bioactive compounds from cinnamon may activate the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), leading to the synthesis of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx-1), and NAD(P)H dehydrogenase [quinone] 1 (NQO-1). Also, these compounds can inhibit nuclear factor kappa B (NF-κB), activator protein 1 (AP-1), and NLR family pyrin domain containing 3 (NLRP3), reducing inflammatory cytokine production.

TLR-4, toll-like receptor 4; ERK, extracellular signal-regulated kinase; AKT, protein kinase B; Keap1, Kelch-like ECH-associated protein 1; TNF-α, tumor necrosis factor alpha; CRP, C-reactive protein; IL, interleukin.

Figure 2.

The potential benefits of cinnamon to patients with diabetes, obesity, or CVDs.

Cinnamon can provide physiological benefits by mimicking insulin action through insulin receptor autophosphorylation of the β-subunit of tyrosine and promoting glucose transporter (GLUT) translocation via the 5' adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Cinnamaldehyde has antidiabetic activity through upregulation of the insulin signaling pathway, induction of peroxisome proliferator-activated receptors (PPARs), and inhibition of α-glucosidase and pancreatic α-amylase. Cinnamon may increase the expression of uncoupling protein 1 (UCP-1), promoting thermogenesis. It can also reduce hepatic expression of sterol regulatory element-binding protein-1c (SREBP-1c) and nuclear factor kappa B (NF-κB) and upregulate PPAR-α, fatty acid synthase, carnitine palmitoyltransferase I (CPT-1), and nuclear factor erythroid 2-related factor 2 (Nrf-2) to promote cytoprotective effects and reduce inflammation. Cinnamaldehyde might act as a natural agonist of transient receptor-ankyrin receptor 1 (TRPA1), reducing ghrelin secretion and food intake. Cinnamon may decrease SREBP-1 and cluster of differentiation 36 (CD36) expression and increase expression of PPAR-γ, reducing oxidative stress, inflammatory burden and, therefore, cardiovascular risk.

LXR-α, liver X receptor alpha; CVD, cardiovascular disease.

Table 1.

Varieties of cinnamons and origins

Cinnamon variety	Scientific names	Common names	Country of origin	Color	Taste
Ceylon cinnamon	Cinnamomum zeylanicum or Cinnamomum verum	Ceylon cinnamon, true cinnamon, Mexican cinnamon	Sri Lanka, southern India	Light to medium reddish brown	Slightly sweetness
Cassia cinnamon	Cinnamomum burmanni	Indonesian cassia, Indonesian cinnamon, Korintje cinnamon, Padang cassia	Indonesia, Philippines	Dark reddish brown	Strong spicy
	Cinnamomum loureiroi	Saigon cinnamon, Vietnamese cassia, Vietnamese cinnamon	Vietnam	Dark reddish brown	Spicy and sweet
	Cinnamomum aromaticum	Chinese cinnamon, Chinese cassia, cassia cinnamon	China, Burma	Dark reddish brown	Mild and slightly sweet

Table 2.

Studies involving cinnamon and antioxidant and anti-inflammatory actions

Reference	Study/samples	Intervention	Results
In vitro study
Uchi et al. (2017) [36]	Human keratinocyte cell line benzo[a]pyrene-stimulated	Cinnamaldehyde (25 μM) or Cinnamomum cassia extract (100 mg/mL)	↑ Nrf2 translocation and HO-1 expression
Uchi et al. (2017) [36]	Human keratinocyte cell line benzo[a]pyrene-stimulated		↓ activation of AHR
Kim et al. (2018) [35]	Raw 264.7 murine macrophage cells	Trans-cinnamaldehyde (25, 50, or 100 μM)	↓ TNF-α, IL-1β, and IL-6 and NO synthesis
Kim et al. (2018) [35]	LPS-induced	Trans-cinnamaldehyde (25, 50, or 100 μM)	↓ TNF-α, IL-1β, and IL-6 and NO synthesis
Schink et al. (2018) [37]	THP-1 monocyte-macrophage cell line TIB-202, LPS-stimulated	Cinnamon compounds (25 μg/mL)	Trans-cinnamaldehyde and p-cymene ↓ IL-8 secretion
Qu et al. (2019) [38]	LPS-stimulated RAW264.7 cells	Cinnamaldehyde (5, 10, or 20 μM) pretreatment	↓ NLRP3 inflammasome, miR-21 and miR-155
Qu et al. (2019) [38]	LPS-stimulated RAW264.7 cells	Cinnamaldehyde (5, 10, or 20 μM) pretreatment	↓ ROS, the phosphorylation of AKT, mTOR, and COX-2 protein level
Cheng et al. (2020) [39]	Human rheumatoid fibroblast-like synoviocyte line MH7A cells IL-1β-induced	Cinnamaldehyde (40, 60, and 80 nM) pretreatment	40, 60, and 80 nM: ↓ TNF-α, IL-6
Chen et al. (2020) [33]	Human osteoarthritis chondrocytes LPS-induced	Cinnamaldehyde pretreatment (10, 20, or 50-μM)	All doses: ↓ IL-6, IL-1β, TNF-α
			↓ MMP-13 and ADAMTS-5
			Doses of 20 and 50 μM: LPS-stimulated NF-κB expression
Ben Lagha et al. (2021) [40]	The monoblastic leukemia cell line U937 LPS-stimulated	Cinnamon bark aqueous extract (32.5 to 500 μg/mL) pretreatment	250 μg/mL: ↓ IL-6, IL-8, and TNF-α
Vallion et al. (2022) [41]	Human keratinocytes cells	100 μM of cinnamaldehyde	↑ Nrf2 accumulation
Vallion et al. (2022) [41]	Human keratinocytes cells	100 μM of cinnamaldehyde	↓ IL-1β transcription
Chen et al. (2022) [42]	LPS-induced human osteoarthritis synovial fibroblasts	Pretreatment with cinnamic aldehyde (20 and 50 μmol/L)	↓ IL‐1β, IL‐6, and TNF‐α
Chen et al. (2022) [42]	LPS-induced human osteoarthritis synovial fibroblasts	Pretreatment with cinnamic aldehyde (20 and 50 μmol/L)	↓ TLR-4 and MyD88 expression
Experimental study
Tuzcu et al. (2017) [9]	HFD rats	Cinnamon polyphenol (100 mg/kg body weight) for 12 weeks	↓ NF-κB p65 expressions
Tuzcu et al. (2017) [9]	HFD rats	Cinnamon polyphenol (100 mg/kg body weight) for 12 weeks	↑ PPAR-α, IRS-1, Nrf2, and HO-1 expressions in the HFD rat livers
Abou El-Ezz et al. (2018) [43]	LPS-induced neuroinflammation mouse model	Trans-cinnamaldehyde (50 mg/kg) intraperitoneally for 1 week	↓ IL-1β levels, MDA, and caspase-3 levels in the hippocampus
			Activate Nrf2
			↑ Glutathione S-transferase
Liu et al. (2020) [44]	in vitro: macrophages (Raw246.7) LPS-induced	In vitro: cinnamaldehyde (6.25, 12.5, or 25 μM)	In vitro: ↓ IL-1β, NLRP3 (12.5, and 25 μM)
	In vivo: arthritis rat model, complete Freund’s adjuvant-induced	In vivo: cinnamaldehyde (200 mg/kg) orally for 4 weeks	↓ TNF-α and NO (6.25, 12.5, and 25 μM)
			In vivo: ↓ IL-1 β in blood
			↓ NLRP3 in synovium
Wang et al. (2020) [45]	Leptin receptor-deficient (db/db) mice	Diet containing 0.02% cinnamaldehyde for 12 weeks	↓ ROS generation, preserved NO production
			↑ p-eNOS
			↑ Nrf2, HO-1 and NQO-1
Ryu et al. (2020) [46]	Mice with cognitive dysfunction induced by d-galactose and aluminum chloride	Trans-cinnamaldehyde (30 mg/kg/day) injected intraperitoneally + treadmill exercise for 5 weeks	↑ Nrf2, NQO-1, HO-1, and SOD-1
Abdel-kawi et al. (2022) [47]	Wistar rats, gastric ulcers ethanol-induced model	2.5 mL/kg of cinnamon oil and omeprazole (20 mg/kg) for 1 week before ulcer induction	↑ CAT, SOD, GPx, and GSH in the stomach
Abdel-kawi et al. (2022) [47]	Wistar rats, gastric ulcers ethanol-induced model		↓ MDA and TNF-α levels
Zou et al. (2022) [34]	Sepsis-induced C57BL/6 J mice	2 g/kg of cinnamyl alcohol by gavage	↓ IL-1β and IL-18
Zou et al. (2022) [34]	Sepsis-induced C57BL/6 J mice	2 g/kg of cinnamyl alcohol by gavage	↓ Expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain in the liver, heart, lungs, and kidneys

ADAMTS-5, metalloproteinase with thrombospondin motif 5; AHR, aryl hydrocarbon receptor; AKT, protein kinase B; CAT, catalase; COX-2, cyclooxygenase type 2; GPx, glutathione peroxidase; GSH, glutathione; HFD, high-fat diet; HO-1, heme oxygenase 1; IL, interleukin; IRS-1, insulin receptor substrate 1; LPS, lipopolysaccharide; MDA, malondialdehyde; MMP-13, matrix metalloproteinase-13; mTOR, mammalian target of rapamycin; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NO, nitric oxide; NQO-1, NAD(P)H dehydrogenase [quinone] 1; Nrf2, nuclear factor erythroid 2-related factor 2; p-eNOS, phosphorylated endothelial nitric oxide synthase; PPAR-α, peroxisome proliferator-activated receptors (PPAR) alpha; ROS, reactive oxygen species; SOD-1, superoxide dismutase 1; TLR-4, toll-like receptor 4; TNF-α, tumor necrosis factor alpha.

Table 3.

Studies involving cinnamon and diabetes

Reference	Study/sample	Intervention	Results
Experimental study
Hafizur et al. (2015) [58]	STZ-induced diabetic rats	5 and 10 mg/kg of cinnamic acid or cinnamaldehyde	Cinnamic acid: ↓ blood glucose, improved glucose tolerance
			↑ Glucose-stimulated insulin secretion in isolated islets.
			Cinnamaldehyde: ↔ glucose-stimulated insulin secretion
Qusti et al. (2016) [59]	STZ-induced diabetic in male albino rats	20% (w/w) cinnamon methanol extract for 28 days	↓ Blood glucose
			↓ IL-6 and MDA
			↑ CAT and SOD
			↓ Urea, Cr, and uric acid
Jawale et al. (2016) [60]	STZ-induced diabetic in rats	10, 20, or 40 mg/kg of cinnamaldehyde for 3 weeks	↓ Blood glucose
Jawale et al. (2016) [60]	STZ-induced diabetic in rats	10, 20, or 40 mg/kg of cinnamaldehyde for 3 weeks	↓ TNF-α and IL-6
Hosni et al. (2017) [61]	STZ-induced diabetic in female albino rats with gestational diabetes	20 mg/kg oral dose of cinnamaldehyde with or without fatty-sucrose diet, or normal diet for 8 weeks	↓ Hyperphagia and glucose intolerance
			↓ Fructosamine, TC, TG, leptin
			↓ TNF-α, MDA, NO
			↑ HDL-C, adiponectin, liver glycogen
			↑ PPAR-γ gene expression
Taheri et al. (2018) [62]	STZ-induced diabetic in adult male Wistar rats	300 mg/kg cinnamon bark powder for 14 days	↓ CYP2D
Abdelmageed et al. (2019) [55]	STZ-induced T2D in male rats	10 mg/kg of cinnamaldehyde for 2 months	↓ OGTT, ITT, FBG
			↓ Insulin and HOMA-IR
			↑ HOMA-β
			↓ MDA
			↑ Aortic GSH, SOD, IRS-1, PI3K-p85, AKT2
Kommula et al. (2020) [63]	Neonatal STZ rat model	3% Cinnamon for 8 months	↓ Fasting and postprandial glucose levels prevented retinal functional abnormalities
Mohammed et al. (2020) [64]	STZ-induced diabetic rats	200 and 400 mg/kg of cinnamon oil emulsion in whey protein concentrate for 1 month	↓ Blood glucose, amylase,
			↓ TC, LDL-C, TG
			↑ Insulin, HDL-C
			↑ Hepatic SOD, GSH
			↓ Hepatic MDA
Niazmand et al. (2021) [65]	STZ-induced diabetic rats	Cinnamon extract (100, 200, 400 mg/kg) and metformin (300 mg/kg) orally for 42 days	↓ MDA level, SOD and CAT activities in the liver and kidney
Sampath et al. (2021) [66]	Gastric emptying in obesity-induced diabetic female mice	Cinnamaldehyde 50 mg per body mass per day for 6 weeks	↓ Body weight gain
			↓ FBG
			↓ HOMA-IR
			↑ Reduced/oxidized glutathione ratio
Vijayakumar et al. (2022) [57]	STZ-induced diabetic rats	Ethanolic bark extracts of Cinnamomum cassia with different concentrations (300, 400, and 500 mg/kg BW) and glibenclamide (3 mg/kg BW)	↑ Activities of mitochondrial enzymes
			↓ Levels of hepatic marker enzymes (AST, ALT, and ALP)
			↓ Urea, Cr, and uric acid
Çelik et al. (2022) [67]	STZ-induced diabetic rats	20 mg/kg of BW of cinnamaldehyde by gavage daily for 1 month	↓ FBG
Çelik et al. (2022) [67]			↓ TG, TC, VLDL, LDL-C, and urea levels
Human study
Bernardo et al. (2015) [68]	Nondiabetic adults	100 mL of cinnamon tea (Cinnamomum burmannii bark) obtained from 60 g sticks of cinnamon soaked into 1,000 mL of water, after OGTT	Slightly ↓ PBG level after OGTT
Sengsuk et al. (2015) [69]	T2D patients	1,500 mg of cinnamon (divided into 3 times a day capsules) or placebo for 2 months	↓ Median glucose, TG, TG/HDL-C ratio, and BP
Sengsuk et al. (2015) [69]	T2D patients		↑ HDL-C and eGFR
Anderson et al. (2015) [71]	Hyperglycemic adults	1 g (divided into 2 capsules) a day of water extract of cinnamon (CinSulin), or placebo for 2 months	↓ FBG, HOMA-IR
			↓ Serum glucose 2 hours after 75 g carbohydrate load
			↓ Fructosamine, fasting insulin
			↓ TC, LDL-C, HDL-C
Azimi et al. (2016) [56]	T2D patients	3 g/day of cinnamon with black tea for 2 months	↓ ICAM-1
Azimi et al. (2016) [56]	T2D patients	3 g/day of cinnamon with black tea for 2 months	↔ BP and endothelial function
Gutierrez et al. (2016) [70]	Young, sedentary, obese women	5 g of encapsulated cassia cinnamon bark for 3 separate days (30-, 60-, 90-, and 120-minute following glucose ingestion)	↔ Insulin resistance and sensitivity
Gutierrez et al. (2016) [70]	Young, sedentary, obese women		↓ Peak blood glucose at 30-time point
Gupta Jain et al. (2017) [72]	Individuals with metabolic syndrome	3 g (divided into 6 capsules) of cinnamon or placebo, for 4 months	↓ FBG, ↓ HbA1c
Gupta Jain et al. (2017) [72]	Individuals with metabolic syndrome		↓ WC, ↓ BMI improved lipid profile, waist-hip ratio, and BP
Talaei et al. (2017) [73]	T2D patients	3 g of cinnamon (divided into 3 capsules-day), for 2 months	↔ FBG, insulin, HbA1c, HOMA-IR, carboxymethyl lysine, total antioxidant capacity, and MDA
Zare et al. (2019) [74]	T2D patients	1 g of cinnamon bark powder (divided into 2 capsules daily) or placebo for 3 months	↓ BMI, body fat, visceral fat
			↓ FBG, HbA1c, fasting insulin, and insulin resistance
			↓ TC, LDL-C, and HDL-C
Kizilaslan and Erdem (2019) [75]	Healthy adult individuals	1 g or 3 g or 6 g/day cinnamon peel (C. cassia), for 40 days	↔ BMI, HbA1c
			Difference in pre-prandial blood glucose (6 g/day)
			Difference in postprandial blood glucose on days 20 and 40 for 1, 3, and 6 g of cinnamon
Davari et al. (2020) [51]	T2D patients	3 g of cinnamon for 2 months	↔ NF-κB, SIRT1, hs-CRP, IL-6, and TNF-α plasma levels
Romeo et al. (2020) [76]	Adults with prediabetes	500 mg cinnamon thrice daily for 3 months	Fasting plasma glucose remained stable only in the cinnamon group
Romeo et al. (2020) [76]	Adults with prediabetes	500 mg cinnamon thrice daily for 3 months	↓ OGTT
Lira Neto et al. (2022) [77]	T2D patients	3 g of cinnamon (capsules daily) for 3 months	↓ HbA1c
Lira Neto et al. (2022) [77]	T2D patients	3 g of cinnamon (capsules daily) for 3 months	↓ Fasting venous glucose
Rachid et al. (2022) [78]	T2D patients	6 g/100 mL of aqueous cinnamon extract (C. burmannii) after 30, 60, 90, and 120 minutes	↔ Area under the curve, glucose conc., variation, and maximum glucose conc

AKT, protein kinase B; AKT2, AKT serine/threonine kinase 2; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; BW, body weight; CAT, catalase; Cr, creatinine; CYP2D, cytochrome P450; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; GSH, glutathione; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-β, homeostasis model assessment of β-cell function; HOMA-IR, homeostasis model assessment-estimated insulin resistance; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; IRS-1, insulin receptor substrate 1; ITT, insulin tolerance test; LDL-C, low-density lipoprotein cholesterol; MDA, malondialdehyde; NF-κB, nuclear factor kappa B; NO, nitric oxide; OGTT, oral glucose tolerance test; PBG, postprandial glucose level; PI3K, phosphoinositide 3-kinase ; PPAR-γ, peroxisome proliferated activated receptor gamma; SIRT 1, silent mating-type information regulation 2 homolog 1; SOD, superoxide dismutase; STZ, streptozotocin; T2D, type 2 diabetes; TC, total cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor alpha; VLDL, very-low-density lipoprotein; WC, waist circumference.

Table 4.

Studies involving cinnamon on obesity

Reference	Study/sample	Intervention	Results
Experimental study
Lopes et al. (2015) [111]	Adult male Wistar rat	400 mg/kg BW/day of cinnamon aqueous extract (Cinnamomum zeylanicum), for 25 days	↔ Food intake and serum lipid profile
			↓ Body mass gain
			↓ Relative mass of WAT
			Leptin mRNA expression in the WAT
			↑ Protein content
Lee et al. (2016) [112]	3T3-L1 preadipocytes cells	50, 100, 200 μg/mL of cinnamon extract (Cinnamomum cassia)	↑ Lipid storage in white adipocytes,
			↑ Fatty acid oxidation capacity
			↑ PGC-1α, CPT-1α, PPARγ, C/EBP-α, and C/EBP-β genes expressions
Khare et al. (2016) [113]	3T3-L1 preadipocytes cells	10, 20, and 40 μM of cinnamaldehyde: in vitro	↑ HPL
	In vivo: male Swiss albino mice	5 mL/kg and 10 mL/kg BW of cinnamaldehyde with a normal or HFD: in vivo	↓ Expression of perilipin and GPD
			↓ PPARγ and C/EBP-α prevented the increase in visceral fat pad weight regulated leptin/ghrelin ratio
			↑ Anorectic gene expression in hypothalamus (POMC, BDNF, UCN, CARTPT, and CCK)
			↓ Glycerol and free fatty acid levels
			↑ Expression levels of lipolysis-promoting genes: HSL, PNPLA2, and MGLL
			↓ IL-1β, COX, MCP1, TNF-α, and IL-6
			↑ Anorectic and lipolytic gene expression
Jiang et al. (2017) [52]	Primary preadipocytes from and human adipose-derived stem cells	200 and 400 μM of cinnamaldehyde	↑ Thermogenesis: ↑ UCP1, FGF21, PKA, phosphorylation of HSL and PLIN1
Jiang et al. (2017) [52]		200 and 400 μM of cinnamaldehyde	↑ Lipid metabolism: Pdk4
Kwan et al. (2017) [114]	3T3-L1 preadipocytes and	80 µg/mL (in vitro) and 500 mg/kg BW (in vivo) cinnamon extract (C. cassia)	Induced browning in white adipocytes: ↑ UCP1 expression; ↑ Prdm16, Cidea, PPARγ, PGC, Cpt1
	Ex vivo: subcutaneous adipose tissue from db/db mice and in vivo/ex vivo DIO mice		Induced browning in subcutaneous adipocytes in db/db mice: UCP1 protein and mRNA Cidea and Prdm16
			DIO mice: ↑ UCP1 expression in the subcutaneous adipose tissue; ↓ BW
Kang et al. (2019) [115]	3T3-L1 and HIB1B preadipocytes cells	10–200 μM of trans-cinnamic acid of bark (C. cassia)	Induced browning in white adipocytes activation of β3AR-PKA-AMPK, TRPA1, and GPR signaling pathways
			↑ Fat oxidation
			↓ Adipogenesis and lipogenesis
Neto et al. (2019) [116]	Lactating dams (Wistar rats) were supplemented, and adult male offspring were evaluated at 180 days old	400 mg/kg BW/day of cinnamon aqueous extract (C. zeylanicum) during lactating period	↑ Visceral obesity
			Hepatic metabolic dysfunction and ↑ lipid accumulation
			↓ Glycogen content in the liver, hyperleptinemia and hyperinsulinemia
Neto et al. (2020) [117]	Adolescent rat model of obesity programmed by early overnutrition	Cinnamaldehyde 40 mg/kg of body mass per day for 29 days	↓ Visceral adipose tissue mass
Ataie et al. (2021) [118]	Adult male Wistar rats with HFD-induced	Cinnamaldehyde 20 mg/kg of body mass per day for 16 weeks	↓ Plasma nitrate and nitrate
			↓ Islet insulin secretion
			↓ iNOS activity
Li et al. (2022) [105]	Adult male Wistar rat obesity HFD-induced	Cinnamon powder 50 or 100 mg/kg BW orally for 12 weeks	↓ Hepatic levels of oxidative and inflammatory biomarkers
			↓ Serum levels of glucose, liver enzymes, insulin, and lipid profiles
			↓ Hepatic expression of SREBP-1c and NF-κB
			↑ PPAR-α, CD36, CPT-1, and Nrf-2
Neto et al. (2022) [119]	Adolescent rat model of obesity programmed by early overnutrition	Cinnamaldehyde 40 mg per kg of body mass per day for 30 days	↓ Adipocyte hypertrophy
			↑ Oxidative pathways (PGC1α, FGF21) in WAT
			↑ Increased BAT thermogenesis markers (PPARα, FGF21, UCP-1)
			↓ WAT adipocyte size
Miah et al. (2022) [120]	Adult Swiss albino mice hyperlipidemia and obesity	10% butter with cinnamon 200 mg, 400 mg, or 600 mg powder per liter drinking water for 10 weeks	↓ TC, LDL-C, and glucose levels
Miah et al. (2022) [120]	Butter enriched HFD-induced		↓ ALT and AST and fat deposition in the liver
Human study
Gupta Jain et al. (2017) [72]	Adults with metabolic syndrome	3 g/day (6 capsules) of cinnamon for 16 weeks	↓ BW, WC, waist-to-hip ratio
Gupta Jain et al. (2017) [72]	Adults with metabolic syndrome	3 g/day (6 capsules) of cinnamon for 16 weeks	↓ % Body fat
Borzoei et al. (2017) [121]	Polycystic ovary syndrome in overweight or obese women	1.5 g cinnamon extract (3 capsules) for 8 weeks	Improved glucose metabolism and lipid profile, ↓ insulin
Khedr et al. (2020) [110]	Overweight /obese adults	1.2 g of Ceylon cinnamon capsules and 120 mg of Orlistat for 15 weeks	↓ BMI
			↓ Lipase activity
			↓ Lipid profile
Wang et al. (2021) [122]	Normal and overweight/obese individuals	1/2 cup dry instant oatmeal with milk prepared with or without 6 g of cinnamon (Korintje cinnamon, from cassia bark), acute intake (4 hours)	↓ Postprandial insulin response in overweight/obese individuals
Wang et al. (2021) [122]	Normal and overweight/obese individuals		↓ Postprandial glucagon levels, glucagon and C-peptide response in normal weight participants
Huang et al. (2022) [123]	Overweight adults	6 g of cinnamon meal on 4 separate visits at least 3 days apart	↓ Postprandial glycemia

ALT, alanine aminotransferase; AMPK, adenosine monophosphate-activated protein kinase; AST, aspartate aminotransferase; BAT, brown adipose tissue; BDNF, brain-derived neurotrophic factor; BMI, body mass index; BW, body weight; C/EBP-α, CCAAT/enhancer-binding protein alpha; C/EBP-β, CCAAT-enhancer-binding protein beta; CARTPT, cocaine amphetamine-related transcript; CCK, cholecystokinin; CD36, cluster of differentiation 36; Cidea, DFFA-like effector A; COX, cyclooxygenase; CPT-1, carnitine palmitoyl transferase 1; CPT-1α, carnitine palmitoyltransferase 1 alpha; DIO, diet-induced obesity; FGF21, fibroblast growth factor 21; GPD, glycerol-3-phosphate dehydrogenase; GPR, G-protein-coupled receptor; HFD, high-fat diet; HSL, hormone-sensitive lipase; IL, interleukin; iNOS, inducible nitric oxide synthase; LDL-C, low-density lipoprotein cholesterol; MCP-1, monocytechemotactic protein 1; MGLL, monoglyceride lipase; NF-κB, factor nuclear kappa B; Nrf-2, nuclear factor erythroid 2-related factor 2; Pdk4, pyruvate dehydrogenase kinase 4; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PKA, protein kinase A; PLIN1, lipid droplet-associated protein perilipin 1; PNPLA2, patatin phospholipase domain containing 2; POMC, proopiomelanocortin; PPARα, peroxisome proliferator-activated receptor alpha; PPARγ, peroxisome proliferator-activated receptor gamma; Prdm16, PR domain containing 16; SREBP-1, sterol regulatory element-binding transcription factor 1; TC, total cholesterol; TNF-α, tumor necrosis factor alpha; TRPA1, necrosis factor receptor-associated protein 1; UCN, urocortin; UCP-1, uncoupling protein 1; WAT, white adipose tissue; WC, waist circumference; β3AR, β3 adrenergic receptor.

Table 5.

Studies involving cinnamon on cardiovascular health

Reference	Study/sample	Intervention	Results
Experimental study
Kwon et al. (2015) [131]	Rat aortic vascular smooth muscle cells	Extract Cinnamomum cassia bark – 10, 30, and 50 µM	↓ PLCγ1, Akt, and P38
			↑ Percentage of G0/G1 phase cells
			↓ PCNA expression
Panickar et al. (2015) [132]	Mouse brain endothelial cells	Cinnamtannin D1 – 10⁻² and 10⁻³ mg/mL	↓ OGD-induced swelling
			↓ Cell swelling in presence of MCP-1
			↓ Mitochondrial ROS
			↓ OGD-induced fluorescence
Chen et al. (2016) [133]	Mice with ischemia/reperfusion-induced brain injury	10, 20, and 30 mg/kg trans-cinnamaldehyde, an essential oil in cinnamon powder 60 minutes before ischemia surgery	↓ Infarction area and neurological deficit score
Chen et al. (2016) [133]	Mice with ischemia/reperfusion-induced brain injury		↓ iNOS, COX-2, NF-κB, mRNA, TNF-α
Kang et al. (2016) [134]	Male rats with metabolic syndrome with cardiac oxidative stress	20, 40, and 80 mg/kg cinnamaldehyde for 5 weeks	↓ HW/BW, TGF-β, p-Smad 2/3 and Smad4
Kang et al. (2016) [134]			↑ GSH/GSSG
Tuzcu et al. (2017) [9]	Rats given high-fat feed	100 mg/kg cinnamon polyphenol extract for 12 weeks	↓ Expression of hepatic SREBP-1c, LXRs, ACLY, FAS, MDA, NF-κB
			↑ PPAR-α, IRS, Nrf2, HO-1, SOD, CAT
			↓ TG, TC, LDL-C
			↓ BW, visceral fat
Nayak et al. (2017) [135]	Mice with dexamethasone-induced atherosclerosis	500 mg/kg and 250 mg/kg cinnamon extract for 12 days	↓ TG, TC, LDL-C
			↑ HDL-C
			↓ Atherosclerotic change of aorta
Sedighi et al. (2018) [136]	Rats with ischemia	Cinnamomum zeylanicum bark extract – 50, 100, or 200 mg/kg – 2 weeks before ischemia	↓ Infarct size
			↓ Ventricular tachycardia, ventricular ectopic beats episodes
			↓ R-wave amplitude
			↑ Heart rate during ischemia
			↓ MDA, cardiactroponin I, LDH
			↑ SOD, GPx
Pulungan and Pane (2020) [137]	Mice (Mus musculus) given high-fat feed	2, 4, and 8 mg/kg cinnamon extract for 2 weeks	↓ TC
Alsoodeeri et al. (2020) [138]	Rats given high-fat feed	2 and 4 g/kg cinnamon powder for 4 weeks	↓ TG, TC, LDL-C
Alsoodeeri et al. (2020) [138]	Rats given high-fat feed		↑ HDL-C
Wang et al. (2020) [45]	Leptin receptor-deficient mice	Diet containing 0.02% cinnamaldehyde for 12 weeks	↑ Nitrotyrosine, NO, NRF2, HO-1, NQO-1
Wang et al. (2020) [45]	Leptin receptor-deficient mice		↓ ROS, p-eNOS
Moreno et al. (2022) [139]	Rings from male Wistar rat thoracic aorta pre	Cinnamon extract (0–380 μg/mL)	Induced concentration-dependent vasodilation
Tian et al. (2022) [140]	Male, cardiac hypertrophy model C57BL/6	Trans-cinnamaldehyde daily at a dosage of 50 mg/kg or 100 mg/kg via oral gavage for 2 weeks	Inhibited induced cardiac hypertrophy
Human study
Ranasinghe et al. (2017) [141]	Healthy adults	85 mg, 250 mg, and 500 mg of C. Zeylanicum (water extract) for a period of 3 months, with dose increased at monthly intervals	SBP, DBP
			↔Renal and liver function, fasting blood glucose, HDL-C, VLDL, and TG
			↓TC and LDL-C
Mirmiran et al. (2019) [142]	Type 2 diabetes patients	3 g cinnamon extract capsules, for 2 months	↓ICAM-1 and VCAM-1 in both cinnamon and placebo groups, but not between groups
Shirzad et al. (2021) [143]	Stage 1 hypertension patients	Cinnamon capsules, 1,500 mg/day, for 2 months	Moderate clinical decrease in mean ambulatory SBP
			↑ HDL-C
			↓ LDL-C levels
Zhang et al. (2022) [144]	Patients with mild stroke or transient ischemic attack	Aspirin-cinnamon group (100 mg/day aspirin + 5 g of cinnamon granules) and aspirin-placebo group (100 mg/day aspirin + placebo granules) for 2 months	Aspirin-cinnamon group:
			↓TG, LDL-C, fasting plasma glucose, HbA1c, Lp-PLA₂, and hs-CRP
			↑ HDL-C
			↓ Carotid atherosclerosis

ACLY, ATP-citrate lyase; Akt, protein kinase B; BW, body weight; CAT, catalase; COX-2, cyclooxygenase type 2; DBP, diastolic blood pressure; FAS, fatty acid synthase; GPx, glutathione peroxidase; GSH/GSSG, glutathione/oxidized glutathione ratio; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HO-1, heme oxygenase 1; hs-CRP, high-sensitivity C-reactive protein; HW/BW, heart-to-body weight; ICAM-1, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthetase; IRS, insulin receptor; LDH, lactate dehydrogenase; LDL-C, low-density lipoprotein cholesterol; Lp-PLA₂, plasma lipoprotein-related phospholipase A₂; LXRs, liver X receptor; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; mRNA, messenger RNA; NF-κB, nuclear factor kappa B; NO, nitric oxide; NQO-1, NAD(P)H dehydrogenase [quinone] 1; NRF2, factor erythroid nuclear factor 2 related to factor 2; OGD, oxygen-glucose deprivation; P38, anti-phospho-p38; PCNA, antiproliferating cell nuclear antigen; p-eNOS, phosphorylated endothelial nitric oxide synthase; PLCγ1, anti-phospho-phospholipase C gamma 1; PPAR-α, peroxisomeproliferator-activated receptor alpha; p-Smad 2/3, phosphorylated Smad2/3; p-Smad4, phosphorylated Smad4; ROS, reactive oxygen species; SBP, systolic blood pressure; SOD, superoxide dismutase; SREBP-1c, sterol regulatory element-binding proteins; TC, total cholesterol; TG, triglyceride; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1; VLDL, very-low-density lipoprotein.

Table 6.

Experimental studies involving cinnamon on kidney diseases

Reference	Study/sample	Intervention	Results
Hussain et al. (2019) [170]	Administration of acetaminophen in BALB/c mice	Pretreatment with 200 mg/kg/day i.g. of cinnamon bark aqueous extract for 2 weeks	Prevention against elevation in serum ALT, AST, Cr, urea
			Prevention against macroscopic and histological alterations in liver and kidney
			Improvement of oxidative balance
Niazmand et al. (2021) [65]	STZ-induced diabetic rats	100, 200, or 400 mg/kg of cinnamon extract for 6 weeks	↓ MDA level, SOD and CAT activities in the liver and kidney
Niazmand et al. (2021) [65]	STZ-induced diabetic rats	100, 200, or 400 mg/kg of cinnamon extract for 6 weeks	↑ GSH and total thiol contents and NO production
Alshahrani et al. (2021) [171]	Male Wistar rats with nephrotoxicity induced by acetaminophen	50, 100, and 200 mg/kg of cinnamon oil with 2 g/kg of acetaminophen, for 15 days	Improvement in serum biochemical markers and oxidative parameters:
			Protected cellular injury in kidney tissue
			↓ IL-1β, IL-6, and caspase 3 and 9
			↑ GSH level and ameliorates antioxidative enzymes (SOD, CAT, GR, and GPx in kidney tissue)
Atsamo et al. (2021) [172]	Male Wistar rats with gentamicin-induced nephrotoxicity	200 and 400 mg/kg/day of Cinnamomum zeylanicum stem bark aqueous extract for 2 weeks concomitantly with gentamicin administration	Prevention of alterations in body weight, serum total proteins, calcium level, kidneys’ relative weight, Cr, urea, and uric acid
			↓ MDA and TNF-α, IL-1β, and IL-6 and nitrites
			↑ GSH, SOD, CAT
			Prevention of histological alterations
Elshopakey and Elazab, (2021) [173]	Broiler chickens with copper-induced nephrotoxicity	200 mg/kg of C. zeylanicum alone or plus probiotic for 6 weeks	Both supplementations:
			↓ Urea, Cr, and uric acid
			In renal tissue:
			↓ MDA, ↑CAT, and GSH, ↓ Copper
			↓ TNF-α, IL-2, Bax, and COX-II in kidneys
			↑ IL-10 and Bcl-2
Xiao (2022) [168]	Sprague-Dawley rats (male) kidney senescence model D-galactose-induced	40 mg/kg/day of cinnamaldehyde for 6 weeks	↓ Blood urea nitrogen and Cr
			In the kidneys: the contours of the proximal and distal convoluted tubules were improved, ↓ the number of nuclear pyknosis, ↓ hyperemia
			↑ Ratio of p-P13K to P13K and the ratio of p-Akt to Akt

Akt, protein kinase B; ALT, alanine transaminase; AST, aspartate transaminase; Bcl-2, B-cell lymphoma 2; CAT, catalase; COX-II, cyclooxygenase; Cr, creatinine; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; IL, interleukin; MDA, malondialdehyde; NO, nitric oxide; p21, p21/WAF1Cip1; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; SOD, superoxide dismutase; TNF-α, tumor necrosis factor alpha.

References

1. Ranasinghe P, Jayawardana R, Galappaththy P, Constantine GR, de Vas Gunawardana N, Katulanda P. Efficacy and safety of ‘true’ cinnamon (Cinnamomum zeylanicum) as a pharmaceutical agent in diabetes: a systematic review and meta-analysis. Diabet Med 2012;29:1480–1492.

2. Kawatra P, Rajagopalan R. Cinnamon: mystic powers of a minute ingredient. Pharmacognosy Res 2015;7(Suppl 1):S1–S6.

3. Parham S, Kharazi AZ, Bakhsheshi-Rad HR, et al. Antioxidant, antimicrobial and antiviral properties of herbal materials. Antioxidants (Basel) 2020;9:1309.

4. Aminzadeh Z, Ziamajidi N, Abbasalipourkabir R. Anticancer effects of cinnamaldehyde through inhibition of ErbB2/HSF1/LDHA pathway in 5637 cell line of bladder cancer. Anticancer Agents Med Chem 2022;22:1139–1148.

5. Shishehbor F, Rezaeyan Safar M, Rajaei E, Haghighizadeh MH. Cinnamon consumption improves clinical symptoms and inflammatory markers in women with rheumatoid arthritis. J Am Coll Nutr 2018;37:685–690.

6. Wang R, Li S, Jia H, et al. Protective effects of cinnamaldehyde on the inflammatory response, oxidative stress, and apoptosis in liver of Salmonella typhimurium: challenged mice. Molecules 2021;26:2309.

7. Yang G, Jin T, Yin S, et al. Trans-Cinnamaldehyde mitigated intestinal inflammation induced by Cronobacter sakazakii in newborn mice. Food Funct 2019;10:2986–2996.

8. Wang F, Pu C, Zhou P, et al. Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2. Cell Physiol Biochem 2015;36:315–324.

9. Tuzcu Z, Orhan C, Sahin N, Juturu V, Sahin K. Cinnamon polyphenol extract inhibits hyperlipidemia and inflammation by modulation of transcription factors in high-fat diet-fed rats. Oxid Med Cell Longev 2017;2017:1583098.

10. Tinti F, Lai S, Noce A, et al. Chronic kidney disease as a systemic inflammatory syndrome: update on mechanisms involved and potential treatment. Life (Basel) 2021;11:419.

11. Borges NA, Barros AF, Nakao LS, Dolenga CJ, Fouque D, Mafra D. Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J Ren Nutr 2016;26:396–400.

12. Mafra D, Borges NA, Lindholm B, Shiels PG, Evenepoel P, Stenvinkel P. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol 2021;17:153–171.

13. Alvarenga L, Cardozo LF, Borges NA, et al. To bee or not to bee?: the bee extract propolis as a bioactive compound in the burden of lifestyle diseases. Nutrition 2021;83:111094.

14. Alvarenga L, Salarolli R, Cardozo LF, et al. Impact of curcumin supplementation on expression of inflammatory transcription factors in hemodialysis patients: a pilot randomized, double-blind, controlled study. Clin Nutr 2020;39:3594–3600.

15. Cardozo LF, Stockler-Pinto MB, Mafra D. Brazil nut consumption modulates Nrf2 expression in hemodialysis patients: a pilot study. Mol Nutr Food Res 2016;60:1719–1724.

16. Esgalhado M, Kemp JA, Paiva BR, et al. Resistant starch type-2 enriched cookies modulate uremic toxins and inflammation in hemodialysis patients: a randomized, double-blind, crossover and placebo-controlled trial. Food Funct 2020;11:2617–2625.

17. Kemp JA, Regis de Paiva B, Fragoso Dos Santos H, et al. The impact of enriched resistant starch type-2 cookies on the gut microbiome in hemodialysis patients: a randomized controlled trial. Mol Nutr Food Res 2021;65:e2100374.

18. Moreira LS, Fanton S, Cardozo L, et al. Pink pressure: beetroot (Beta vulgaris rubra) as a possible novel medical therapy for chronic kidney disease. Nutr Rev 2022;80:1041–1061.

19. Salarolli RT, Alvarenga L, Cardozo LF, et al. Can curcumin supplementation reduce plasma levels of gut-derived uremic toxins in hemodialysis patients?: a pilot randomized, double-blind, controlled study. Int Urol Nephrol 2021;53:1231–1238.

20. Lee R, Balick MJ. Sweet wood: cinnamon and its importance as a spice and medicine. Explore (NY) 2005;1:61–64.

21. Jamali N, Jalali M, Saffari-Chaleshtori J, Samare-Najaf M, Samareh A. Effect of cinnamon supplementation on blood pressure and anthropometric parameters in patients with type 2 diabetes: a systematic review and meta-analysis of clinical trials. Diabetes Metab Syndr 2020;14:119–125.

22. Gul S, Safdar M. Proximate composition and mineral analysis of cinnamon. Pak J Nutr 2009;8:1456–1460.

23. Rao PV, Gan SH. Cinnamon: a multifaceted medicinal plant. Evid Based Complement Alternat Med 2014;2014:642942.

24. Jiang TA. Health benefits of culinary herbs and spices. J AOAC Int 2019;102:395–411.

25. Singh G, Maurya S, DeLampasona MP, Catalan CA. A comparison of chemical, antioxidant and antimicrobial studies of cinnamon leaf and bark volatile oils, oleoresins and their constituents. Food Chem Toxicol 2007;45:1650–1661.

26. Hussain Z, Khan JA, Rashid H. Cinnamomum zeylanicum (Darchini): a boon to medical science and a possible therapy for stress-induced ailments. Crit Rev Eukaryot Gene Expr 2019;29:263–276.

27. Konda MR, Alluri KV, Janardhanan PK, Trimurtulu G, Sengupta K. Combined extracts of Garcinia mangostana fruit rind and Cinnamomum tamala leaf supplementation enhances muscle strength and endurance in resistance trained males. J Int Soc Sports Nutr 2018;15:50.

28. Manaf A, Tjandrawinata RR, Malinda D. Insulin sensitizer in prediabetes: a clinical study with DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa. Drug Des Devel Ther 2016;10:1279–1289.

29. Schöttker B, Saum KU, Jansen EH, et al. Oxidative stress markers and all-cause mortality at older age: a population-based cohort study. J Gerontol A Biol Sci Med Sci 2015;70:518–524.

30. Gyurászová M, Gurecká R, Bábíčková J, Tóthová Ľ. Oxidative stress in the pathophysiology of kidney disease: implications for noninvasive monitoring and identification of biomarkers. Oxid Med Cell Longev 2020;2020:5478708.

31. Checa J, Aran JM. Reactive oxygen species: drivers of physiological and pathological processes. J Inflamm Res 2020;13:1057–1073.

32. Shang C, Lin H, Fang X, et al. Beneficial effects of cinnamon and its extracts in the management of cardiovascular diseases and diabetes. Food Funct 2021;12:12194–12220.

33. Chen P, Ruan A, Zhou J, et al. Cinnamic aldehyde inhibits lipopolysaccharide-induced chondrocyte inflammation and reduces cartilage degeneration by blocking the nuclear factor-kappa B signaling pathway. Front Pharmacol 2020;11:949.

34. Zou L, Li C, Chen X, et al. The anti-inflammatory effects of cinnamyl alcohol on sepsis-induced mice via the NLRP3 inflammasome pathway. Ann Transl Med 2022;10:48.

35. Kim ME, Na JY, Lee JS. Anti-inflammatory effects of trans-cinnamaldehyde on lipopolysaccharide-stimulated macrophage activation via MAPKs pathway regulation. Immunopharmacol Immunotoxicol 2018;40:219–224.

36. Uchi H, Yasumatsu M, Morino-Koga S, Mitoma C, Furue M. Inhibition of aryl hydrocarbon receptor signaling and induction of NRF2-mediated antioxidant activity by cinnamaldehyde in human keratinocytes. J Dermatol Sci 2017;85:36–43.

37. Schink A, Naumoska K, Kitanovski Z, et al. Anti-inflammatory effects of cinnamon extract and identification of active compounds influencing the TLR2 and TLR4 signaling pathways. Food Funct 2018;9:5950–5964.

38. Qu S, Shen Y, Wang M, Wang X, Yang Y. Suppression of miR-21 and miR-155 of macrophage by cinnamaldehyde ameliorates ulcerative colitis. Int Immunopharmacol 2019;67:22–34.

39. Cheng WX, Zhong S, Meng XB, et al. Cinnamaldehyde inhibits inflammation of human synoviocyte cells through regulation of Jak/Stat pathway and ameliorates collagen-induced arthritis in rats. J Pharmacol Exp Ther 2020;373:302–310.

40. Ben Lagha A, Azelmat J, Vaillancourt K, Grenier D. A polyphenolic cinnamon fraction exhibits anti-inflammatory properties in a monocyte/macrophage model. PLoS One 2021;16:e0244805.

41. Vallion R, Hardonnière K, Bouredji A, et al. The inflammatory response in human keratinocytes exposed to cinnamaldehyde is regulated by Nrf2. Antioxidants (Basel) 2022;11:575.

42. Chen P, Zhou J, Ruan A, Zeng L, Liu J, Wang Q. Cinnamic aldehyde, the main monomer component of cinnamon, exhibits anti-inflammatory property in OA synovial fibroblasts via TLR4/MyD88 pathway. J Cell Mol Med 2022;26:913–924.

43. Abou El-Ezz D, Maher A, Sallam N, El-Brairy A, Kenawy S. Trans-cinnamaldehyde modulates hippocampal Nrf2 factor and inhibits amyloid beta aggregation in LPS-induced neuroinflammation mouse model. Neurochem Res 2018;43:2333–2342.

44. Liu P, Wang J, Wen W, et al. Cinnamaldehyde suppresses NLRP3 derived IL-1β via activating succinate/HIF-1 in rheumatoid arthritis rats. Int Immunopharmacol 2020;84:106570.

45. Wang P, Yang Y, Wang D, et al. Cinnamaldehyde ameliorates vascular dysfunction in diabetic mice by activating Nrf2. Am J Hypertens 2020;33:610–619.

46. Ryu JS, Kang HY, Lee JK. Effect of treadmill exercise and trans-cinnamaldehyde against d-galactose- and aluminum chloride-induced cognitive dysfunction in mice. Brain Sci 2020;10:793.

47. Abdel-Kawi SH, Hashem KS, Saad MK, Fekry G, Abdel-Hameed EM. The ameliorative effects of cinnamon oil against ethanol-induced gastric ulcer in rats by regulating oxidative stress and promoting angiogenesis. J Mol Histol 2022;53:573–587.

48. Haidari F, Mohammadshahi M, Abiri B, Guest PC, Zarei M, Fathi M. Testing the effects of cinnamon extract supplementation on inflammation and oxidative stress induced by acrylamide. Methods Mol Biol 2022;2343:179–190.

49. Zhao H, Zhang M, Zhou F, et al. Cinnamaldehyde ameliorates LPS-induced cardiac dysfunction via TLR4-NOX4 pathway: the regulation of autophagy and ROS production. J Mol Cell Cardiol 2016;101:11–24.

50. Li AL, Li GH, Li YR, et al. Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases. Phytomedicine 2019;53:143–153.

51. Davari M, Hashemi R, Mirmiran P, et al. Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB and sirtuin-1 (SIRT1) in type 2 diabetes: a randomized, double blind, and controlled clinical trial. Nutr J 2020;19:1.

52. Jiang J, Emont MP, Jun H, et al. Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming. Metabolism 2017;77:58–64.

53. Liao JC, Deng JS, Chiu CS, et al. Anti-inflammatory activities of Cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Alternat Med 2012;2012:429320.

54. Zareie A, Sahebkar A, Khorvash F, Bagherniya M, Hasanzadeh A, Askari G. Effect of cinnamon on migraine attacks and inflammatory markers: a randomized double-blind placebo-controlled trial. Phytother Res 2020;34:2945–2952.

55. Abdelmageed ME, Shehatou GS, Abdelsalam RA, Suddek GM, Salem HA. Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn Schmiedebergs Arch Pharmacol 2019;392:243–258.

56. Azimi P, Ghiasvand R, Feizi A, et al. Effect of cinnamon, cardamom, saffron and ginger consumption on blood pressure and a marker of endothelial function in patients with type 2 diabetes mellitus: a randomized controlled clinical trial. Blood Press 2016;25:133–140.

57. Vijayakumar K, Rengarajan RL, Suganthi N, et al. Acute toxicity studies and protective effects of Cinnamon cassia bark extract in streptozotocin-induced diabetic rats. Drug Chem Toxicol 2022;45:2086–2096.

58. Hafizur RM, Hameed A, Shukrana M, et al. Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro. Phytomedicine 2015;22:297–300.

59. Qusti S, El Rabey HA, Balashram SA. The hypoglycemic and antioxidant activity of cress seed and cinnamon on streptozotocin induced diabetes in male rats. Evid Based Complement Alternat Med 2016;2016:5614564.

60. Jawale A, Datusalia AK, Bishnoi M, Sharma SS. Reversal of diabetes-induced behavioral and neurochemical deficits by cinnamaldehyde. Phytomedicine 2016;23:923–930.

61. Hosni AA, Abdel-Moneim AA, Abdel-Reheim ES, Mohamed SM, Helmy H. Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress. Biomed Pharmacother 2017;88:52–60.

62. Taheri A, Lavasani H, Kasirzadeh S, Sheikholeslami B, Ardakani YH, Rouini MR. Changes in CYP2D enzyme activity following induction of type 2 diabetes, and administration of cinnamon and metformin: an experimental animal study. Xenobiotica 2018;48:984–989.

63. Kommula SR, Vadakattu SS, Myadara S, Putcha UK, Tamanam RR, Palla S. Cinnamon attenuated long-term IGT-induced retinal abnormalities via regulation of glucose homeostasis in neonatal streptozotocin induced rat model. Indian J Clin Biochem 2020;35:442–450.

64. Mohammed KA, Ahmed HM, Sharaf HA, et al. Encapsulation of cinnamon oil in whey protein counteracts the disturbances in biochemical parameters, gene expression, and histological picture of the liver and pancreas of diabetic rats. Environ Sci Pollut Res Int 2020;27:2829–2843.

65. Niazmand S, Mirzaei M, Hosseinian S, et al. The effect of Cinnamomum cassia extract on oxidative stress in the liver and kidney of STZ-induced diabetic rats. J Complement Integr Med 2021;19:311–321.

66. Sampath C, Wilus D, Tabatabai M, Freeman ML, Gangula PR. Mechanistic role of antioxidants in rescuing delayed gastric emptying in high fat diet induced diabetic female mice. Biomed Pharmacother 2021;137:111370.

67. Çelik R, Mert H, Comba B, Mert N. Effects of cinnamaldehyde on glucose-6-phosphate dehydrogenase activity, some biochemical and hematological parameters in diabetic rats. Biomarkers 2022;27:270–277.

68. Bernardo MA, Silva ML, Santos E, et al. Effect of cinnamon tea on postprandial glucose concentration. J Diabetes Res 2015;2015:913651.

69. Sengsuk C, Sanguanwong S, Tangvarasittichai O, Tangvarasittichai S. Effect of cinnamon supplementation on glucose, lipids levels, glomerular filtration rate, and blood pressure of subjects with type 2 diabetes mellitus. Diabetol Int 2015;7:124–132.

70. Gutierrez JL, Bowden RG, Willoughby DS. Cassia cinnamon supplementation reduces peak blood glucose responses but does not improve insulin resistance and sensitivity in young, sedentary, obese women. J Diet Suppl 2016;13:461–471.

71. Anderson RA, Zhan Z, Luo R, et al. Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose. J Tradit Complement Med 2015;6:332–336.

72. Gupta Jain S, Puri S, Misra A, Gulati S, Mani K. Effect of oral cinnamon intervention on metabolic profile and body composition of Asian Indians with metabolic syndrome: a randomized double -blind control trial. Lipids Health Dis 2017;16:113.

73. Talaei B, Amouzegar A, Sahranavard S, Hedayati M, Mirmiran P, Azizi F. Effects of cinnamon consumption on glycemic indicators, advanced glycation end products, and antioxidant status in type 2 diabetic patients. Nutrients 2017;9:991.

74. Zare R, Nadjarzadeh A, Zarshenas MM, Shams M, Heydari M. Efficacy of cinnamon in patients with type II diabetes mellitus: a randomized controlled clinical trial. Clin Nutr 2019;38:549–556.

75. Kizilaslan N, Erdem NZ. The effect of different amounts of cinnamon consumption on blood glucose in healthy adult individuals. Int J Food Sci 2019;2019:4138534.

76. Romeo GR, Lee J, Mulla CM, Noh Y, Holden C, Lee BC. Influence of cinnamon on glycemic control in individuals with prediabetes: a randomized controlled trial. J Endocr Soc 2020;4:bvaa094.

77. Lira Neto JC, Damasceno MM, Ciol MA, et al. Efficacy of cinnamon as an adjuvant in reducing the glycemic biomarkers of type 2 diabetes mellitus: a three-month, randomized, triple-blind, placebo-controlled clinical trial. J Am Nutr Assoc 2022;41:266–274.

78. Rachid AP, Moncada M, Mesquita MF, Brito J, Bernardo MA, Silva ML. Effect of aqueous cinnamon extract on the postprandial glycemia levels in patients with type 2 diabetes mellitus: a randomized controlled trial. Nutrients 2022;14:1576.

79. Stevens N, Allred K. Antidiabetic potential of volatile cinnamon oil: a review and exploration of mechanisms using in silico molecular docking simulations. Molecules 2022;27:853.

80. Costello RB, Dwyer JT, Saldanha L, Bailey RL, Merkel J, Wambogo E. Do cinnamon supplements have a role in glycemic control in type 2 diabetes?: a narrative review. J Acad Nutr Diet 2016;116:1794–1802.

81. Roussel AM, Hininger I, Benaraba R, Ziegenfuss TN, Anderson RA. Antioxidant effects of a cinnamon extract in people with impaired fasting glucose that are overweight or obese. J Am Coll Nutr 2009;28:16–21.

82. Anand P, Murali KY, Tandon V, Murthy PS, Chandra R. Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and GLUT4 translocation in experimental diabetic rats. Chem Biol Interact 2010;186:72–81.

83. Shen Y, Fukushima M, Ito Y, et al. Verification of the antidiabetic effects of cinnamon (Cinnamomum zeylanicum) using insulin-uncontrolled type 1 diabetic rats and cultured adipocytes. Biosci Biotechnol Biochem 2010;74:2418–2425.

84. Shen Y, Honma N, Kobayashi K, et al. Cinnamon extract enhances glucose uptake in 3T3-L1 adipocytes and C2C12 myocytes by inducing LKB1-AMP-activated protein kinase signaling. PLoS One 2014;9:e87894.

85. Mohamed Sham Shihabudeen H, Hansi Priscilla D, Thirumurugan K. Cinnamon extract inhibits α-glucosidase activity and dampens postprandial glucose excursion in diabetic rats. Nutr Metab (Lond) 2011;8:46.

86. Derosa G, Sahebkar A, Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol 2018;233:153–161.

87. Li JE, Futawaka K, Yamamoto H, et al. Cinnamaldehyde contributes to insulin sensitivity by activating PPARδ, PPARγ, and RXR. Am J Chin Med 2015;43:879–892.

88. Sun P, Li K, Wang T, et al. Procyanidin C1, a component of cinnamon extracts, is a potential insulin sensitizer that targets adipocytes. J Agric Food Chem 2019;67:8839–8846.

89. Baker WL, Gutierrez-Williams G, White CM, Kluger J, Coleman CI. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care 2008;31:41–43.

90. Davis PA, Yokoyama W. Cinnamon intake lowers fasting blood glucose: meta-analysis. J Med Food 2011;14:884–889.

91. Akilen R, Tsiami A, Devendra D, Robinson N. Cinnamon in glycaemic control: systematic review and meta analysis. Clin Nutr 2012;31:609–615.

92. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med 2013;11:452–459.

93. Mandal A, Sharma S, Rani R, Ranjan S, Kant R, Mirza A. Impact of cassia bark consumption on glucose and lipid control in type 2 diabetes: an updated systematic review and meta-analysis. Cureus 2021;13:e16376.

94. 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.

95. Abdali D, Samson SE, Grover AK. How effective are antioxidant supplements in obesity and diabetes? Med Princ Pract 2015;24:201–215.

96. O’Toole PW, Shiels PG. The role of the microbiota in sedentary lifestyle disorders and ageing: lessons from the animal kingdom. J Intern Med 2020;287:271–282.

97. Than WH, Chan GC, Ng JK, Szeto CC. The role of obesity on chronic kidney disease development, progression, and cardiovascular complications. Adv Biomark Sci Technol 2020;2:24–34.

98. D’Agati VD, Chagnac A, de Vries AP, et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016;12:453–471.

99. DeBoer MD, Filipp SL, Musani SK, Sims M, Okusa MD, Gurka M. Metabolic syndrome severity and risk of CKD and worsened GFR: The Jackson Heart Study. Kidney Blood Press Res 2018;43:555–567.

100. Marlatt KL, Ravussin E. Brown adipose tissue: an update on recent findings. Curr Obes Rep 2017;6:389–396.

101. Camacho S, Michlig S, de Senarclens-Bezençon C, et al. Anti-obesity and anti-hyperglycemic effects of cinnamaldehyde via altered ghrelin secretion and functional impact on food intake and gastric emptying. Sci Rep 2015;5:7919.

102. Legrand C, Merlini JM, de Senarclens-Bezençon C, Michlig S. New natural agonists of the transient receptor potential Ankyrin 1 (TRPA1) channel. Sci Rep 2020;10:11238.

103. Grahame Hardie D. Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharm Sin B 2016;6:1–19.

104. Kopp C, Singh SP, Regenhard P, Müller U, Sauerwein H, Mielenz M. Trans-cinnamic acid increases adiponectin and the phosphorylation of AMP-activated protein kinase through G-protein-coupled receptor signaling in 3T3-L1 adipocytes. Int J Mol Sci 2014;15:2906–2915.

105. Li B, Li J, Hu S. Cinnamon could improve hepatic steatosis caused by a high-fat diet via enhancing hepatic beta-oxidation and inhibiting hepatic lipogenesis, oxidative damage, and inflammation in male rats. J Food Biochem 2022;46:e14077.

106. Bano F, Ikram H, Akhtar N. Neurochemical and behavioral effects of Cinnamomi cassiae (Lauraceae) bark aqueous extract in obese rats. Pak J Pharm Sci 2014;27:559–563.

107. Yazdanpanah Z, Azadi-Yazdi M, Hooshmandi H, Ramezani-Jolfaie N, Salehi-Abargouei A. Effects of cinnamon supplementation on body weight and composition in adults: a systematic review and meta-analysis of controlled clinical trials. Phytother Res 2020;34:448–463.

108. Mousavi SM, Karimi E, Hajishafiee M, Milajerdi A, Amini MR, Esmaillzadeh A. Anti-hypertensive effects of cinnamon supplementation in adults: a systematic review and dose-response meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2020;60:3144–3154.

109. Keramati M, Musazadeh V, Malekahmadi M, et al. Cinnamon, an effective anti-obesity agent: evidence from an umbrella meta-analysis. J Food Biochem 2022;46:e14166.

110. Khedr NF, Ebeid AM, Khalil RM. New insights into weight management by orlistat in comparison with cinnamon as a natural lipase inhibitor. Endocrine 2020;67:109–116.

111. Lopes BP, Gaique TG, Souza LL, et al. Cinnamon extract improves the body composition and attenuates lipogenic processes in the liver and adipose tissue of rats. Food Funct 2015;6:3257–3265.

112. Lee SG, Siaw JA, Kang HW. Stimulatory effects of Cinnamon extract (Cinnamomum cassia) during the initiation stage of 3T3-L1 adipocyte differentiation. Foods 2016;5:83.

113. Khare P, Jagtap S, Jain Y, et al. Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice. Biofactors 2016;42:201–211.

114. Kwan HY, Wu J, Su T, et al. Cinnamon induces browning in subcutaneous adipocytes. Sci Rep 2017;7:2447.

115. Kang NH, Mukherjee S, Yun JW. Trans-cinnamic acid stimulates white fat browning and activates brown adipocytes. Nutrients 2019;11:577.

116. Neto JG, Bento-Bernardes T, Pazos-Moura CC, Oliveira KJ. Maternal cinnamon intake during lactation led to visceral obesity and hepatic metabolic dysfunction in the adult male offspring. Endocrine 2019;63:520–530.

117. Neto JG, Boechat SK, Romão JS, Pazos-Moura CC, Oliveira KJ. Treatment with cinnamaldehyde reduces the visceral adiposity and regulates lipid metabolism, autophagy and endoplasmic reticulum stress in the liver of a rat model of early obesity. J Nutr Biochem 2020;77:108321.

118. Ataie Z, Dastjerdi M, Farrokhfall K, Ghiravani Z. The effect of cinnamaldehyde on iNOS activity and NO-induced islet insulin secretion in high-fat-diet rats. Evid Based Complement Alternat Med 2021;2021:9970678.

119. Neto JG, Boechat SK, Romão JS, Kuhnert LR, Pazos-Moura CC, Oliveira KJ. Cinnamaldehyde treatment during adolescence improves white and brown adipose tissue metabolism in a male rat model of early obesity. Food Funct 2022;13:3405–3418.

120. Miah MA, Himel MH, Sujan KM, Mustari A, Haque MI. Protective effects of cinnamon powder against hyperlipidemia and hepatotoxicity in butter fed female albino mice. Saudi J Biol Sci 2022;29:3069–3074.

121. Borzoei A, Rafraf M, Niromanesh S, Farzadi L, Narimani F, Doostan F. Effects of cinnamon supplementation on antioxidant status and serum lipids in women with polycystic ovary syndrome. J Tradit Complement Med 2017;8:128–133.

122. Wang J, Wang S, Yang J, et al. Acute effects of cinnamon spice on post-prandial glucose and insulin in normal weight and overweight/obese subjects: a pilot study. Front Nutr 2021;7:619782.

123. Huang Y, Tsai MF, Thorat RS, et al. Endothelial function and postprandial glucose control in response to test-meals containing herbs and spices in adults with overweight/obesity. Front Nutr 2022;9:811433.

124. Said S, Hernandez GT. The link between chronic kidney disease and cardiovascular disease. J Nephropathol 2014;3:99–104.

125. Hadi A, Campbell MS, Hassani B, Pourmasoumi M, Salehi-Sahlabadi A, Hosseini SA. The effect of cinnamon supplementation on blood pressure in adults: a systematic review and meta-analysis of randomized controlled trials. Clin Nutr ESPEN 2020;36:10–16.

126. Ghavami A, Haghighian HK, Roshanravan N, et al. What is the impact of cinnamon supplementation on blood pressure?: a systematic review and meta-analysis. Endocr Metab Immune Disord Drug Targets 2021;21:956–965.

127. Maierean SM, Serban MC, Sahebkar A, et al. The effects of cinnamon supplementation on blood lipid concentrations: a systematic review and meta-analysis. J Clin Lipidol 2017;11:1393–1406.

128. Qin B, Polansky MM, Anderson RA. Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats. Horm Metab Res 2010;42:187–193.

129. Tsui PF, Lin CS, Ho LJ, Lai JH. Spices and atherosclerosis. Nutrients 2018;10:1724.

130. Krittanawong C, Isath A, Scott CZ, et al. Association between cinnamon consumption and risk of cardiovascular health: a systematic review and meta-analysis. Am J Med 2022;135:110–117.

131. Kwon H, Lee JJ, Lee JH, et al. Cinnamon and its components suppress vascular smooth muscle cell proliferation by up-regulating cyclin-dependent kinase inhibitors. Am J Chin Med 2015;43:621–636.

132. Panickar KS, Qin B, Anderson RA. Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by cinnamtannin D1, green tea extract, and resveratrol in vitro. Nutr Neurosci 2015;18:297–306.

133. Chen YF, Wang YW, Huang WS, et al. Trans-cinnamaldehyde, an essential oil in cinnamon powder, ameliorates cerebral ischemia-induced brain injury via inhibition of neuroinflammation through attenuation of iNOS, COX-2 expression and NFκ-B signaling pathway. Neuromolecular Med 2016;18:322–333.

134. Kang LL, Zhang DM, Ma CH, et al. Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation. Sci Rep 2016;6:27460.

135. Nayak IN, Chinta R, Jetti R. Anti-atherosclerotic potential of aqueous extract of Cinnamomum zeylanicum bark against glucocorticoid induced atherosclerosis in wistar rats. J Clin Diagn Res 2017;11:FC19–FC23.

136. Sedighi M, Nazari A, Faghihi M, et al. Protective effects of cinnamon bark extract against ischemia-reperfusion injury and arrhythmias in rat. Phytother Res 2018;32:1983–1991.

137. Pulungan A, Pane YS. The benefit of cinnamon (Cinnamomum burmannii) in lowering total cholesterol levels after consumption of high-fat containing foods in white mice (Mus musculus) models. F1000Res 2020;9:168.

138. Alsoodeeri FN, Alqabbani HM, Aldossari NM. Effects of cinnamon (Cinnamomum cassia) consumption on serum lipid profiles in albino rats. J Lipids 2020;2020:8469830.

139. Moreno EK, de Macêdo IY, Batista EA, et al. Evaluation of antioxidant potential of commercial cinnamon samples and its vasculature effects. Oxid Med Cell Longev 2022;2022:1992039.

140. Tian J, Shan XL, Wang SN, et al. Trans-cinnamaldehyde suppresses microtubule detyrosination and alleviates cardiac hypertrophy. Eur J Pharmacol 2022;914:174687.

141. Ranasinghe P, Jayawardena R, Pigera S, et al. Evaluation of pharmacodynamic properties and safety of Cinnamomum zeylanicum (Ceylon cinnamon) in healthy adults: a phase I clinical trial. BMC Complement Altern Med 2017;17:550.

142. Mirmiran P, Davari M, Hashemi R, et al. A randomized controlled trial to determining the effect of cinnamon on the plasma levels of soluble forms of vascular adhesion molecules in type 2 diabetes mellitus. Eur J Clin Nutr 2019;73:1605–1612.

143. Shirzad F, Morovatdar N, Rezaee R, Tsarouhas K, Abdollahi Moghadam A. Cinnamon effects on blood pressure and metabolic profile: a double-blind, randomized, placebo-controlled trial in patients with stage 1 hypertension. Avicenna J Phytomed 2021;11:91–100.

144. Zhang L, Li Z, Wu Y, et al. Cinnamon and aspirin for mild ischemic stroke or transient ischemic attack: a pilot trial. Clin Ther 2022;44:482–490.

145. Shiels PG, Painer J, Natterson-Horowitz B, Johnson RJ, Miranda JJ, Stenvinkel P. Manipulating the exposome to enable better ageing. Biochem J 2021;478:2889–2898.

146. Ooijevaar RE, Terveer EM, Verspaget HW, Kuijper EJ, Keller JJ. Clinical application and potential of fecal microbiota transplantation. Annu Rev Med 2019;70:335–351.

147. Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012;7:e47713.

148. Yiu JH, Dorweiler B, Woo CW. Interaction between gut microbiota and toll-like receptor: from immunity to metabolism. J Mol Med (Berl) 2017;95:13–20.

149. Mafra D, Borges N, Alvarenga L, et al. Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients 2019;11:496.

150. Kumar Singh A, Cabral C, Kumar R, et al. Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients 2019;11:2216.

151. Lee SC, Hsu JS, Li CC, Chen KM, Liu CT. Protective effect of leaf essential oil from Cinnamomum osmophloeum Kanehira on endotoxin-induced intestinal injury in mice associated with suppressed local expression of molecules in the signaling pathways of TLR4 and NLRP3. PLoS One 2015;10:e0120700.

152. Van Hul M, Geurts L, Plovier H, et al. Reduced obesity, diabetes, and steatosis upon cinnamon and grape pomace are associated with changes in gut microbiota and markers of gut barrier. Am J Physiol Endocrinol Metab 2018;314:E334–E352.

153. Shin NR, Whon TW, Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 2015;33:496–503.

154. Li AL, Ni WW, Zhang QM, et al. Effect of cinnamon essential oil on gut microbiota in the mouse model of dextran sodium sulfate-induced colitis. Microbiol Immunol 2020;64:23–32.

155. De Filippis A, Ullah H, Baldi A, et al. Gastrointestinal disorders and metabolic syndrome: dysbiosis as a key link and common bioactive dietary components useful for their treatment. Int J Mol Sci 2020;21:4929.

156. Wang L, Hou Y, Yi D, et al. Beneficial roles of dietary Oleum cinnamomi in alleviating intestinal injury. Front Biosci (Landmark Ed) 2015;20:814–828.

157. Sun K, Lei Y, Wang R, Wu Z, Wu G. Cinnamicaldehyde regulates the expression of tight junction proteins and amino acid transporters in intestinal porcine epithelial cells. J Anim Sci Biotechnol 2017;8:66.

158. Qi L, Mao H, Lu X, Shi T, Wang J. Cinnamaldehyde promotes the intestinal barrier functions and reshapes gut microbiome in early weaned rats. Front Nutr 2021;8:748503.

159. Hong S, Cha KH, Park JH, et al. Cinnamic acid suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota. J Nutr Biochem 2022;101:108900.

160. Craven H, McGuinness D, Buchanan S, et al. Socioeconomic position links circulatory microbiota differences with biological age. Sci Rep 2021;11:12629.

161. Hariri M, Ghiasvand R. Cinnamon and chronic diseases. Adv Exp Med Biol 2016;929:1–24.

162. Chao LK, Chang WT, Shih YW, Huang JS. Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts. Toxicol Appl Pharmacol 2010;244:174–180.

163. Kooman JP, Kotanko P, Schols AM, Shiels PG, Stenvinkel P. Chronic kidney disease and premature ageing. Nat Rev Nephrol 2014;10:732–742.

164. Zheng H, Whitman SA, Wu W, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 2011;60:3055–3066.

165. Stenvinkel P, Shiels PG. Long-lived animals with negligible senescence: clues for ageing research. Biochem Soc Trans 2019;47:1157–1164.

166. Tung YT, Chua MT, Wang SY, Chang ST. Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresour Technol 2008;99:3908–3913.

167. Chericoni S, Prieto JM, Iacopini P, Cioni P, Morelli I. In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. J Agric Food Chem 2005;53:4762–4765.

168. Xiao Q. Cinnamaldehyde attenuates kidney senescence and injury through PI3K/Akt pathway-mediated autophagy via downregulating miR-155. Ren Fail 2022;44:601–614.

169. Fanton S, Cardozo LF, Combet E, et al. The sweet side of dark chocolate for chronic kidney disease patients. Clin Nutr 2021;40:15–26.

170. Hussain Z, Khan JA, Arshad A, Asif P, Rashid H, Arshad MI. Protective effects of Cinnamomum zeylanicum L. (Darchini) in acetaminophen-induced oxidative stress, hepatotoxicity and nephrotoxicity in mouse model. Biomed Pharmacother 2019;109:2285–2292.

171. Alshahrani S, Ashafaq M, Hussain S, et al. Renoprotective effects of cinnamon oil against APAP-Induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats. Saudi Pharm J 2021;29:194–200.

172. Atsamo AD, Lontsie Songmene A, Metchi Donfack MF, Ngouateu OB, Nguelefack TB, Dimo T. Aqueous extract from Cinnamomum zeylanicum (Lauraceae) stem bark ameliorates gentamicin-induced nephrotoxicity in rats by modulating oxidative stress and inflammatory markers. Evid Based Complement Alternat Med 2021;2021:5543889.

173. Elshopakey GE, Elazab ST. Cinnamon aqueous extract attenuates diclofenac sodium and oxytetracycline mediated hepato-renal toxicity and modulates oxidative stress, cell apoptosis, and inflammation in male albino rats. Vet Sci 2021;8:9.

174. Hajimonfarednejad M, Ostovar M, Raee MJ, Hashempur MH, Mayer JG, Heydari M. Cinnamon: a systematic review of adverse events. Clin Nutr 2019;38:594–602.

175. Yun JW, You JR, Kim YS, et al. In vitro and in vivo safety studies of cinnamon extract (Cinnamomum cassia) on general and genetic toxicology. Regul Toxicol Pharmacol 2018;95:115–123.

176. Gu DT, Tung TH, Jiesisibieke ZL, Chien CW, Liu WY. Safety of cinnamon: an umbrella review of meta-analyses and systematic reviews of randomized clinical trials. Front Pharmacol 2022;12:790901.

TOOLS

METRICS

5 Web of Science
5 Crossref
5 Scopus
5,415 View
173 Download

ORCID iDs

Laís de Souza Gouveia Moreira
https://orcid.org/0000-0003-0576-1418

Isabela de Souza da Costa Brum
https://orcid.org/0000-0002-1392-403X

Drielly C. M. de Vargas Reis
https://orcid.org/0000-0002-5250-7220

Liana Trugilho
https://orcid.org/0000-0002-3282-4755

Tuany R. Chermut
https://orcid.org/0000-0001-8907-4134

Marta Esgalhado
https://orcid.org/0000-0002-0370-5175

Ludmila F. M. F. Cardozo
https://orcid.org/0000-0001-8507-2369

Peter Stenvinkel
https://orcid.org/0000-0002-8785-4820

Paul G. Shiels
https://orcid.org/0000-0002-7577-9843

Denise Mafra
https://orcid.org/0000-0001-6752-6056

Related articles

Pharmacologic therapeutics in sarcopenia with chronic kidney disease2024 March;43(2)

Urinary podocyte markers in diabetic kidney disease2024 May;43(3)

Vitamin D and narrowband ultraviolet B phototherapy for chronic kidney disease-associated pruritus2024 March;43(2)

Novel biomarkers for diabetic kidney disease2022 September;41(Suppl 2)

Healthy aging and chronic kidney disease2022 November;41(6)

Editorial Office: #301, (Miseung Bldg.) 23, Apgujenog-ro 30-gil, Gangnam-gu, Seoul 06022, Korea
Tel: +82-2-3486-8736 Fax: +82-2-3486-8737 E-mail: registry@ksn.or.kr