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Title: Curcumin as a functional food-derived factor: degradation products,

metabolites, bioactivity, and future perspectives

(Review article)
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Food & Function Accepted Manuscript

Author: Takanori Tsuda

College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi

487-8501, Japan

Corresponding author: Takanori Tsuda, Ph.D.

Professor
College of Bioscience and Biotechnology, Chubu University,
1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
Tel. & Fax: +81-568-51-9659
E-mail: tsudat@isc.chubu.ac.jp

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Abstract

Curcumin is a polyphenol found in turmeric (Curcuma longa), used as a spice, food

coloring, and as a traditional herbal medicine. It has been shown that curcumin has health

benefits such as antioxidant, anti-inflammatory, and anticancer properties, improvement of

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brain function, and control of obesity and diabetes. However, native curcumin is easily

Food & Function Accepted Manuscript

degraded and has low oral bioavailability, and a recent report has expressing doubt towards

curcumin’s various effects. To overcome its low bioavailability, various curcumin

formulations with enhanced bioavailability are currently being developed. This review

discusses the chemistry, metabolism, and absorption of curcumin, to which various reported

health benefits have been ascribed, as well as curcumin’s degradation products and

metabolites and their possible functions. Moreover, the research trend towards the obesity-

and diabetes-preventing/suppressing aspects of curcumin and the latest case studies on highly

water-dispersible and bioavailable curcumin formulation will be discussed. We summarize the

challenges concerning research into curcumin’s health benefits as follows: clarifying the

relationship between curcumin’s health benefits and the formation of curcumin-derived

oxidation and degradation products and metabolites, determining whether curcumin itself or

other components in turmeric are responsible for its effects, and conducting further human

trials in which multiple research groups employ the same samples and conditions.

High-bioavailability formulations would be useful in such future studies.

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1. Introduction

Curcumin is a polyphenol found in turmeric (Curcuma longa) and used as a spice,

food coloring, and traditional herbal medicine. Besides its antioxidant and anti-inflammatory

activities, curcumin is reported to have health benefits such as improved brain function and

properties1.
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anticancer/anti-atherosclerotic Curcumin formulations with enhanced

Food & Function Accepted Manuscript

bioavailability are currently being developed, and the relationship between curcumin

degradation products and metabolites and their potential health benefits are being investigated.

However, a recent report expressing doubt about the health benefits of curcumin has emerged2.

The authors stated that curcumin is one of the worst pan-assay interference compounds, and

concluded that there is no evidence of any specific therapeutic benefits, despite many research

papers to the contrary. However, Bahadori and Demiray recently re-reviewed the paper and

rebutted the assertion that the health benefits of curcumin are doubt in the letter to the editor3.

This review discusses the chemistry, metabolism, and absorption of curcumin, to

which various reported health benefits have been ascribed, as well as the degradation products

and metabolites and their possible functions. Moreover, the research trend towards the

obesity- and diabetes-preventing/suppressing aspects of curcumin and the latest case studies

on highly water-dispersible and bioavailable curcumin formulations will be discussed. Finally,

the review will be concluded with the challenges and future perspectives for research into the

health benefits of curcumin from the point of view of functional food science.

2. Curcumin’s chemistry, metabolism, absorption, and mechanism of biological activity

2.1 Chemistry and cleavage

Turmeric’s curcuminoid content is 2–9%4. Commercial turmeric extracts contain

approximately 70–75% curcumin, with about 20% demethoxycurcumin and 5%

bisdemethoxycurcumin as structural curcumin analogs5 (Fig 1). Curcumin displays keto-enol

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tautomerism with the keto and enol forms existing in given proportions; when dissolved, the

enol form predominates (Fig 2). Curcumin is a relatively unstable compound that degrades

quickly in neutral to alkaline solutions. The degradation products of curcumin include ferulic

acid, feruloyl methane, and vanillin6, 7. According to a recent study, these are the minor

degradation products of curcumin, while the majority comprises autoxidation products7 and
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Food & Function Accepted Manuscript

chiefly bicyclopentadione8, 9 (Fig. 3).

2.2 Bioavailability

The bioavailability of curcumin has been studied extensively in rodents and

humans10, 11. For instance, the Cmax of 0.5 g curcumin administered orally was found to be 60

ng/mL in rats12. A different research group found that the Cmax of 1 g curcumin administered

orally was 500 ng/mL in rats13. Tritium-labeled curcumin administration in rats revealed that

most of the 3H radioactivity was found in feces and the levels in urine were very low14, 15. In

addition, the bioavailability of both demethoxycurcumin and bisdemethoxycurcumin is

significantly lower than that of curcumin in mice16. In humans, the Cmax of 2 g curcumin

administered orally is 6 ng/mL, while that of 10–12 g is approximately 50 ng/mL17. In another

study, 12 colorectal cancer patients with liver metastasis were given 450–3,600 mg curcumin

for a week before surgery. The results show that hardly any curcumin was detected in the liver

and that their levels of oxidative DNA changes were no different from before curcumin

dosing began18. One result that is consistent among those reports is the low bioavailability of

curcumin. However, it should be noted that the bioavailability of curcumin may be influenced

by the food matrix (e.g., lipids and proteins).

2.3 Metabolism
19–21
Various review articles on curcumin metabolism have been published . An in

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vitro study found that the most frequently detected metabolite after the incubation of

curcumin with the microsome fraction of rat and human intestinal and liver tissue

homogenates is curcumin glucuronide. Curcumin incubation with the cytosol fraction

produced curcumin sulfate and hexahydrocurcumin, along with a minute amount of

tetrahydrocurcumin22. Another study reports that in addition to curcumin glucuronide,

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tetrahydrocurcumin glucuronide and hexahydrocurcumin glucuronide appear as metabolites

after intravenous and intraperitoneal administration of curcumin in mice23. In rats, most

metabolites of curcumin administered orally are found as conjugates (curcumin glucuronide,

curcumin sulfate) in blood, while little of the free form is detected24, 25. Similarly, glucuronide

conjugates and sulfate conjugates are detected in humans after the oral administration of

curcumin, but intact curcumin is barely detected26 (Fig 4).

2.4 Do curcumin’s degradation products and metabolites have health benefits?

Comparison with anthocyanin studies–

Curcumin’s low bioavailability is related to its low solubility in water. The solubility

of curcumin in water is said to be about 400 ng/mL at pH 7.427. The small amount of

curcumin that is absorbed by the body exists mostly as conjugates in the blood, and very little

exists in free form. In addition, curcumin itself has low chemical stability, giving rise to

various degradation products. Hence, it was hypothesized that the degradation and oxidation

products and metabolites of curcumin are involved in the biological activities of curcumin.

Like curcumin, anthocyanins are also plant pigments, chemically unstable, and have

low bioavailability. Anthocyanin studies may thus provide useful insights into the biological

activities of curcumin. Anthocyanins are a group of flavonoids that act as red and purple

pigments, and are known for their various biological activities28, 29. In 1999, we reported the

detection of protocatechuic acid in rats for the first time; this compound is a degradation

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product/metabolite of anthocyanins derived from the B-ring of cyanidin 3-glucoside30. Recent

findings point to the importance of phenolic acids (protocatechuic acid, syringic acid, vanillic

acid, phloroglucinol aldehyde, phloroglucinol acid, gallic acid, etc.), which are degradation

products and metabolites of anthocyanins, in the biological activities of berries29, 31–38. These

phenolic acids have also been detected as metabolites in humans39. The bioavailability of
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anthocyanins is quite low (about 0.1%) when considering the parent compound alone.

Furthermore, it is unclear how anthocyanins can display such varied biological activities

considering their structural instability. A recent study using isotopes has shown that

anthocyanin bioavailability could amount to 10% or more, considering the various

degradation products and metabolites that are detected in the blood after consumption40.

Moreover, since is clear that the degradation products and metabolites of anthocyanins remain

in the circulation for a long time41, it is plausible that they could be involved in the biological

activities of anthocyanins42.

Could the various biological activities of curcumin also be explained by the

degradation products and metabolites? According to Shen et al., the degradation products are

important in explaining the biological activities of curcumin because they, including ferulic

acid and vanillin, display antioxidant and anti-inflammatory activities43,44. However, studies

comparing the degradation products such as ferulic acid and vanillin with the parent

compound curcumin using various cancer models have shown that the activities of the

degradation products are lower than curcumin7, 45–47. There are few reports on the biological

activities of curcumin oxidation products. Schneider et al. stated that although there is no

solid evidence of curcumin oxidation products in vivo, they are an important factor in

explaining the polypharmacology of curcumin9. If curcumin oxidation products display

biological activities, such activities should diminish when curcumin oxidation is inhibited.

However, when curcumin oxidation was inhibited in the presence of an antioxidant, the

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antiproliferative effect observed was more pronounced than it had been without inhibition48.

Furthermore, Sanidad et al. reported that the inhibitory effect of a curcumin oxidative product,

bicyclopentadione, produced a weaker inflammatory response in RAW 264.7 macrophage

cells than curcumin49. However, one must bear in mind that these are the results of in vitro
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studies. Thus, it is not clear whether curcumin’s biological activities can be explained by its

Food & Function Accepted Manuscript

degradation and oxidation products. Future studies may be able to confirm this mechanism.

Is it possible that curcumin’s main metabolite, curcumin glucuronide, is involved in

the biological activities of curcumin? Although there are few reports on the biological

activities of curcumin glucuronide, it seems that this metabolite does not explain the

antiproliferative and anti-inflammatory activities of curcumin50, 51. In their in vitro study,

Choudhury et al. showed that the antioxidant capacities of curcumin monoglucuronide and

curcumin diglucuronide are much lower than that of curcumin52. However, Luis et al.

concluded from their study on the oxidative transformation mechanism of curcumin by human

leukocytes that curcumin glucuronide is not entirely without beneficial effects53. Whether

curcumin glucuronide and other metabolites of curcumin can explain the biological activities

has yet to be validated. Recently, our group, in collaboration with Ozawa et al. demonstrated

that an increase in blood curcumin glucuronide concentration brings about an increase in free

form curcumin concentration, resulting in the suppression of human colon carcinomas

implanted in mice (Fig. 5)54. This interesting result suggests that enhanced bioavailability

formulations of curcumin could facilitate the promotion of curcumin’s biological activities, as

we examine next.

3. Anti-obesity and antidiabetic aspects of curcumin’s health benefits and highly

water-dispersible and bioavailable curcumin formulation

There are many research publications on the health benefits of curcumin from the

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cellular to animal level, including human trials. Since there are many reviews on curcumin’s

biological activities, especially those providing overviews on its anti-proliferative and

anti-inflammatory, anti-cancer, anti-cardiovascular disease, and anti-neurodegenerative

disease effects55, 56, this review will focus on the antidiabetic and anti-obesity activities. A
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selection of reports relating to these topics will be presented, as well as our own recent case

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studies on highly water-dispersible and bioavailable curcumin formulations.

3.1 Anti-obesity and anti-diabetes effects

El-Moselhy et al. reported that dietary curcumin (80 mg/kg) administered to mice on

a high-fat diet significantly lowered the fasting blood glucose levels and TNF-α

concentrations, and inhibited the lowering of glucose tolerance57. Similarly, curcumin intake

(4 g/kg diet) significantly suppressed weight gain, decreased the amount of white adipose

tissue, and improved insulin sensitivity in a diet-induced obesity model58. Dietary curcumin

(0.2 g/kg, 6 weeks) administered to obesity and diabetes model mice (db mice) significantly

decreased HOMA-IR and HbA1c levels and reduced the activity of hepatic gluconeogenic

enzyme59. Adiponectin is an adipocytokine that increases insulin sensitivity and its blood

concentrations are raised by curcumin. According to Weisberg et al., mice fed with a high-fat

diet containing 3% curcumin displayed increased insulin sensitivity and blood adiponectin

concentrations as well as suppressed weight gain. Similar results have been obtained with ob

mice of an obesity/diabetes model60.

Here are some of the few human trial reports on curcumin’s anti-obesity and

anti-diabetes effects. Wickenberg et al. found no effects of oral turmeric intake (capsules) on

glucose tolerance in their trial, in which 14 healthy subjects were given 6 g turmeric powder

together with glucose61. They did, however, find a rise in blood insulin. In a trial in 65

patients diagnosed with metabolic syndrome, Yang et al. found that a 12-week-long intake

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of 1.89 g turmeric extract curcumin extract (630 mg capsule taken 3×/day) had no influence

on HbA1c or body weight, but blood triglyceride and low-density lipoprotein cholesterol

levels were significantly decreased62. An example of a randomized double-blind

placebo-controlled trial case is that conducted by Chuengsamarn et al in 240 pre-diabetes

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individuals. Here, a group of patients were given a curcumin capsule 1.5 g/day containing

Food & Function Accepted Manuscript

turmeric extract (75–85% curcuminoids) for 9 months. Compared to the placebo group,

glucose tolerance significantly improved and blood adiponectin concentrations increased63.

This same research group ran another trial with 213 type 2 diabetes patients at risk of

atherogenesis, in which one group of patients took the same type of capsules as those in the

previous trial for 6 months. Compared to the placebo group, they had lower HOMA-IR, lower

visceral fat mass, and higher blood adiponectin64. In another group’s randomized double-blind

placebo controlled trial involving a total of 100 type 2 diabetic patients with obesity, an oral

intake of 300 mg/day curcumin formulation (curcumin 36.06%, demethoxycurcumin 18.85%,

bisdemethoxycurcumin 42.58%) for 3 months resulted in lower HbA1c and HOMA-IR levels

compared to the placebo65. Several excellent reviews can help provide a better understanding

of the anti-diabetes and anti-obesity effects56, 66, 67.

The possibility that curcumin degradation and oxidation products and metabolites,

including their conjugates, have biological activities was discussed in section 2.4, but could

these compounds be involved in the anti-obesity and anti-diabetes effects? Diets

supplemented with ferulic acid significantly inhibited body fat accumulation68, 69

and

improved hyperglycemia70 in mice and rats. In each case, high doses of ferulic acid rather

than curcumin were administered. A study in humans assessing various polyphenol

metabolites suggests that ferulic acid excreted in urine is not significantly associated with

type 2 diabetes risk71. There are no reports on vanillin or bicyclopentadione (curcumin

oxidation product), nor on curcumin’s main metabolite, curcumin glucuronide. For now, there

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is no evidence that the administration of curcumin’s degradation products and metabolites

have any effects.

In short, although there are data showing some degree of curcumin’s inhibitory

effects on diabetes and obesity, there are also reports of no effects; in either case, the
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curcumin doses administered were high. This is because curcumin is not water soluble and

Food & Function Accepted Manuscript

has very low bioavailability. To remedy this problem, various curcumin formulations are
11, 72, 73
being designed and developed . Some use nanoparticles74–76, others use micronization

and surface finishing techniques to improve the stability of dispersion in aqueous

solutions77, 78. Other examples include micellization by conjugating with phospholipids13, 79

and wrapping with liposomes80, 81. Such formulations may be effective in bringing about

curcumin’s various biological activities against diabetes, obesity, and other conditions,

although care should be taken to avoid increasing the bioavailability to toxic levels. To

illustrate these possibilities, we next present our own work on curcumin’s glucose

tolerance-improving effect via the stimulation of glucagon-like peptide-1 (GLP-1) secretion.

3.2 Improved glucose tolerance by highly water-dispersible and bioavailable curcumin

formulation, via the stimulation of GLP-1 secretion

Incretin is the collective term for peptide hormones that are released from the gut

following food intake and act on pancreatic β-cells to stimulate insulin secretion. Incretin

comprises glucose-dependent insulinotropic polypeptide and GLP-1, which is an effective

target in the prevention and treatment of type 2 diabetes. It has been found that GLP-1

sensitivity in the pancreatic β-cells of type 2 diabetics is not diminished82. Indeed, inhibitors

of GLP-1 degradation and degradation-resistant GLP-1 receptor agonists are being used as

treatments. From a food and nutritional science point of view, the ideal strategy to augment

blood GLP-1 concentration is to stimulate the secretion of endogenous GLP-1 using dietary

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factors83.

Our group investigated dietary factors with GLP-1 secretion-stimulating effects in

cells, and found several candidates, including curcumin84–89. Curcumin displays a strong

GLP-1 secretion-stimulating effect84. A structure-activity relationship study using curcumin

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analogs revealed that a β-diketone structure and an aromatic ring with at least one methoxy

Food & Function Accepted Manuscript

group is required to stimulate the secretion of GLP-1. Curcumin, with its β-diketone structure

and two methoxy groups, was the most potent candidate. Bisdemethoxycurcumin, which lacks

the methoxy group, and tetrahydrocurcumin, which lacks the β-diketone structure, were both

unable to stimulate GLP-1 secretion84. For the stimulation of GLP-1 secretion by

enteroendocrine cells, factors such as water dispersibility and solubility in the intestine

become more important than the absorption, metabolism, and blood concentrations of

curcumin itself. A highly water-dispersible, highly bioavailable curcumin formulation has

been previously developed using a surface-controlled submicron particle formation

technology77. We found that this formulation significantly improves glucose tolerance by

blood glucose-dependently stimulating insulin secretion via the stimulation of GLP-1

secretion88. However, since no significant effect is observed using native curcumin, we

believe that the high water dispersibility of our formulation enabled the stimulation of

enteroendocrine cells. Furthermore, our study showed that the molecular target of curcumin is

the G protein coupled receptors 40/12088. This study is an example of a curcumin formulation

enabling an effect that native curcumin could not otherwise achieve (Fig. 6).

4. Challenges and future perspectives

A recent report by medical chemists has cast doubt on the effects of curcumin 2. What

should be the stance of functional food scientists towards the research into the health benefits

of curcumin, and how should we proceed? Many functional food scientists are interested in

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and working on the health benefits of curcumin or turmeric, the molecular mechanisms,

curcumin’s metabolic pathways, and the relationship between the biological activities and

degradation products and metabolites, as well as how much curcumin to consume and in what

form. Functional food scientists did not find curcumin as a result of drug screening, assessing
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the fluorescence strength of bonds between curcumin and proteins associated with a disease

Food & Function Accepted Manuscript

(note that curcumin is fluorescent, so care should be taken when searching for molecular

targets of curcumin). We know about the high degradability and low bioavailability of

curcumin from our experience of studies into the health benefits of polyphenols such as

anthocyanins, as mentioned in 2.428, 29. A highly water-dispersible and highly bioavailable

curcumin formulation would be a useful tool, as discussed in 3.2. However, bioavailability

should remain limited to avoid toxicity, and care should be taken over the dosage. In addition,

the evaluation methods for the biological activities need to be thoroughly validated.

From the above-mentioned issues, the challenges concerning research into the health

benefits of curcumin can be summed up by the following three points: First, it is necessary to

establish the relationship between the health benefits of curcumin and the formation of

curcumin-derived oxidation and degradation products and metabolites. Are curcumin-derived

degradation and oxidation products detected in the body after curcumin intake? Could the

health benefits of curcumin be explained by the degradation and oxidation products or

metabolites alone? If these hypotheses hold true, then how much of the degradation products

or metabolites are required to achieve health benefits? Moreover, would the difference in

intestinal microflora play a role in the manifestation of health benefits, and conversely, would

curcumin intake have any impact on the gut microflora? Such questions require clarification.

Second, one should be aware of substances besides curcumin that are contained in the

turmeric extracts used in human trials. It is necessary to determine whether curcumin itself is

responsible for the effects, or if other components in turmeric such as curcumin analogs and

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compounds with completely unrelated structures are responsible. The possibility that

curcumin manifests its effects in concert with another substance should also be investigated.

The influence of consuming traditional herbal medicine containing curcumin on the

bioavailability and bioactivity may provide further insight.

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Third, curcumin’s effects on humans have not been thoroughly validated, and there are some

Food & Function Accepted Manuscript

conflicting results. Further trials need to be randomized, double-blind, and placebo-controlled.

More importantly, cross-sectional studies in which each research group employs the same

samples and conditions must be performed. High bioavailability formulations would be useful

in such studies, provided that the same formulation is used under uniform conditions.

Many studies on the health benefits of curcumin have been performed thus far.

Although there are contradictory results that have raised some doubts, these studies provide

data and suggestions to further the research. Let us hope that the challenges above will be

overcome and advances in functional food research into curcumin could contribute greatly to

the maintenance of health.

Conflict of interest

The author declares no conflict of interest.

Acknowledgements

This study was supported in part by Grants-in-Aid for Scientific Research

(No.17K07804) from the Japan Society for Promotion of Science.

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25 C. Ireson, et al., Characterization of metabolites of the chemopreventive agent curcumin

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in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to

inhibit phorbol ester-induced prostaglandin E2 production, Cancer

Res., 2001, 61, 1058-1064.

26 K. Vareed, et al., Pharmacokinetics of curcumin conjugate metabolites in healthy human

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subjects, Cancer Epidemiol. Biomarkers Prev., 2008, 17, 1411-1417.

Food & Function Accepted Manuscript

27 H. H. Tønnesen, et al., Studies of curcumin and curcuminoids. XXVII. Cyclodextrin

complexation: solubility, chemical and photochemical stability, Int. J.

Pharm., 2002, 244, 127–135.

28 T. Tsuda, Dietary anthocyanin-rich plants: biochemical basis and recent progress in health

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29 T. Tsuda, Recent Progress in Anti-Obesity and Anti-Diabetes Effect of Berries,

Antioxidants, 2016, 5, 13.

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Lett., 1999, 449, 179-182.

31 K. Keppler and H.-U. Humpf, Metabolism of anthocyanis and their phenolic degradation

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32 A.M. Aura, et al., In vitro metabolism of anthocyanins by human gut microflora, Eur. J.

Nutr., 2005, 44, 133–142.

33 J. He, et al., Analysis of anthocyanins in rat intestinal contents—Impact of anthocyanin

chemical structure on fecal excretion. J. Agric. Food Chem., 2005, 53, 2859–2866.

34 S. C. Forester, and A .L. Waterhouse, Identification of Cabernet Sauvignon anthocyanin

gut microflora metabolites, J. Agric. Food Chem., 2008, 56, 9299–9304.

35 S. C. Forester and A. L. Waterhouse, Gut metabolites of anthocyanins, gallic

acid, 3-O-methylgallic acid, and 2,4,6-trihydroxybenzaldehyde, inhibit cell proliferation

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36 M. Avila, et al., Bioconversion of anthocyanin glycosides by Bifidobacteria and

Lactobacillus, Food Res. Int., 2009, 42, 1453–1461.

37 M. P. Gonthier, et al., Microbial aromatic acid metabolites formed in the gut account for a

major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols, J.
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Food & Function Accepted Manuscript

38 G. Borges, et al., The bioavailability of raspberry anthocyanins and ellagitannins in rats,

Mol. Nutr. Food Res., 2007, 51, 714–725.

39 P. Vitaglione, et al., Protocatechuic acid is the major human metabolite of

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40 C. Czank, et al., Human metabolism and elimination of the anthocyanin,

cyanidin-3-glucoside: A 13C-tracer study, Am. J. Clin. Nutr., 2013, 97, 995–1003.

41 W. Kalt, et al., Anthocyanin metabolites are abundant and persistent in human urine, J.

Agric. Food Chem., 2014, 62, 3926–3934.

42 M. A. Lila, et al., Unraveling Anthocyanin Bioavailability for Human Health, Annu. Rev.

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43 L. Shen and H. F. Ji, Contribution of degradation products to the anticancer activity of

curcumin, Clin. Cancer Res., 2009, 15, 7108-7019.

44 L. Shen and H. F. Ji, The pharmacology of curcumin: is it the degradation products?

Trends Mol. Med., 2012, 18, 138-144.

45 M. Deters, et al., Different curcuminoids inhibit T-lymphocyte proliferation

independently of their radical scavenging activities, Pharm. Res., 2008, 25, 1822–1827.

46 L. E. Wright, et al., Bioactivity of turmeric-derived curcuminoids and related metabolites

in breast cancer, Curr. Pharm. Des., 2013, 19, 6218–6225.

47 M. T. Huang, et al., Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and

ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate,

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Cancer Res., 1988, 48, 5941–5946.

48 Y. Nimiya, et al., Redox modulation of curcumin stability: Redox active antioxidants

increase chemical stability of curcumin, Mol. Nutr. Food Res., 2016, 60, 487–494.

49 K. Z. Sanidad, et al., Effects of Stable Degradation Products of Curcumin on Cancer Cell

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Proliferation and Inflammation, J. Agric. Food Chem., 2016, 64, 9189–9195.

Food & Function Accepted Manuscript

50 A. Pal, et al., Curcumin glucuronides: assessing the proliferative activity against human

cell lines, Bioorg. Med. Chem., 2014, 22, 435–439.

51 M. Shoji, et al., Comparison of the effects of curcumin and curcumin glucuronide in

human hepatocellular carcinoma HepG2 cells, Food Chem., 2014, 151, 126–132.

52 A. K. Choudhury, et al., Synthesis and Evaluation of the Anti-Oxidant Capacity of

Curcumin Glucuronides, the Major Curcumin Metabolites,

Antioxidants, 2015, 4, 750-767.

53 P. B. Luis, et al., Oxidative metabolism of curcumin-glucuronide by peroxidases and

isolated human leukocytes, Biochem. Pharmacol., 2017, 132, 143–149.

54 H. Ozawa, et al., Curcumin β-D-glucuronide plays an important role to keep high levels

of free-form curcumin in the blood, Biol. Pharm. Bull. , 2017, 40: 1515–1524.

55 G. Kumar et al., Molecular mechanisms underlying chemopreventive potential of

curcumin: Current challenges and future perspectives, Life Sci., 2016, 148: 313–328.

56 A. B. Kunnumakkara et al., Curcumin, the golden nutraceutical: multitargeting for

multiple chronic diseases, Br. J. Pharmacol., 2017, 174: 1325–1348.

57 M. A. El-Moselhy, et al., The antihyperglycemic effect of curcumin in high fat diet fed

rats. Role of TNF-α and free fatty acids, Food .Chem. Toxicol., 2011, 49, 1129-1140.

58 W. Shao, et al., Curcumin prevents high fat diet induced insulin resistance and obesity via

attenuating lipogenesis in liver and inflammatory pathway in adipocytes, PLoS

One, 2012, 7, e28784.

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59 K. I. Seo, et al., Effect of curcumin supplementation on blood glucose, plasma insulin,

and glucose homeostasis related enzyme activities in diabetic db/db mice, Mol. Nutr.

Food Res., 2008, 52, 995–1004.

60 S. P. Weisberg, et al., Dietary curcumin significantly improves obesity-associated

Published on 23 November 2017. Downloaded by Fudan University on 24/11/2017 01:26:45.

inflammation and diabetes in mouse models of diabesity,

Food & Function Accepted Manuscript

Endocrinology, 2008, 149, 3549-3558.

61 J. Wickenberg, et al., Effects of Curcuma longa (turmeric) on postprandial plasma

glucose and insulin in healthy subjects, Nutrition J., 2010, 9, 43.

62 Y. S. Yang, et al., Lipid-lowering effects of curcumin in patients with metabolic

syndrome: a randomized, double-blind, placebo-controlled trial, Phytother.

Res., 2014, 28, 1770–1777.

63 S. Chuengsamarn, et al., Curcumin extract for prevention of type 2 diabetes, Diabetes

Care, 2012, 35, 2121-2127.

64 S. Chuengsamarn, et al., Reduction of atherogenic risk in patients with type 2 diabetes by

curcuminoid extract: a randomized controlled trial, J. Nutr. Biochem., 2014, 25, 144-150.

65 L. X. Na, et al., Curcuminoids exert glucose-lowering effect in type 2 diabetes by

decreasing serum free fatty acids: a double-blind, placebo-controlled trial, Mol. Nutr.

Food Res., 2013, 57, 1569-1577.

66 A. S. Jiménez-Osorio et al., Curcumin and insulin resistance–Molecular targets and

clinical evidences, BioFactors, 2016, 42: 561–580.

67 J. Hajavi et al., Curcumin: A naturally occurring modulator of adipokines in diabetes, J.

Cell Biochem., 2017, 118: 4170-4182.

68 A. Narasimhan, et al., Ferulic acid exerts its antidiabetic effect by modulating

insulin-signalling molecules in the liver of high-fat diet and fructose-induced type-2

diabetic adult male rat, Appl. Physiol. Nutr. Metab., 2015, 40, 769-781.

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69 T. S. de Melo, et al., Ferulic acid lowers body weight and visceral fat accumulation via

modulation of enzymatic, hormonal and inflammatory changes in a mouse model of

high-fat diet-induced obesity, Brazilian J. Med. Biol. Res., 2017, 50, e5630.

70 N. J. Salazar-López, et al., Ferulic Acid on Glucose Dysregulation, Dyslipidemia, and

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Inflammation in Diet-Induced Obese Rats: An Integrated Study, Nutrients, 2017, 9, 675.

Food & Function Accepted Manuscript

71 Q. Sun, et al., Urinary Excretion of Select Dietary Polyphenol Metabolites Is Associated

with a Lower Risk of Type 2 Diabetes in Proximate but Not Remote Follow-Up in a

Prospective Investigation in 2 Cohorts of US Women, J. Nutr., 2015, 145, 1280–1288.

72 H. R. Rahimi, et al., Novel delivery system for natural products: Nano-curcumin

formulations, Avicenna J. Phytomed., 2016, 6, 383-398.

73 F. Ullah, et al., High bioavailability curcumin: an anti-inflammatory and neurosupportive

bioactive nutrient for neurodegenerative diseases characterized by chronic

neuroinflammation, Arch. Toxicol., 2017, 91, 1623–1634.

74 J. Shaikh, et al., Nanoparticle encapsulation improves oral bioavailability of curcumin by

at least 9-fold when compared to curcumin administered with piperine as absorption

enhancer, Eur. J. Pharm. Sci., 2009, 37, 223–230.

75 M. M. Yallapu, et al., Fabrication of curcumin encapsulated PLGA nanoparticles for

improved therapeutic effects in metastatic cancer cells, J. Colloid Interface

Sci., 2010, 351, 19–29.

76 R. K. Gangwar, et al., Curcumin conjugated silica nanoparticles for improving

bioavailability and its anticancer applications, J. Agric. Food

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77 H. Sasaki, et al., Innovative preparation of curcumin for improved oral bioavailability,

Biol. Pharm. Bull., 2011, 34, 660–665.

78 T. Morimoto, et al., Drinkable preparation of Theracurmin exhibits high absorption

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efficiency--a single-dose, double-blind, 4-way crossover study, Biol. Pharm.

Bull., 2013, 36, 1708–1714.

79 A. Liu, et al., Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat

plasma and application to pharmacokinetic study of phospholipid complex of curcumin, J.

Published on 23 November 2017. Downloaded by Fudan University on 24/11/2017 01:26:45.

Pharm. Biomed. Anal., 2006, 40, 720–727.

Food & Function Accepted Manuscript

80 L. Li, et al., Liposome-encapsulated curcumin: in vitro and in vivo effects on

proliferation, apoptosis, signaling, and angiogenesis, Cancer, 2005, 104, 1322–1331.

81 A. H. Matloob, et al., Increasing the stability of curcumin in serum with liposomes or

hybrid drug-in-cyclodextrin-in-liposome systems: a comparative study, Int. J.

Pharm., 2014, 476, 108–115.

82 J. A. Lovshin and D. J. Drucker, Incretin-based therapies for type 2 diabetes mellitus, Nat.

Rev. Endocrinol., 2009, 5, 262–269.

83 T. Tsuda, Possible abilities of dietary factors to prevent and treat diabetes via the

stimulation of glucagon-like peptide-1 secretion, Mol. Nutr. Food

Res., 2015, 59, 1264-1273.

84 M. Takikawa, et al., Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag

cells via Ca2+/calmodulin-dependent kinase II activation, Biochem. Biophys. Res.

Commun., 2013, 435, 165-170.

85 R. Nagamine, et al., Dietary sweet potato (Ipomoea batatas L.) leaf extract attenuates

hyperglycaemia by enhancing the secretion of glucagon-like peptide-1 (GLP-1), Food

Funct., 2014, 5, 2309-2316.

86 M. Kato, et al., The Anthocyanin Delphinidin 3-Rutinoside Stimulates Glucagon-Like

Peptide-1 Secretion in Murine GLUTag Cell Line via the Ca2+/Calmodulin-Dependent

Kinase II Pathway, PLoS One, 2015, 10, e0126157.

87 M. Kato, et al., Low-molecular fraction of wheat protein hydrolysate stimulates

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glucagon-like peptide-1 secretion in an enteroendocrine L cell line and improves glucose

tolerance in rats, Nutr Res., 2017, 37, 37-45.

88 M. Kato, et al., Curcumin improves glucose tolerance via stimulation of glucagon-like

peptide-1 secretion, Mol. Nutr. Food Res., 2017, 61, 1600471.

Published on 23 November 2017. Downloaded by Fudan University on 24/11/2017 01:26:45.

89 T. Tani, et al., Delphinidin 3-rutinoside-rich blackcurrant extract ameliorates glucose

Food & Function Accepted Manuscript

tolerance by increasing the release of glucagon-like peptide-1 secretion, Food Sci.

Nutr., 2017, 5, 929-933.

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Figure legend

Fig. 1 Chemical structures of curcuminoids.

Fig. 2 Keto-enol tautomerization of curcumin.

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Food & Function Accepted Manuscript

Fig. 3 Degradation pathways of curcumin (cleavage and oxidation).

Fig. 4 Metabolism of curcumin (conjugation and reduction).

Fig. 5 Schematic representation of the in vivo dynamics of curcumin metabolism following

oral administration of curcumin and intravenous administration of curcumin monoglucuronide

in rats (Reproduced with permission from reference No.54., Copyright 2017, The

Pharmaceutical Society of Japan.). CMG, curcumin monoglucuronide.

Fig. 6 Proposed mechanism of the secretion of GLP-1 induced by curcumin. Curcumin

significantly ameliorates glucose tolerance via the stimulation of GLP-1 secretion followed by

the induction of insulin secretion. These effects may be mediated by G protein-coupled

receptor 40/120. This figure was reprinted from reference No. 88. CaMKII;

Ca2+/calmodulin-dependent kinase II, ER; endoplasmic reticulum, GPR; G protein coupled

receptor, IP3R; D-myo-inositol 1,4,5-trisphosphate receptor, PLC; phospholipase C.

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Fig. 1
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Fig. 2
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Fig. 3
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Fig. 4
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Fig. 5
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Fig. 6
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