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The sources and mechanisms of bioactive

ingredients in coffee†
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Cite this: Food Funct., 2019, 10, 3113

G. L. Hu,a,b X. Wang,a,b L. Zhanga and M. H. Qiu *a,b

Received 13th February 2019,
Accepted 15th May 2019
DOI: 10.1039/c9fo00288j
rsc.li/food-function
Coffee bioactive components include caffeine, chlorogenic acids (CGAs), trigonelline, tryptophan alka-
loids, diterpenes and other secondary metabolites. During roasting, coffee metabolites undergo complex
Maillard reactions, producing melanoidins and other degradation products, the most controversial among
which is acrylamide, an ingredient widely found in baked food and listed as a second class carcinogen.
Green and roasted coffee ingredients have good biological activities for the prevention of cardiovascular
disease, and antibacterial, anti-diabetic, neuroprotection, and anti-cancer activities. To better understand
the relationship between coffee ingredients and human health, and to effectively use the active ingredi-
ents, it is essential to understand the sources of coffee active ingredients and their mechanisms of action
in the organism. This paper systematizes the available information and provides a critical overview of the
sources of coffee active ingredients and the mechanisms of action in vivo or in vitro, and their combined
effects on common human diseases.

1. Introduction discovered from coffee in recent years, such as diterpenes,

Coffee is the most popular beverage around the world. Coffee
drinking is closely related to human health. Long-term
research studies show that the bioactivity of coffee is closely
related to CGAs, caffeine, trigonelline, and coffee melanoidins.
In addition, diterpenoids in coffee, especially cafestol and
kahweol (C&K) and their derivatives, significantly affect the bio-
logical activity of coffee. In recent years, with the deepening of
coffee research, more and more coffee diterpenoids, which have
anti-cancer, anti-oxidation or other functions, have been discov-
ered. Our team discovered a variety of diterpenoids from coffee
Arabica which was planted in Yunnan Province, China, and
found that most of them have significant biological activity.
Additionally, we firstly discovered the presence of triterpenoids
in green beans and concluded that they were derived from seed
coats; unfortunately, we did not find their biological activity.1
All along, although in different articles there are biosyn-
thetic pathways involved in caffeine, CGA, there is no article
detailing the sources of various bioactive compounds present
in coffee. In particular, the sources of trace components newly
a
State Key Laboratory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201,
Yunnan, China. E-mail: mhchiu@mail.kib.ac.cn; Fax: +86-0871-65223325;
Tel: +86-0871-65223327
b
University of Chinese Academy of Sciences, Beijing 100049,
People’s Republic of China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9fo00288j
have been rarely summarized.
At present, research methods for the physiological func-
tions of coffee are mainly divided into observational studies of
large samples, crude studies based on coffee extracts, and
detailed studies focusing on individual ingredients. In the past,
when summarizing coffee ingredients and diseases, research
studies tended to focus more on observational studies and meta
analyses. With the deep understanding of the mechanisms of
all ingredients, it is necessary to respectively summarize the bio-
active mechanisms of coffee ingredients. In addition, it is worth
noting that the prevention of various diseases by coffee is
usually the joint actions of multiple components, and some-
times the synergistic effect of various types of compounds is
better than the activity alone,2 Therefore, it is necessary to sum-
marize the mechanisms of coffee active ingredients from the
perspective of diseases.
In this paper, we systematically summarized the biosyn-
thetic pathways of coffee active ingredients and, for the first
time, classified the sources of coffee diterpenes and speculated
their biosynthetic pathways. At the same time, we separately
detailed the mechanisms of the main active ingredients in
coffee based on existing research data, and summarized their
joint roles in the prevention of common human diseases.
2. Bioactive ingredients in coffee
Green coffee beans are mainly composed of carbohydrates
(59–61%), lipids (11–17%), proteins (10–16%), phenols

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(6–10%), minerals (4%), fatty acids (2%), caffeine (1–2%), trigo-
nelline (1%) and free amino acids (<1%). During the roasting
process, carbohydrates (38–42%), proteins (8–14%), phenols
(3–4%) and free amino acids are reduced, while the change of
lipids (11–17%), minerals (5%), fatty acids (3%), caffeine
(1–2%) and trigonelline (1%) is small (Fig. 1A and B).3 The
process of coffee roasting is accompanied by the Maillard reac-
tion, resulting in complex and diverse coffee melanoidins, which
account for 29% of the total weight of roasted coffee (Fig. 1B).
The lipid part of coffee consists mainly of triacylglycerols and
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esters of diterpene alcohols, which account for 75.2% and 18.5%
of the total lipid content, respectively, and contains a small
amount of esters of steroids (3.2%), diterpene alcohols (∼0.4%),
sterols (2.2%), tocopherols (∼0.05%), phosphatides (∼0.4%), and
tryptamine derivatives (∼0.8%) (Fig. 1C). So far, most of the diter-
penes found in coffee have been present in the form of fatty acid
esters, with the highest content of cafestol, kahweol, and
16-methoxycafestol (16-OMC) in all coffee diterpenes. The
content of these three diterpenes varied among different coffee
species. The content of kahweol in Arabica was significantly
higher than that of Robusta. 16-OMC is only present in Arabica
coffee or in microdistribution in Arabica coffee (Fig. 1D).4,5
2.1 Caffeine
Caffeine is a trimethylxanthine compound whose xanthine
skeleton is derived from purine nucleosides. The purine
Fig. 1 (A) Main ingredients of green coffee; (B) main ingredients of roasted coffee. The ingredients marked in green indicate a decrease in content;
(C) main ingredients of coffee lipids; (D) the content of major diterpenes in Arabica and Robusta coffee.
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nucleoside is converted to xanthine nucleoside, which is the
first key intermediate in the caffeine biosynthetic pathway.
There may be multiple biosynthetic pathways in caffeine
(Fig. 2); all possible pathways are caused by xanthosine or
xanthine undergoing three methylations and eventually
forming caffeine. The main biosynthetic pathway found in
coffee so far is: xanthosine → 7-methylxanthine → theobro-
mine → caffeine, which is catalyzed by three methyl-
transferases from the SABATH (salicylic acid, benzoic acid,
theobromine methyltransferase) family.6
Almost all consumed caffeine can be distributed through-
out the body through the absorption of the stomach and intes-
tine. Once absorbed, caffeine will play multiple roles in the
body, especially in the brain by inhibiting the adenosine recep-
tors which enable the regulation of multiple physiological
activities through endogenous adenosine.7 Adenosine recep-
tors include subtypes A1, A2A, A2B and A3, caffeine A1 subtypes
are mainly distributed in the central nervous system and peri-
pheral nervous system, especially in the hippocampus, cerebel-
lum, hypothalamus and cortex, and they are also distributed
in the kidneys, lungs, bladder and heart. Long-term studies
have shown that inhibition of the A1 subtype can alleviate
hypertension, enhance cognitive function, relieve Alzheimer’s
disease, ease anxiety, and can also treat congestive heart
failure and polar renal dysfunction. The A2A receptor is mainly
distributed in the dopamine-rich region of brain tissue while
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Fig. 2 Twelve possible synthetic pathways and neurodegenerative disease prevention mechanisms for caffeine. The main biosynthetic pathway is
marked in colors.6,8
the A2B receptor is mainly distributed in the digestive system,
and the A3 receptor is widely distributed in the spleen, lungs,
heart, kidneys and other organs and the surface of inflamma-
tory cells. A large number of experiments have shown that, as
an adenosine receptor inhibitor, caffeine administered at
different doses and different phases can alter the expression of
different subtypes of adenosine receptors, enhance or attenu-
ate their biological effects, and it plays the most prominent
role in the A1 and A2A subtypes. Both the A1 and A2A subtypes
are associated with the mental excitatory effects of caffeine,
but the A1 subtype is more critical. Animal model experiments
show that caffeine can effectively inhibit A1 and A2A subtype
receptors of microglia to reduce the microglia-mediated
inflammatory environment and finally prevent neurodegenera-
tive diseases (Fig. 2).8 The core structure of caffeine is also
widely used by researchers as the basic skeleton of novel ade-
nosine receptor antagonists. In addition to affecting adenosine
receptors, acute and chronic, caffeine intervention can also
cause different changes in the expression of a series of recep-
tors such as the 5-hydroxytryptamine (5-HT) receptor, cholin-
ergic receptor, opioid receptor, and GABA receptor.
2.2 CGAs
The synthesis starting material of CGAs is D-glucose, and
D-glucose produces phosphoglycerate acid and erythrose
4-phosphate through the glycolytic pathway (EMP) and
pentose phosphate pathway (PPP) cycle, respectively, and they
can react to synthesize 5-dehydroquinic acid. 5-Dehydroquinic
acid is catalytically converted to quinic acid and shikimic acid.
Quinic acid is used as a raw material for the synthesis of
CGAs, and shikimic acid is converted to phenylalanine by the
shikimic acid pathway. Phenylalanine can further form hydro-
xycinnamic acid and caffeic acid through the cinnamic acid
pathway. Finally, hydroxycinnamic acid or caffeic acid is esteri-
fied with quinic acid to form CGAs (Fig. 3).
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So far, the biological activities discovered in CGAs in
human and animal research studies can be summarized by
the following categories:
(1) Prevent diseases caused by free radical damage, such as
free radical induced cardiovascular damage, nervous system
damage, liver damage and tumors.
(2) Control the inflammatory response in the body by inhi-
biting the release of certain inflammatory mediators such as
TNF-α, IL-6 and IL-1β,9,10 thereby controlling various diseases
caused by inflammation,11–13 for example, acute liver injury,
gastrointestinal disease, and endothelial dysfunction.9,14
(3) Promote glucose metabolism by activating or inhibiting
enzyme activity in the body, reducing insulin tolerance, and
increasing insulin secretion,15 thereby lowering blood glucose
concentration and treating diabetes. One of the most impor-
tant metabolic pathways is thought to inhibit the glucose-6-
phosphate system and subsequently delay glucose uptake in
the intestine.16,17 In addition, a rat model test found that
CGAs can down-regulate blood glucose levels by directly inhi-
biting G6Pase activity and related effects of hepatic
gluconeogenesis.18
(4) Prevent obesity and cardiovascular disease by promoting
lipid metabolism. For instance, oxidative modification of low-
density lipoproteins (LDLs) is an important risk factor in the
pathogenesis of arteriosclerosis,19 while an in vivo study
carried out with 11 healthy male students found that CGAs
can prevent cardiovascular-related diseases by lowering the
level of LDL-cholesterol in the body.20
(5) Additionally, CGAs can also lower blood pressure by pro-
moting the release of NO and inhibiting the activity of angio-
tensin-converting enzyme.21
2.3 Maillard products
The Maillard reaction, also known as the non-enzymatic
browning reaction, widely occurs in the roasting process of
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Fig. 3 Biosynthesis pathway of CGAs. Quinic acid is an intermediate of the shikimic acid pathway, and hydroxycinnamic acid or caffeic acid is pro-
duced by the cinnamic acid pathway. They serve as starting materials for the synthesis of CGAs.
daily foods such as coffee, tobacco, bread, etc. When the temp-
erature of beans rises to about 154 °C, the Maillard reaction
begins (Fig. 4). It is a complex reaction between amino com-
pounds and reducing sugars, which can take place between
aldehydes, ketones, peptides, proteins, and even ammonia. To
date, people only know the chemical process of producing low
and medium molecular weight products in this reaction, and
the polymers produced by this reaction still remain unknown.
The Maillard reaction can be divided into three stages: early
stage, middle stage and final stage.
In the 1950s, Hodge proposed the Maillard reaction route,
which proposed the initial steps of the Maillard reaction and
was widely used to explain the production process of low mole-
cular weight (LMW) Maillard reaction products. In the early
stage, the carbonyl group of the reducing sugar is added to the
amino group, and dehydrated to form a Schiff base, and the
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Schiff base is cyclized to form N-glucosamine, which is con-
verted into 1-amino-1-deoxy-2-ketosaccharide through
Amadori rearrangement. In the middle stage, Amadori com-
pounds are degraded to produce reducing ketones or furfural
compounds, and the numerous reactive intermediates formed
by the reaction can continue to react with the amino com-
pounds. In addition, the condensate of the dicarbonyl com-
pound and the amino acid produced by the degradation of the
Amadori compound can further undergo Strecker degradation
(Fig. S1†).
The final stage of the Maillard reaction in coffee may
produce a range of compounds that are beneficial to human
health, especially the HMWM which are habitually called mel-
anoidins. Exploring the formation of such compounds and
their mechanism of action is a valuable but challenging area
of coffee research. The origin and detailed structural features
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Fig. 4 The curve of the coffee baking process. Melanoidins and acryl-
amide are mainly produced in the Maillard stage, and the amount of
acrylamide is decreased close to the first burst until completion.
of the HMWM remain uncertain, and three hypotheses
for melanogenesis have been proposed, all based on the
Maillard reaction. One theory is that HMWM is produced by a
condensation reaction of LMW compounds, and the conden-
sation reaction occurs at the final stage of the Maillard reac-
tion (Fig. S1B†).22 Another theory is that HMWM is obtained
by the crosslinking reaction of LMW compounds with protein
side chains.23 The third theory holds that the skeleton of
HMWM is produced in the early stage of the Maillard reaction
by sugar degradation products.24 Apart from LMW com-
pounds, proteins and polysaccharides, phenols, which exist in
the form of glycosidic linkages, are also major players in the
formation of melanoidins, accounting for nearly 10% of the
weight.25 A recent study showed that transglycosylation
reactions (TGRs) are the main mechanism for the addition
of phenolic substances to HMWM.26 Galactomannan and
type II arabinogalactan are the most abundant coffee
bean polysaccharides, which react with LMW, proteins
and phenolic compounds to form melanoidins during
baking.27
Animal model experiments show that melanoidins can
exert antioxidant effects on the body. The mechanism may be
due to their free radical scavenging and metal chelation
ability. It is also found that their antioxidant activity is largely
due to the copolymerization of phenolic substances such as
CGAs. Low molecular weight compounds released from mela-
noidins after gastrointestinal digestion exerted the highest
antioxidant activity, even higher than that of compounds
bound ionically to melanoidins.28 Melanoidins have a good
preventive effect on free radical-induced diseases such as liver
injury, atherosclerosis, and colon cancer; this activity may be
related to the bonded-CGAs.29,30 Melanoidins can also inhibit
diseases caused by inflammation in the body by inhibiting the
release of inflammatory factors. In addition, melanoidins may
also increase the antioxidative capacity inside the cell by indu-
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cing Nrf2-regulated signaling pathways not only in different
cell types, but also in intact gut tissue.31
Both soluble and insoluble melanoidins can act as func-
tional dietary fibers to quench radical species in the gastroin-
testinal tract due to their antioxidant activity.32 Melanoidins
escape digestion and pass through the upper gastrointestinal
tract where they can interact with the different microbial
species present in the hindgut,33 and part of the coffee
melanoidins are fermented by microorganisms in the gut and
exhibited the properties of soluble dietary fibers.34,35
Melanoidins can produce antimicrobial activity through che-
lating with metal ions, and three different mechanisms were
found: (1) Melanoidins mediate antibacterial activity by chelat-
ing with ions in the medium at low concentrations. (2) In a bac-
terial strain capable of producing a siderophore, melanoidins
reduce the activity of the strain by chelating with the sidero-
phore-Fe3+ complex. (3) Higher concentrations of coffee melano-
idin can remove Mg2+ from the outer membrane, promote cell
membrane destruction and release intracellular molecules.36
Melanoidins have also been found to lower blood pressure
by modulating the in vitro activity of angiotensin-I converting
enzyme (ACE) and prevent colon cancer by inhibiting the
in vitro activity of matrix metalloproteases (MMPs), a family of
endo-peptidases that play a central role in tumor growth and
metastasis.28 In general, coffee melanoidins have diverse bio-
logical activities in living organisms; however, the complex
structures largely limit the study of their biological activities,
and it is worthwhile to conduct some more systematic research
studies in the future.
Acrylamide is mainly produced by the Maillard reaction of
asparagine and reducing sugars, and is considered to be a sub-
stance having neurotoxicity and potential carcinogenic activity.
Once ingested, it can be rapidly distributed to whole body
tissues and metabolized by cytochrome P450 2E1 to
glycidamide;37,38 glycidamide can also produce genotoxic char-
acter via forming adducts with proteins and DNA in vivo.39
Reducing the production of acrylamide during the roasting
processes of coffee is challenging and has become a hot
research area. Xu et al. found that the content of acrylamide in
the whole programme increased at first but decreased close to
the first burst until completion (Fig. 4).40 Properly shortening
the roasting time before the 1st crack stage and prolonging the
time after the 1st crack stage may help reduce the production
of acrylamide.
Furan and furan derivatives are also produced during the
roasting of coffee beans via the degradation or oxidation of
carbohydrates, amino acids, ascorbic acid, and polyun-
saturated fatty acids.41–43 Furan in coffee has recently received
significant attention due to it being classified as being “poss-
ibly carcinogenic to humans” (Group 2B), based on animal
trials, by the International Agency for Research on Cancer
(IARC, 1995). Their concentration present in beverages is
closely related to the variety, pretreatment method, roasting
degree and brewing method.44,45 Due to their strong volatility,
furans and furan derivative compounds will decrease signifi-
cantly during processing.45,46
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2.4 Diterpenoids
In the 1930s, researchers found C&K in coffee and incorrectly
identified them as a steroid. In the 1940s–1950s, several
researchers spent nearly 20 years determining the chemical
structure of coffee alcohol. Subsequently, in 1989, 16-OMC was
found in the coffee oil of Robusta coffee, and its structure was
determined by synthesis. 16-OMC, which is an ideal biomarker
for distinguishing Robusta from Arabica, has been considered
to exist only in Robusta coffee in the past. However, recently, it
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was also found in Arabica coffee. C&K and 16-OMC are mainly
esterified with various fatty acids, and rarely exist as free forms.
In the 21st century, more and more researchers, including
our team, found that there are various forms of diterpenes in
coffee; most of them are derivatives of C&K and 16-OMC. So
far, nearly 100 diterpenes with different structures have been
identified in coffee. Through structural classification, we
divided them into oxidized diterpenoids, rearranged diter-
penes, tetrahydrofuran-type diterpenes, pyrolyzed diterpenes,
γ-lactone-type diterpenes, Δ4,18-type diterpenes, degraded-type
diterpenes and Villanova-type diterpenes (Fig. 5), and specu-
lated their biosynthetic pathways (Fig. S2†). Until now, most of
the diterpenes found in coffee have been derived from the
Fig. 5 Eight types of diterpenes from coffee. All the coffee diterpenes are derived from the kauran skeleton via oxidation, condensation, rearrange-
ment and other catalytic reactions.
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kauran skeleton via oxidation, condensation, rearrangement
and other catalytic reactions in coffee plants; a few of them
may also be produced during the roasting processes.
Because of the rich content in coffee, the bioactivity of C&K
has been extensively studied. C&K can increase serum chole-
sterol levels of gerbils and rats by increasing the activity of
cholesterol transfer proteins and accumulating extracellular
cholesterol.47 In addition, C&K were shown to have anticarci-
nogenic, antioxidant, anti-inflammatory and hypercholestero-
lemic activities.48,49 C&K palmitates are potent inducers of glu-
tathione S-transferase activity and induce xenobiotic detoxifi-
cation in the gut and mucosa of mice. It is worth mentioning
that the biological activity seems to be closely related to the
furan ring of cafestol and kahweol; the compound loses its
activity after the furan ring is destroyed. C&K were also found
to reduce the metabolic toxic substances by inhibiting
N-acetyltransferase in vitro and in model rats, thereby playing a
role in glycosidic protection.50 The good bioactivity of C&K and
their rich content in coffee mean that they have the potential
to be the starting material for drugs.
Studies have found that other types of diterpenes also have
good biological activity. Interestingly, the degree of oxidation
at the 19 site has a large effect on the intensity of the activity;
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for instance, 6a,17-dihydroxy-ent-kauran-19-al showed strong
in vitro inhibitory activity against human ovarian cancer cell
line A2780 (IC50 0.38 μM) and human lung cancer cell 95-D
(IC50 19.38 μM), while when the aldehyde group located at the
19 site is oxidized to a carboxyl group, it loses activity to
human ovarian cancer cell A2780 and has a reduced activity
against 95-D (IC50 39.83 μM).51
2.5 Trigonelline
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The amount of trigonelline synthesized in the pericarp is
much higher than that in the seeds, but some of the trigonel-
line synthesized in the pericarp can be transported to the
seeds, leading to the amount of trigonelline in seeds being
higher than that in the pericarp. Quinolinic acid, an inter-
mediate synthesized from the pyrimidine nucleotide, enters
the pyridine nucleotide cycle, nicotinamide—nicotinic acid—
nicotinic acid mononucleotide (NaMN)—nicotinic acid—
adenine dinucleotide (NaAD)—NAD—nicotinamide mononu-
cleotide (NMN)—nicotinamide, and trigonelline is finally syn-
thesized from the nicotinic acid produced by this cycle
(Fig. 6).52
Studies on the bioactivity of trigonelline are focused on the
prevention of cardiovascular disease, neuroprotection and
anticarcinogens. Trigonelline regulates key enzymes of glucose
and lipid metabolism, such as glucokinase, glucose-6-phos-
phatase, fatty acid synthase, and carnitine palmitoyl transfer-
ase in diabetic rats, which leads to its activity in lowering
blood sugar, cholesterol and blood lipid.53,54 There are two car-
dinal mechanisms for trigonelline to exert anticancer activity
which do not directly exert cytotoxicity to kill cancer cells. One
is to prevent cell invasion, an important means of cancer cell
proliferation.55 The other is to regulate the expression of tran-
scription factor Nrf2. The transcription factor Nrf2 is activated
to protect cells from harm when cells are invaded. However,
the Nrf2 factor is also present in cancer cells, so there is often
inhibition during chemotherapy. An experiment using pan-
Fig. 6 The biosynthetic pathways of trigonelline in coffee. NaMN, nicotinic acid mononucleotide; NaAD, adenine dinucleotide; NMN, nicotinamide
mononucleotide; NAD, nucleosidase; PRPP, 5-phosphoribosyl-1-pyrophosphate.52
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creatic carcinoma cell lines and H6c7 pancreatic duct cells as
models found that trigonelline can inhibit the expression of
Nrf2 in cancer cells and improve the effect of chemotherapy.56
Experiments have shown that trigonelline enters the brain
through the blood–brain barrier, which can improve the
memory of rats and exert neuroprotective activity, but does not
clarify its mechanism of action.
3. Coffee active ingredients and
diseases
3.1 Cardiovascular disease
The relationship between coffee drinking and cardiovascular
disease has been controversial. Several studies have shown
that drinking coffee may increase the incidence of cardio-
vascular disease. A study surveyed 24 710 Finns without a
record of drug treatment for hypertension and assessed their
daily coffee consumption through a questionnaire. During the
survey, 2505 participants started antihypertensive drug treat-
ment. The result showed that drinking coffee seems to
increase the risk of antihypertensive drug treatment, and this
risk was higher among subjects with low to medium coffee
intake.57 However, most follow-up studies did not have direct
evidence that coffee can cause cardiovascular disease.
Subsequent research studies showed that moderate coffee con-
sumption could reduce blood pressure,58–60 prevent stroke and
heart diseases,61–63 and reduce the risk of type 2 diabetes.64
The main components that exhibit anti-cardiovascular activity
in coffee are considered to be CGAs, trigonelline, caffeine, and
melanoidins (see Table S1† for more information about their
anti-cardiovascular disease mechanisms).
Blood pressure of spontaneously hypertensive rats injected
with coffee extracts or chlorogenic acid can be significantly
improved. The mechanism may be that ferulic acid, a metabo-
lite of CGAs, acts on NO from the inner wall of blood vessels,
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and regulates the tension of blood vessels by improving the
bioavailability of NO.65,66 In addition, the antihypertensive
effect of CGAs has been observed in both animal models and
hypertensive patients to be affected by hydroxyhydroquinone,
which was produced during coffee roasting.66–68
According to a study conducted by Shamil et al., CGA
(5-CQA) inhibited platelet activity at 50 nM, suggesting that it
can be used as a good antithrombotic agent.69
Pharmacokinetic studies have shown that the consumption of
2–3 cups of coffee can reach the 5-CQA active concentration,
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but its metabolism in the human body is fast, and it is necess-
ary to consume regularly to maintain its plasma concen-
tration.70 It was found that the pyridinium compounds 1,3-
and 1,4-dimethylpyridine formed during the heat treatment of
trigonelline or the roasting of coffee also showed slight antith-
rombotic activity in a rat model.71
Some coffee melanoidins showed significant ACE inhibitory
activity, and their activity was positively correlated with the
degree of heating. The ACE inhibitory activity is associated
with the complex structure of melanoidins, but is also attribu-
table in part to low molecular weight compounds such as
natural phenolic compounds that are not chemically bonded
to melanoidins; therefore, melanoidins can also act as a
carrier protectant.72
Although it has been thought in the past, consumption of a
large amount of coffee containing C&K may cause cardio-
vascular disease because C&K consumption can increase the
amount of cholesterol in the human body.47 However, the rec-
ommendation for daily intake of C&K not exceeding 300 mg in
the 1960s lacked sufficient scientific evidence. In the latest
version of the US Dietary Guidelines (2015–2020), the chole-
sterol “300 mg daily intake limit” was removed, and cholesterol
is no longer considered to be “a worrying nutrient”, meaning
that moderate drinking of coffee containing C&K will not con-
tribute to cardiovascular disease.
3.2 Antibacterial activity
A secondary analysis of the 2003–2004 U.S. health and nutri-
tion survey data showed that compared with those who do not
drink coffee, a coffee drinker’s MRSA nasal cavity risk is
reduced by about a half,73 suggesting that the coffee com-
ponents can be used to resist the invasion of human patho-
gens. CGAs, melanoidins, dicarbonyl compounds, polysacchar-
ides and some other trace ingredients play great roles in the
antibacterial activity of coffee (see Table S2† for more infor-
mation about their antibacterial activities).
Suarez-Quiroz, et al. screened the in vitro antimicrobial
activity of CGAs and dodecyl chloride (DCGA) against different
bacterial strains.74 CGAs have inhibitory activity against both
Gram-positive and Gram-negative bacteria, among which, they
exhibit bactericidal activity against Pseudomonas fluorescens
and Staphylococcus aureus; DCGA is active against Gram-posi-
tive bacteria and inactive against Gram-negative bacteria. Both
the CGA and DCGA exhibit anti-Aspergillus activity and have
higher inhibitory activity against ochratoxin A than aflatoxin
B1. This work reported for the first time that the CGA and
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DCGA were used as antibacterial agents, antifungal agents and
antimycotic agents, suggesting that CGA compounds are prom-
ising as preservatives in foods or non-food products. In
addition to the antibacterial activity alone by chelating with
metal ions as mentioned above, when coffee is roasted, CGAs
can also be part of HMWM by the Maillard reaction, in combi-
nation with HMWM to exert antibacterial activity.36
3′,4′-Dihydroxyacetophenone is an antimicrobial substance
in coffee grounds, and the antimicrobial activity of the 3′,4′-
dihydroxyacetophenone isomers depends on the binding site
of the hydroxyl group.75 Glyoxal, methylglyoxal and diacetyl
and other α-dicarbonyl compounds formed during the roast-
ing of coffee are the main active substances in brewing coffee
against Sa. aureus and St. mutans; adding caffeine with weak
intrinsic antibacterial activity to a mixture of alpha-dicarbonyl
compounds may synergistically enhance the antibacterial
activity of alpha-dicarbonyl compounds.2
3.3 Anti-diabetic activity
Extensive epidemiological studies have shown that coffee
intake reduces the risk of diabetes in humans. Among all the
active ingredients, caffeine, CGAs and trigonelline play the
most prominent roles to prevent diabetes76–79 (see Table S3†
for more information about their anti-diabetic mechanisms).
It was found in the study of streptozotocin-induced niacin-
amide-induced type 2 diabetes in mice that metabolites of
caffeine in the gastrointestinal tract protected the pancreas
from type 2 diabetes.80 Besides, Cheng et al. 2011 proposed
that the intake of caffeine and caffeic acid could inhibit the
misfolding of human amylin polypeptide (hIAPP) and reduce
the incidence of type 2 diabetes.81
CGAs have a similar protective effect on the pancreas to
caffeine.82 CGAs can increase the body’s insulin response and
may be the component that normalizes the acute glucose
response. However, randomized crossover studies have shown
that there is no significant difference in the effect of different
CGA levels on glucose and insulin in humans.83 Henry-Vitrac
et al. found that a coffee extract, Svetol, inhibited glucose-6-
phosphatase hydrolysis in human liver microsomes, which
could reduce the production of hepatic glucose through this
inhibition and achieve antidiabetic effects, and CGAs (caffeoyl-
quinic acid and di-caffeoylquinic acid) were the main ingredi-
ents that promoted this process.84 Acetylcholinesterase (AChE)
activity and lipid peroxidation will increase in the cerebral
cortex in diabetic rats, while Stefanello et al. found that the
CGA and CA inhibited AChE activity in diabetic rats, prevented
diabetes-induced lipid peroxidation, improved memory and
reduced anxiety, suggesting that it can be used to prevent dia-
betes-induced brain disorders.85
Trigonelline can improve symptoms of diabetes in rats by
regulating glucose and lipid metabolism key enzymes (such as
glucokinase, glucose-6-phosphatase, fatty acid synthase, etc.).86
Treated with trigonelline for 4 weeks, the blood glucose, chole-
sterol, and triglyceride levels in the diabetic rats were signifi-
cantly reduced.87 Hong et al. found that trigonelline in coffee
can improve auditory threshold changes caused by diabetic
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Food & Function
neuropathy and delay the latency of auditory evoked potentials
in mice, which may help improve diabetes-induced hearing
impairment.88 However, another study found that trigonelline
(50 mg kg−1 daily for four weeks) increased bone mineral
density and cancellous bone strength in nicotinamide/strepto-
zotocin-treated rats, which means that improper intake of tri-
gonelline may increase diabetes-induced skeletal system
diseases.89
3.4 Neuroprotection
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A large number of epidemiological studies have shown that
coffee has the efficacy of preventing neurodegenerative dis-
eases such as Parkinson’s disease (PD), Alzheimer’s disease
and depression.90 However, most of the research results are
from observational experiments, and there are few studies on
the mechanisms of specific secondary metabolites in coffee
(see Table S4† for more information). The association between
coffee and PD risk is related to gender, and it is usually more
related to men than women. This gender difference may be
related to the secretion of estrogen. Women who use coffee
during the use of postmenopausal hormones will increase the
risk of PD. Although the cause of this adverse effect of estrogen
is currently unclear, the more common current guess is that
estrogen replacement therapy may inhibit cytochrome P-450
(CYP1A)-mediated metabolism.
Among all the secondary metabolites of coffee, caffeine has
the most significant effect on the nervous system, and it may
be the main active substance of the coffee components to
prevent PD. It has been demonstrated that caffeine is resistant
to dopaminergic neurotoxicity in animal models, and its
mechanism of action may be to block A2 adenosine receptors
to stimulate dopamine release, thereby improving the function
of the dopaminergic system.91 Recently, a study showed that
eicosanoyl-5-hydroxytryptamide, which was purified from
coffee as an agent that leads to enhanced enzymatic activity of
the specific phosphatase PP2A that dephosphorylates the
pathogenic protein α-synuclein, works in synergy with caffeine
in protecting against mouse models of PD and dementia with
Lewy bodies. The mechanism of this synergy is also through
enhancing PP2A, which is dysregulated in the brains of indi-
viduals with these α-synucleinopathies.92
Extensive studies have shown that caffeine and other bio-
logically active molecules in coffee can reduce the risk of
depression.93–97 For example, Hall et al. studied the effects of
caffeine on the behavior of depressed mice. Behavioral studies
showed that caffeine-injected mice did not undergo tail sus-
pension or forced swimming tests.98 Although many studies
have provided evidence that caffeine has antidepressant
activity, the mechanism of action has not yet been fully eluci-
dated. As the understanding of the pathogenesis of depression
continues to deepen, it is expected to have a deeper under-
standing of the antidepressant mechanism of caffeine.
3.5 Anticancer activity
Although laboratory data indicate that certain components of
coffee may cause DNA mutations and inhibit tumor suppres-
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Review
sion mechanisms,99–101 subsequent research studies have not
confirmed this point. Recent studies based on human and
animals have shown that coffee may play a role in preventing
colon cancer, rectal cancer, breast cancer, hepatocellular carci-
noma, and prostate cancer.102–104 Caffeine, coffee melanoi-
dins, CGAs, C&K, and trigonelline are the main substances
that produce anticancer activity (see Table S5† for more infor-
mation about their anticancer mechanisms).
Hirose et al. examined the relationship between coffee
intake and hormone-related cancer risk in Japanese women
and used a multivariate logistic regression model to determine
whether there was a correlation between caffeine intake and
endometrial cancer, and found that coffee consumption
reduces the risk of endometrial cancer in subjects.105
Interestingly, in another epidemiological survey, opposite
results were obtained. A survey of 5847 postmenopausal
women with an effective cancer status by Yuan et al. found
that the incidence of endometrial cancer in women who con-
sumed varying degrees of caffeine increased significantly com-
pared with women without caffeine intake.106
Zinc-containing matrix metalloproteinases MMP-1, MMP-2,
and MMP-9 play a pivotal role in the pathogenesis of colorectal
cancer. De Marco et al. found that melanoidins isolated from
coffee beans can effectively inhibit the activities of MMP-1,
MMP-2 and MMP-9 with IC (50) values ranging between 0.2
and 11 mg mL−1 in vitro, indicating that coffee melanoidins
have important values in the study of colorectal cancer.107
CGAs can induce selective killing of lung cancer cells (A549)
while normal lung fibroblasts (MRCS) are unaffected.101
Another study in vitro found that CGAs can inhibit CT-26 colon
cancer cell-induced lung metastasis by blocking the phos-
phorylation of extracellular regulatory protein kinase (ERK).108
In addition, CGAs can also exert anti-cancer effects in vitro
through other mechanisms, such as reducing DNA methyl-
ation by inhibiting DNA methyltransferases, and the IC50
value of CGAs was 0.75 µM.109
The transcription factor Nrf2 can be involved in regulating
the drug resistance of cancer cells, and trigonelline can
increase the sensitivity of pancreatic cancer and colon cancer
cell lines to anticancer drugs by inhibiting Nrf2 activity in
tumor-bearing mice.56 In another study, rat ascites liver cancer
cell line AH109A was used to infect rats, trigonelline was able
to resist the invasion of liver cancer cells at a concentration of
2.5–4.0 μM, but it did not inhibit the differentiation of liver
cancer cells.110 However, studies have also shown that trigonel-
line has a proliferative effect on breast cancer cells.
Trigonelline produces phytoestrogens, which activates the
estrogen receptor (ER) at a concentration of 100 pM and sig-
nificantly induces the proliferation of MCF-7 breast cancer
cells.111
C&K has been a relatively important part of coffee anti-
cancer research in recent years, but the mechanism of apopto-
sis they mediate is not fully studied; most of the anti-cancer
research studies about C&K or other diterpenoids were limited
to in vitro trails. Park et al. found that kahweol inhibited mark-
edly the proliferation of human colorectal cancer cell lines
Food Funct., 2019, 10, 3113–3126 | 3121

Review
such as HCT116, SW480 via inhibiting the cyclin D1 protein
level in HCT116 and SW480 cells. In the following study, they
found that kahweol can also induce apoptosis through activat-
ing the transcription factor 3-mediated pathway in human col-
orectal cancer cells.112 In some other studies, C&K were also
found to exert anticancer activity by increasing overall gluta-
thione transferase, inhibiting CYP450s, and inducing phase II
detoxifying and antioxidant enzymes.113–115
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4. Conclusions
In addition to the HMWM, the sources of other types of
coffee main bioactive substances have been clarified. The
complexity of the reaction process leads to the possibility
that the structure of HMWM formed under the same reaction
conditions may be different, which leads to different
mechanisms.
From the existing epidemiological literature reports, despite
a small number of negative reports, coffee consumption tends
to benefit human health. For a single coffee component, some
specific trace constituents in roasted coffee like acrylamide
and furan, although there is no convincing evidence to prove it
to be the case, may have a negative impact on human health,
while caffeine, CGAs, melanoidins, diterpeniod and trigonel-
line showed anti-cardiovascular disease, anti-diabetic, neuro-
protection and anticancer activity through multiple mecha-
nisms of action. It is worth mentioning that, as with most
drug research studies, the mechanisms of action in model
animals or in vitro are often hard to repeat in humans.
In In vivo studies, the effects of coffee active ingredients
are greatly affected by the location, gender, and individual
differences of the subjects. The results obtained are less repro-
ducible, which is a factor that needs attention when conduct-
ing mechanism research in the future.
Conflicts of interest
The authors are not aware of any affiliations, memberships,
funding, or financial holdings that might be perceived as
affecting the objectivity of this review.
Acknowledgements
This study was supported financially by the National Natural
Science Foundation of China, China (No. 31670364),
Foundational Project of Key Laboratory of Tobacco Chemistry
of Yunnan Province, R&D Center of China Tobacco Yunnan
Industrial Co., Ltd (KCFZ-2017-1096), Project of Key New
Productions of Yunnan Province, China (No. 2015BB002), the
STS Programme of Chinese Academy of Sciences, China
(KFJ-SW-STS-143-8), and the Special Fund Project of Pu’er
municipal government, China (2018), as well as the
Foundation of State Key Laboratory of Phytochemistry and
Plant Resources in West China, China (P2015-ZZ09).
3122 | Food Funct., 2019, 10, 3113–3126
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Food & Function
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