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Bioactive Compounds in Coffee and Their Role in Lowering

This review discusses the bioactive compounds in coffee, such as caffeine, chlorogenic acid, and trigonelline, and their roles in reducing the risk of various health issues, including cancer and cardiovascular diseases. Moderate coffee consumption is linked to lower risks of degenerative diseases, while excessive intake may lead to health concerns. The article emphasizes the importance of understanding coffee's health benefits and the impact of its aroma and chemical composition on consumer preferences.

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Bioactive Compounds in Coffee and Their Role in Lowering

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Abebe Chindi

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Received: 9 December 2022 | Revised: 4 November 2023 | Accepted: 7 November 2023

DOI: 10.1002/fsn3.3848

REVIEW

Bioactive compounds in coffee and their role in lowering the

risk of major public health consequences: A review

Markos Urugo Makiso1,2 | Yetenayet Bekele Tola2 | Onwuchekwa Ogah3 |

Fitsum Liben Endale4

1
Department of Food Science and
Postharvest Technology, College Abstract
of Agricultural Sciences, Wachemo
This article addresses the bioactive components in coffee aroma, their metabolism,
University, Hossana, Ethiopia
2
Department of Postharvest Management,
and the mechanism of action in lowering the risk of various potential health problems.
College of Agriculture and Veterinary The main bioactive components involved in the perceived aroma of coffee and its re-
Medicine, Jimma University, Jimma,
Ethiopia
lated health benefits are caffeine, chlorogenic acid (CGA), trigonelline, diterpenes, and
3
Department of Applied Biology, Ebonyi melanoids. These compounds are involved in various physiological activities. Caffeine
State University, Isieke, Nigeria has been shown to have anticancer properties, as well as the ability to prevent the
4
Department of Public Health, College of
onset and progression of hepatocellular carcinoma and to be anti-inflammatory. CGA
Medicine and Health Sciences, Wachemo
University, Hossana, Ethiopia exhibits antioxidant action and is implicated in gut health, neurodegenerative disease
protection, type 2 diabetes, and cardiovascular disease prevention. Furthermore, to-
Correspondence
Markos Urugo Makiso, Department gether with diterpenes, CGA has been linked to anticancer activity. Trigonelline, on
of Food Science and Postharvest
the other side, has been found to lower oxidative stress by increasing antioxidant
Technology, College of Agricultural
Sciences, Wachemo University, PO enzyme activity and scavenging reactive oxygen species. It also prevents the forma-
Box 667, Hosanna, Ethiopia.
tion of kidney stones. Diterpenes and melanoids possess anti-inflammatory and anti-
Email: markosmakiso@gmail.com and
markosmaki@wcu.edu.et oxidant properties, respectively. Consuming three to four cups of filtered coffee per
day, depending on an individual's physiological condition and health status, has been
linked to a lower risk of several degenerative diseases. Despite their health benefits,
excessive coffee intake above the recommended daily dosage, calcium and vitamin D
deficiency, and unfiltered coffee consumption all increase the risk of potential health
concerns. In conclusion, moderate coffee consumption lowers the risk of different
noncommunicable diseases.

KEYWORDS
caffeine, chlorogenic acid, coffee aroma, health benefits, trigonelline

1 | I NTRO D U C TI O N as its pleasant flavor and aroma (Farag et al., 2022; Pohl et al., 2012).
Over 166 million bags of coffee were consumed in the fiscal year
Coffee is the most popular beverage consumed worldwide and has 2020–2021 globally, with an estimated daily consumption of over
several positive health and economic effects (Esteban et al., 2020; 1.6 billion cups (Farag et al., 2022; Statista, 2022). Global demand
Haile et al., 2020; Wu et al., 2022). It is consumed daily by millions of for coffee climbed steadily by 2.2% on average between 2016–2017
individuals who enjoy its stimulating and refreshing qualities as well and 2019–2020 (Mas Aparisi, 2021). Several variables, including

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.

Food Sci Nutr. 2023;00:1–31. wileyonlinelibrary.com/journal/fsn3 | 1

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2 MAKISO et al.

the improvement in bean quality, the growth of specialty coffee this article aimed to review recent scientific reports on aroma im-
shops, and the spread of literature relating coffee use to health ad- pact bioactive compounds of Arabica and Robusta coffees and their
vantages, could explain the ongoing rise in coffee demand (Celli & health benefits.
Camargo, 2019).
Numerous scientific studies have shown that drinking cof-
fee lowers the risk of certain health complications, including 2 | M E TH O D O LO G Y
type II diabetes, heart disease, liver cirrhosis, obesity, and can-
cer (Iriondo-dehond et al., 2020; Kusumah & Mejia, 2022; Núñez The most relevant articles on the coffee aroma impact compounds
et al., 2020; Wu et al., 2022). Coffee's high antioxidant activ- and their health benefits were explored from related databases such
ity and bioactive components are typically responsible for the as Google Scholar, Web of Science, PubMed, Science Direct, and
beverage's positive health effects (Esteban et al., 2020; Haile Virtual Library of Health. Key terms used in the data search were
et al., 2020; Iriondo-dehond et al., 2020; Núñez et al., 2020; Saud “coffee”, “coffee species”, “health benefits of coffee”, “aroma active
& Salamatullah, 2021). Coffee, both green and roasted, contains compounds of coffee”, “aroma active compounds of Arabica and
a variety of bioactive substances, including phenolic acids, pri- Robusta coffee”, “health benefits of caffeine, CGA, trigonelline, dit-
marily chlorogenic acids (CGAs), lactones (CQAs, caffeoylquinic erpenes, and melanoids”. Furthermore, the references of selected
acids, FQAs, feruloylquinic acids, and diCQAs, dicaffeoylquinic publications were examined to obtain further relevant articles. As
acids with at least three isomers per class), methylxanthines (caf- shown in Figure 1, the search criteria included all peer-reviewed ar-
feine, theophylline, and theobromine), diterpenes (cafestol and ticles published in English between 2004 and September 2023. A
kahweol; Haile et al., 2020; Jeszka-skowron et al., 2020; Saud & total of 707 articles were collected. Articles that passed the title and
Salamatullah, 2021; Wu et al., 2022). Some of these elements play abstract screening process were then read in their entirety by two
crucial roles as precursors to the coffee aroma both before and members to determine their eligibility to be included in the review.
after roasting (Bastian et al., 2021; Haile et al., 2020). During the eligibility screening, articles that met the following crite-
The primary ingredients for the aroma and bioactivity of coffee ria were included in the review: (1) has been peer reviewed; (2) has
include caffeine (CAF), CGA, trigonelline (TGA), nicotinic acid, and been published in English; (3) has been published between 2004 and
sucrose (Jeszka-skowron et al., 2020; Stefanello et al., 2018). Coffee 2023; and (4) the full text of the article is available. In the screening
aroma is one of the most distinguishing qualities of this commod- step, 510 articles that failed to meet the eligibility criteria were re-
ity and the most important factor influencing consumers' accep- jected, and the remaining 197 articles were identified as eligible and
tance and preference (Caporaso et al., 2018; Turan et al., 2021). The used as information sources for this review article.
chemical makeup of the bean, genetic strain, geographic location,
climate, annual rainfall, agricultural practice, and the processing
method used are all directly related to the aroma of coffee (Procida 3 | CO FFE E S PEC I E S
et al., 2020). Species differences in the coffee may bring difference
in the chemical makeup of the coffee. There have been more than The coffee plant is a woody perennial evergreen shrub with white
120 coffee species discovered so far, but only two of them, Coffea flowering plants that produce fruits called “cherries” that contain
arabica (Arabica) and Coffea canephora (Robusta), supply 99% of two seeds known as “coffee beans” (Bliss, 2017). Economically im-
the world's coffee needs (Angeloni et al., 2021; Farag et al., 2022; portant coffee species originate from Africa and belong to the fam-
Moeenfard & Alves, 2020; Zhang et al., 2020). ily Rubiaceae, genus Coffea (Adronikos, 2019). Coffea arabica and
Arabica and Robusta beans have different chemical makeup C. canephora are the two most traded and consumed coffee spe-
and consequently they have different flavor profiles. Arabica beans cies globally. Coffea arabica accounts for 70% of the world's coffee
produce a superior taste in the cup, more flavorful and complex production, and C. canephora and Coffea liberica cover the remain-
than Robusta beans. On the other hand, Robusta often produce a ing share (Angeloni et al., 2021; Nunez et al., 2020, 2021). Coffee
more bitter beverage with a musty flavor and more body (Ogutu grows in over 70 countries in tropical regions (Hunt et al., 2020).
et al., 2022; Seninde & Chambers IV, 2020; Wongsa et al., 2019). The Specifically, the tropics of Cancer and Capricorn, known as the “bean
differences in sensory qualities may influence consumers' prefer- belt”, such as Ethiopia, Brazil, Costa Rica, and Indonesia, are prefer-
ences, feelings, or attitudes regarding coffee consumption (Seninde able for coffee growth (Bliss, 2017). It takes 3 years to develop from
& Chambers IV, 2020). Nowadays consumers are increasingly in- seed germination to first flowering and fruit production (Rodrigues
terested in their diet and health. However, it remains unclear what et al., 2013). The growth requirement varies for different coffee
consumers think about coffee's health advantages. Only 16% of species but generally, they require a well-distributed annual rain-
Americans who drink coffee are aware of its health advantages, and fall, with temperature between 15°C and 30°C and dry season for
66% choose to limit their caffeine intake. Many European customers up to 5 months. Coffea arabica and C. canephora are coffee species
are perplexed about how coffee affects their health, with 49% of adapted to tropical highlands and lowlands, respectively (Angeloni
them believing that it does (Samoggia & Riedel, 2019). As a result, et al., 2021; Pohlan & Janssens, 2010).
|

F I G U R E 1 A schematic diagram

Identification
Total studies retrieved through Additional studies
detailing the article search and selection.
database searching (n=655) indentified from the
reference list of collected
studies (n=52)

Total articles gathered by the team members on coffee

Screening
species, coffee aroma impact compounds, their health benefits,
and their mechanism of action (n=707)

Total
Total articles screened after removing articles
duplicates and irrelevant studies (n=429) excluded
(n=274)

Eligibility Total full

text articles
Total full text articles assessed for eligibility
excluded
(n=197)
with reasons
(n=236)

Total studies included in the qualitative and

quantitative synthesis (n=193)
Included

Articles included in this review article development (n=193)

4 | CO FFE E A RO M A I M PAC T 4.1 | Nonvolatile components of coffee

CO M P O U N D S
Nonvolatile coffee chemicals include, for instance, lipids, CGAs,
The pleasurable flavor and aroma of coffee are largely attributed to a organic acids, some minerals, melanoids, and nitrogen-containing
variety of biochemical components. Both genetic and environmental substances like trigonelline and caffeine (Cordoba et al., 2020).
factors have an impact on these biochemical components (Getachew Caramelization, Maillard reaction, and pyrolysis occur during high-
et al., 2020). Green coffee contains different components, namely, temperature roasting. They degrade some nonvolatile components
methylxanthines (caffeine, theophylline, and theobromine), CGA, like proteins and carbohydrates and give rise to the formation of
trigonelline, lipids, carbohydrates, especially insoluble polysac- various bioactive compounds with high and medium volatility that
charides such as cellulose, hemicelluloses, sugars including arab- impart the aroma and flavor of coffee (Farah, 2012).
inose, fructose, galactose, glucose, raffinose, sucrose, stachyose,
free amino acids, fiber, water, and minerals (Mengistu et al., 2020;
Pimpley et al., 2020). In addition, they are known to have nonvolatile 4.1.1 | Caffeine (1,3,7-trimethylxanthine;
fractions of aliphatic acids such as citric acid, malic acid, quinic acid, C8H10N4O2)
and acetic acid along with the volatile ones such as acetic acid, pro-
panoic acid, butanoic acid, hexanoic acid, and decanoic acid (Pimpley Caffeine is one of the pharmacologically active methylxanthines
et al., 2020). Caffeine, CGA, and sucrose are the major components found in coffee. It has an effect on the central nervous system,
and precursors of coffee cup quality (Tolessa et al., 2019). Generally, heart, gastrointestinal system, and respiratory systems (DePaula
nonvolatile components of coffee are responsible for taste sen- & Farah, 2019; Jeszka-skowron et al., 2020). Caffeine is the major
sations of the coffee like sourness, bitterness, and astringency, compound in coffee responsible for psychostimulating sensations
whereas volatile compounds of coffee are responsible for the aroma and imparts body, strength, and 10% of the perceived bitterness
of the coffee (Buffo & Cardelli-freire, 2004). Due to their differing of brewed coffee (Sharma, 2020; Sunarharum, 2016). However, it is
chemical makeups, roasted Arabica and Robusta green beans have colorless and odorless at room temperature and dissolves in boiled
different flavor characteristics (Seninde & Chambers IV, 2020). water (DePaula & Farah, 2019). It is found in twice the amount higher
|

F I G U R E 2 Chemical structure of
caffeine and its metabolites (Anastasiadi
et al., 2021).

F I G U R E 3 Chemical structure of
chlorogenic acids and its derivatives
(Hernandez-Estrada, 1985).

in C. canephora (1.5%–4.0%) than in C. arabica (0.7%–1.6%; Jeszka- 12%–18% of the dry matter basis of green coffee. The compound
skowron et al., 2020). Caffeine is relatively heat stable and not af- has antioxidant properties and also has both pharmacological and
fected by roasting temperature, but slight loss occurs as a result of physiological effects (Farah & Lima, 2019; Pinheiro et al., 2020). The
sublimation (Farah, 2012). Brewed coffee contains 135 mg of caf- chemical structure of CGA and its derivatives are indicated below
feine per cup (237 mL, 8 oz); instant coffee contains 76–106 mg; and in Figure 3. There are three different classes of CGAs that cover
decaffeinated instant contains 5 mg of caffeine per cup (Morgan 80% of the total CGA content of coffee; these are CQA, diCQA,
et al., 2013). However, according to the study, commercial espresso and FQA (Pimpley et al., 2020). During roasting, CGAs degrade into
coffees have a 6-fold range of caffeine levels, a 17-fold range of CQA lower molar compounds called lactones and phenolic derivatives like
contents, and a fourfold range of CQA–caffeine ratio. These vari- caffeic acids. These compounds further hydrolyze or isomerize to
ations are due to batch-to-batch differences in bean composition, impart aroma and taste such as bitterness and astringency to the
possible Arabica–Robusta bean blending, and roasting and grind- coffee (Pinheiro et al., 2020). Depending on the type of coffee and
ing procedures (Crozier et al., 2012). These differences significantly brewing method, one cup (200 mL) of coffee contains between 20
limit the validity of epidemiological study conclusions. The chemi- and 675 mg of CGAs (Jeszka-Skowron et al., 2016).
cal structure of caffeine and its metabolites are indicated below in
Figure 2.
4.1.3 | Trigonelline (N-methyl nicotinic acid;
C7H7NO2)
4.1.2 | Chlorogenic acid (5-CQA; C16H18O9)
It is a plant alkaloid formed by methylation of the nitrogen atom of
Chlorogenic acid is a derivative of trans-cinnamic acids (caffeic, feru- nicotinic acid by the catalytic effect of NaMN nucleotidase, NaR
lic, or p-coumaric) and quinic acid by esterification reaction (Pinheiro nucleotidase, and nicotinate methyl transferase (Arai et al., 2015;
et al., 2020). It is the major polyphenol of coffee and comprises Mohamadi et al., 2017). It is found in the range of 0.6%–1.3% in
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|5

F I G U R E 4 Structure of trigonelline and related nicotinic acid metabolites (Ashihara et al., 2015).
MAKISO et al.
|

Arabica coffee and 0.3–0.9% in Robusta green bean (Mohamadi 4.1.4 | Lipids
et al., 2017). Trigonelline has pharmacological effect but its level
significantly decreases after roasting (Mengistu et al., 2020). Lipids affect the stability of the foam in the drink and are important
During coffee roasting, trigonelline induces demethylation of for flavor retention. In addition to having a taste and smell, lipids are
niacin (Vitamin B3 or nicotinic acid), volatile coffee constituents known to retain volatile chemicals within the foam layer. Growing
such as pyridines, pyrrole derivatives, methyl esters of nicotinic circumstances have an impact on lipids, and studies have shown
acid, and other compounds responsible for coffee aroma (Jeszka- that these variables have a negative link with lipid accumulation in
skowron et al., 2020; Mohamadi et al., 2017). Figure 4 below shows coffee beans (Godos et al., 2014; Ren et al., 2019). Arabica coffee
the chemical structure of trigonelline and related nicotinic acid me- has a lipid content that is substantially higher than Robusta coffee
tabolites. Table 1 presents the nonvolatile aroma impact biochemi- at 8%–18% of its dry matter, with triglycerides making up 75% of
cal compositions of Arabica and Robusta coffee and their role in this content and esters of fatty acids diterpenes making up 20%
the perceived sensation. (Kitzberger et al., 2016). The main diterpenes in coffee oil include

TA B L E 1 Aroma impact compounds of roasted Arabica and Robusta coffees and their role in the perceived sensation.

Their amount

Nonvolatile compounds Coffea arabica Coffea canephora Role on perceived sensation

Caffeine 0.6%–1.2% dwb* 2.2%–2.8% dwb Responsible for bitterness, body, and
strength of brewed coffee
Melanoids/humic acid 16.0%–17.0% dwb 16.0%–17.0% dwb Important for roasted coffee color
Carboxylic acids
Citric acid Essential for sourness of coffee
Malic acid
Acetic acid
Chlorogenic acids
Cinnamic acid 3.4%–7.24% dwb 5.17%–14.4% dwb All are responsible for astringency
Caffeic acid
Ferulic acid
Isferulic acid
Sinapic acid and their degradation product
Quinic acid
Trigonelline
Contains two derivatives namely: nicotinic 0.6%–1.3% dwb 0.3%–0.9% dwb Have role on bitterness of coffee
acid and N-methylnicotinamide and nicotinic acid has nutritional
importance
Carbohydrates
Arabinogalactose 43.0%–45.0% dwb 46.9%–48.3% dwb Contribute to the retention of volatiles
Cellulose and play role in viscosity of coffee
brew
Hemicelluloses
Pectins
Lipids
Triglycerides 14.5%–20.0% dwb 11.0%–16.0% dwb Important for viscosity of brew, foam
Terpenes stability, flavor retention

Tocopherols
Sterols
Minerals
Potassium around 40% W/W manganese, 3.5%–4.5% dwb 4.6%–5.0% dwb They catalyze different reactions during
iron, copper coffee storage and roasting

Source: Campa et al. (2004), Sanlier et al. (2019); Yeretzian et al. (2019).
Abbreviation: dwb*, dry weight basis.
|

cafestol, kahweol, and 16-O-methyl cafestol (16-OMC), and a cup early phases (Golon et al., 2014; Hu et al., 2019; Iriondo-dehond
of unfiltered coffee has 3–6 mg of each of these diterpenes (Ren et al., 2021).
et al., 2019). Kahweol, cafestol, and 16-OMC levels varied among Early in the process, the amino group is combined with the carbonyl
various species of coffee, and this has made them a crucial tool group of the reducing sugar, which is then dehydrated to create a Schiff
for identifying them. Studies revealed that Arabica coffees grown base. The Schiff base is then cycled to create N-glucosamine, which
under typical soil and climate circumstances and Arabica coffees is then transformed into 1-amino-1-deoxy-2-ketosaccharide through
with C. canephora introgressions have different diterpene contents an Amadori rearrangement. Amadori compounds are converted to
(Kitzberger et al., 2013, 2016). The chemical structure of common reducing ketones or furfural compounds by a series of reactions that
lipids in coffee is presented in Figure 5. also generate a large number of reactive intermediates (Nakamura &
Kawaharada, 2021). Additionally, Strecker degradation may be ap-
plied to the condensate of the dicarbonyl compound and the amino
4.1.5 | Melanoids acid created by the breakdown of the Amadori compound. Coffee's
Maillard reaction can result in a variety of substances that are good
The Maillard reaction, sometimes referred to as the nonenzymatic for our health, particularly high molecular weight molecules (HMWM),
browning reaction, is frequently experienced during the roasting also known as melanoidins (Bikaki et al., 2021; Hu et al., 2019; Iriondo-
of coffee and many other culinary items. When the temperature of dehond et al., 2021). Figure 6 depicts the schematic representation of
roasting coffee beans reaches roughly 154°C, a complicated reac- the Maillard reaction steps in the formation of melanoids.
tion known as the Maillard reaction occurs between amino com- In addition to LMW chemicals, proteins, and polysaccharides,
pounds and reducing sugars (Golon et al., 2014; Hu et al., 2019). phenols, which take the form of glycosidic bonds, play a significant
This reaction can also occur between aldehydes, ketones, pep- role in the synthesis of melanoidins and make up approximately 10%
tides, proteins, and even ammonia. The polymers formed by this of the total weight (Lima, 2010). A study revealed that the primary
reaction are still a mystery; all that is now known about them is mechanism for the addition of phenolic compounds to HMWM is
the chemical mechanism that results in low- and medium-molecu- transglycosylation reactions (Moreira et al., 2017). The most prev-
lar-weight products. Early stage, middle stage, and ultimate stage alent polysaccharides in coffee beans are galactomannan and type
are three divisions that can be made of them. Hodge developed II arabinogalactan, which when baked with LMW, proteins, and
the Maillard reaction method in the 1950s, which was extensively phenolic chemicals produce melanoidins (Hu et al., 2019). An aver-
used to describe how low-molecular-weight (LMW) Maillard reac- age coffee drinker (four cups/day) can acquire 1.5 g of melanoidins
tion products are produced. It postulated the Maillard reaction's from this source. The estimated quantity of melanoidins per serving

F I G U R E 5 Chemical structure of common lipids in coffee (Silva et al., 2012; Vandeponseele et al., 2020).
|

size for various coffee brew preparations ranges from 99 to 433 mg for its aroma compounds, harvesting and postharvesting practices,
(Iriondo-dehond et al., 2021). The chemical structure of melanoids is sorting, storage, and transport. These parameters adjust the ge-
depicted in Figure 7 below. netic predisposition and affect the biochemical composition of the
green bean as it goes to roasting. Finally, the roasting conditions,
grinding, and extraction process cumulatively alter the aroma of
4.2 | Volatile aroma compounds of coffee the coffee (Girmay et al., 2019; Yeretzian et al., 2019). During
the roasting of coffee, different flavor and aroma compounds
The aroma of coffee is affected by environmental factors such as are formed due to Maillard, thermal degradation, and pyrolysis
climatic factors and soil factors, genetic predispositions of the cof- reactions. The Maillard reaction results in the formation of pyr-
fee that contain a specific set of chemical precursors and bases roles, thiols, pyrazines, pyridines, thiophenes, and furans. Thermal
degradation produces various products of caramelization and a
diverse group of phenolic compounds. The pyrolysis reaction pro-
duces a diverse range of organic compounds, including alcohols,
aldehydes, carboxylic acids, furans, ketones, pyrazines, and pyr-
roles (Toledo et al., 2016; Yeretzian et al., 2019).
One of the most crucial elements for determining coffee
quality is the volatile portion of roasted coffee, and it might be
significant at the time of purchase (Procida et al., 2020). As of
now, approximately 1000 volatile compounds have been identi-
fied as part of the volatile composition of roasted coffee (Toledo
et al., 2016; Wang, Pan, et al., 2022; Wang, Wang, et al., 2022;
Yeretzian et al., 2019). The volatile fraction of the roasted arabica
samples seems to be distinguished by the presence of high levels
of pyridine, diacetyl, propyl formate, acetone, and 2,3-pentanedi-
one, whereas the Robusta samples appear to be distinguished by
the presence of high levels of methylbutyrate, 2,3-dimethylpyr-
azine, and 3-hexanone (Procida et al., 2020). Table 2 below indi-
cates a list of key volatile compounds of roasted Arabica coffee
with their respective aroma descriptor.
Moreover, some volatile compounds formed during coffee
roasting are used as a marker to identify the effect of roasting on
the coffee. 1H-indole is used as an indicator of light roast effect,
4-ethyl-2-methoxyphenol as a scorched effect on coffee, phe-
F I G U R E 6 Schematic representation of melanoid formation due nol as a dark effect of roasting, 3-hydroxy-2-methylpyran-4-one
to Maillard reaction (Tamanna & Mahmood, 2015). (maltol) as a baked effect of roasting, and 2,5-dimethylfuran as an

F I G U R E 7 Chemical structure of melanoids (Moreira et al., 2012).

TA B L E 2 Volatile aroma compounds of roasted coffee.

Key odorants Volatile compounds Aroma descriptor

Aldehyde 2-methylbutanal Rancid, almond-like, toasty

2-methylpropanal Toasty, Caprylic, cheesy, dark chocolate, ethereal, fruity, malty,
pungent
3-methylbutanal Fruity, almond-like, toasty, ethereal, chocolaty, peachy. fatty
(E)-2-nonenal Fatty, green, cucumber, citrus
Acetaldehyde Pungent, ethereal, fresh, lifting, penetrating, fruity, musty
4-methoxybenzaldehyde Sweet, powdery, vanilla, anise, woody, coumarin, creamy
Phenyl acetaldehyde Sweet, fruity, honey, floral, fermented
Propanal Ethereal, pungent, earthy, alcoholic
Acid 2-methylbutryic acid Acidic, fruity, dirty, cheese
3-nethylbutryic acid Cheesy, dairy, acidic, sour, pungent, fruity, stinky
Esters Ethyl-2-methybutyrate Fruit, berry
Ethyl-3-methybutyrate Fruity
Furan Furfural (2-((methylthio)methyl)furan; 2-furfuryl Sweet, brown, woody, bread, caramellic
methyl sulfide)
2-furan, ethanol acetate/furfuryl acetate Smoke, roast, onion, garlic, sulfurous, pungent, vegetable,
horseradish
2-methylfuran Onion, garlic, sulfurous, pungent, vegetable, creamy
5-methyl-2-furan carboxaldehyde/2-methyl furfural Burnt, ethereal (mild), gasoline, acetone, chocolate
Furfuryl formate Sweet, caramellic, bready, brown, coffee-like
Furfuryl methyl ether Ethereal
Furfuryl disulfide Roasted coffee
Sulfur containing Dimethyl trisulfide bis(2-methyl-3-furyl)disulfide Sulfurous, coffee, roasted chicken, meaty, onion, cabbage
compounds Methanol Boiled potato-like, musty, tomato, earthy, vegetable, creamy
Thiols 3-mercapto-3-methyl butyl formate Green blackcurrant, herbal, fruity, roasted, sweaty
2-furfuryl thiol Roasted (coffee-like), sulfurous
2-methyl-3-furanthiol Sulfurous, meaty, fishy, metallic, boiled
3-mercapto-3-methyl butyl acetate Roasty, fruity, sulfurous, sweet
3-methyl-2-butane-1-thiol Sulfurous, smoky, leek, onion
Methanethiol Rotten eggs, meat or fish, cabbage, garlic, cheesy
Thiophene 3-methylthiophene Fatty, wine
Thiazole 2,4-dimethyl-5-ethylthiazole Nutty, roasted, meaty, earthy
Furanone Dihydro-2-methyl-3(2H)-furanone Sweet, bread, buttery, natty
2-ethyl-4-hydroxy-5methyl-3(2H)-furanone Sweet, caramel, candy
(Homofuraneol)
3-hydroxy-4,5-dimethyl-2(5H)-furanone (Sotolone) Extremely sweet, strong caramel, maple, burnt sugar, coffee
4-hydroxy-2,5-dimethyl, 3(2H)-furanone (furaneol) Sweet, candy, caramel, strawberry, sugar
5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone Seasoning-like, caramel-like
(abhexon)
5-ethyl-4-hydroxy-2-methyl-3 (2H)-furanone Sweet, caramel, bread, maple, brown sugar, burnt
Ketone 1-octen-3-one Herbal, mushroom, earthy, musty, dirty
2,3-hexadione Burnt, buttery, caramel, chocolate cream, creamy, fruity, oily, pear,
sweet
2,3-butanedione Buttery, creamy, fatty, oily, sweet, vanilla
2,3-pentandione Butter, caramel, creamy, penetrating, sweet
4-(4-hydroxyphenyl)-2-butanone Sweet fruity, berry, jam, raspberry, ripe, floral (raspberry ketone)
1-(2-furanyl)-2-butanone Rummy

(Continues)
|

TA B L E 2 (Continued)

Key odorants Volatile compounds Aroma descriptor

Norisoprenoid (E)-β-damascenone Honey-like, fruity, apple, rose, honey, tobacco, sweet

Phenolic Guaiacol Phenolic, burnt, smoke, spice, vanilla, woody
compounds 4-ethyl guaiacol Spicy, smoky, bacon, phenolic, clove
4-vinyl guaiacol Spicy, dry woody, fresh amber, cedar, roasted peanut
Vanillin Sweet, vanilla, creamy
Pyrazines 2,3-dimethylpyrazine Nutty, coffee, peanut butter, walnut, caramel, leather
2,5-dimethylpyrazine Cocoa, roasted nuts, roast beef, woody, grass, medical
2,3-diethyl-5methylpyrazine (hazelnut pyrazine) Roasted nuts, musty, meaty, vegetable, roasted hazelnut
2-ethyl-3,5-dimethylpyrazine Roasted nuts
2-ethyl-3,6-dimethyl-pyrazine (3,6-cocoa pyrazine) Potato, cocoa, roasted, nutty
2-methoxy-3,5-dimethylpyrazine (3,5-cocoa pyrazine) Earthy, burnet, almonds, roasted nuts, coffee
2-methoxy-3,2-methylpropyrazine Green, pea green, bell pepper
2-methoxy-3-isopropylpyrazine Earthy, pea, bean
2-ethyl-2ethyl-5-methylpyrazine Earthy
6,7-dihydro-5-methyl-5H-cyclopentapyrazine Roasted nuts, earthy, baked potato, peanut, roasted
Ethylpyrazine Peanut butter, musty, nutty, woody, roasted cocoa
Pyridine Pyridine Fishy
Pyrrole Sweet, nutty, ethereal
1-methylpyrrole Smoky, woody, herbal, negative notes; defective beans
Terpene Linalool Flowery, citrus, orange, Terpene, waxy, rose
Limonene Citrus, herbal, Terpene, camphor
Geraniol Sweet, floral, fruity, rose, waxy, citrus

Source: Yeretzian et al. (2019).

TA B L E 3 Key compounds responsible

Volatile compound Aroma descriptor
for coffee aroma.
2-Methylpropanal Sweet caramel notes
2-Methylbutanal Sweet, caramel notes
3-Methylbutanal Sweet, caramel notes
2-Ethyl-3,5-dimethylpyrazine Earthy notes
2-Ethnyl-3,5-dimethylpyrazine Earthy notes
2,3-Diethyl-5-methylpyrazine Earthy notes
3-Isobutayl-2-methoxypyrazine Earthy notes
2-Furfunylthiol Roasty, sulfury notes
4-Vinylguaiacol Phenolic
Acetaldehyde Fruity, flowery
Propanal Fruity flowery
5-Ethyl-3-hydroxy-4-methyl-2(5H)-furanone/furaneol Sharp

Source: Yeretzian et al. (2019).

underdeveloped defect marker of roasting. However, according to 5 | COFFEE A ROMA IMPAC T COMP OU NDS
different scientific findings, all of the volatile aroma compounds of A ND THEIR HE A LTH B ENEFITS
coffee are not necessary for the aroma of roasted coffee and 12 of
them have been identified as critical for the aroma of coffee. Table 3 5.1 | Caffeine
depicts volatile compounds with their respective aromas and their
absence in coffee individually or as a group has a significant effect Within 45 min of ingestion, caffeine is entirely absorbed by the small
on the aroma (Yeretzian et al., 2019). intestine and stomach and reaches its peak blood levels between
|

15 and 120 min later. Almost all (99%) of the ingested caffeine is ab- variability (Nehlig, 2018). Caffeine metabolism varies greatly between
sorbed into the bloodstream (Acikalin & Sanlier, 2021; DePaula & individuals, owing primarily to differences in CYP1A2 enzyme activity,
Farah, 2019). It is transported throughout the body after being ab- and there has recently been renewed interest in identifying polymor-
sorbed and is then digested in the liver. In the liver cells, caffeine is phisms that influence caffeine metabolism. Some variation in CYP1A2
metabolized to produce uracil derivatives, dimethyl and monometh- activity can be attributed to genetic polymorphisms in the CYP1A2
ylxanthines, and dimethyl and monomethyluric acids (Arnaud, 2011). gene, which can result in increased or decreased enzyme inducibil-
The majority of caffeine and other methylxanthine metabolism pro- ity (Grosso & Bracken, 2005). A gene polymorphism explains a large
cesses are carried out by phase I (cytochrome P450 CYP) enzymes, portion of the variability in CYP1A2 activity. After caffeine consump-
particularly CYP1A2, a significant P450 enzyme that makes up about tion, an A to C substitution at position 163 (rs762551) in the CYP1A2
13% of the total content of this enzyme group in the human liver. gene reduces enzyme inducibility as measured by plasma or urinary
Nearly 90% of caffeine metabolism is carried out by the CYP1A2 iso- caffeine-to-metabolite ratios (Nehlig, 2018).
form (Arnaud, 2011; DePaula & Farah, 2019; Djordjevic et al., 2008). The stimulation of brain activity, mood improvement, and physical
The other routes involve the actions of monooxygenase, N- performance are the most well-known short-term effects of caffeine
acetyltransferase, CYP1A1, CYP2E1, and CYP2A6, among others consumption. Nevertheless, over the past decades, a number of epi-
(Burdan, 2015; Lima & Farah, 2018). The predominant caffeine demiological studies have found a link between moderate coffee con-
metabolites, methylated xanthines and methyluric acids, are elim- sumption and a lower relative risk of developing chronic degenerative
inated in urine, whereas paraxanthine is the main caffeine metab- diseases. Moreover, it is reported to have many of these advantages,
olite in plasma. The first step in caffeine CYP1A2 metabolism is such as a decreased risk of Alzheimer's and Parkinson's diseases (PDs),
3-demethylation, which results in 1,7-dimethylxanthine (paraxan- and there are also hepatoprotective effects via anti-inflammatory and
thine), which accounts for approximately 84% of the major caffeine antioxidant functions (Gökcen & Şanlier, 2019; Tofalo et al., 2016).
metabolites. Caffeine may potentially be converted to theobro-
mine (12%) by the CYP1A2 enzyme (DePaula & Farah, 2019).
CYP2E1 catalyzes the metabolism of theobromine and theoph- 5.1.1 | Psychostimulating effect of caffeine
ylline (4%) by 7-and 1-demethylation of caffeine (Burdan, 2015).
Caffeine can be transformed to 1,3,7-methyluric acid, but to a The stomach and intestines can absorb almost all of the caffeine
lesser extent. The main primary caffeine metabolite, paraxanthine, taken and distribute it throughout the body. Once ingested, caf-
may be demethylated by CYP1A2 to produce the main metabolite, feine will function in a variety of ways in the body, particularly in
1-methylxanthine (70%), which may then be oxidized to 1-methy- the brain. It will antagonize adenosine receptors and affect both
luric acid by xanthine oxidase (Lima & Farah, 2018). the peripheral and central nervous systems because of the struc-
Secondary metabolites, such as 7-methylxanthine (20%), may also tural similarities (Figure 8) between adenosine and caffeine (Gaspar
be metabolized to 7-methyluric acid (Arnaud, 2011; Burdan, 2015). & Ramos, 2015). Mainly, it blocks adenosine receptors that allow
Likewise, paraxanthine can be acetylated by N-acetyltransferase 2 endogenous adenosine to regulate a wide range of physiological
to produce 5-acetylamino-6-formylamino-3-methyluracil, an unsta- processes (Ferre et al., 2018). Adenosine receptors have several
ble molecule that can be nonenzymatically deformylated to produce subtypes, including A1, A2A, A2B, and A3 (Effendi et al., 2020).
5-acetylamino-6-amino-3-methyluracil, or it can be hydroxylated by Caffeine A1 subtypes are primarily located in the central nerv-
CYP2A6 to produce 1,7-dimethyl (Acikalin & Sanlier, 2021; DePaula ous system and peripheral nervous system, particularly in the hip-
& Farah, 2019; Lima & Farah, 2018). pocampus, cerebellum, hypothalamus, and cortex. They are also
Caffeine consumption and its direct effects are clearly influenced found in the kidneys, lungs, bladder, and heart. Inhibition of the A1
by genetics. This modulation occurs at both the pharmacodynamic and subtype has been proven to reduce anxiety, congestive heart fail-
pharmacokinetic levels, and it has been linked to caffeine response ure, and polarized renal dysfunction. It can help improve cognitive

F I G U R E 8 Chemical structures of
adenosine receptor and caffeine.
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F I G U R E 9 Schematic representation of the antagonistic interactions between adenosine A2A and dopamine D2 receptors in striato-
Gpe projection neurons. At the plasma membrane level, stimulation of A2A receptors results in decreased affinity of the dopamine D2
receptor for agonists. At the cytoplasmic level, A2A receptors stimulate, whereas D2 receptors inhibit the production of cAMP. This results
in opposite regulation of the state of phosphorylation of DARPP-32 and downstream target proteins involved in the control of the activity
of striato-Gpe neurons. In the nucleus, the opposite regulation of the cAMP/PKA pathway results in the opposite regulation of CREB
phosphorylation and IEG expression. Green and red arrows indicate positive and negative regulations, respectively (Fisone et al., 2004).

performance and treat Alzheimer's disease (AD) and hypertension protooncogenes, inactivation of tumor suppressor genes, and/or
(DePaula & Farah, 2019). inactivation of genomic stability genes (de Melo Pereira et al., 2020).
The A2A receptor is mostly found in the dopamine-rich region Caffeine inhibits the release of several procarcinogenic cytokines
of brain tissue, the A2B receptor is primarily found in the digestive by increasing the expression of key tumor suppressor proteins,
system, and the A3 receptor is generally present on the surface of including p16, p21, p53, and Cav-1 (Al-Ansari & Aboussekhra, 2014).
inflammatory cells as well as in the spleen, lungs, heart, and other or- In another way, caffeine alters the development of cancer via the
gans. Numerous clinical and animal studies have demonstrated that defense of cells against damage brought on by ROS. In this regard,
caffeine acts as an adenosine receptor inhibitor, altering the expres- coffee is viewed as a possible anticarcinogen and may reduce ROS
sion of various adenosine receptor subtypes and enhancing or atten- through a direct antioxidant impact (de Melo Pereira et al., 2020).
uating their biological effects. It is most notable for its effects on the Moreover, numerous epidemiological studies have shown that
A1 and A2A subtypes. Both the A1 and A2A subtypes are linked to caffeine has anticancer properties through reducing the expression
caffeine's mental stimulant effects, but the A1 subtype plays a more of factor-1, matrix 2-metalloproteinase, and transforming growth
important role (Effendi et al., 2020; Hu et al., 2019). Caffeine can ef- factor in cancer-associated fibroblasts as well as the level of actin
ficiently suppress the A1 and A2A subtype receptors of microglia in in smooth muscle, which are important markers of myofibroblasts,
animal models, which lowers the inflammatory environment caused by inhibiting extracellular signal-regulated kinases-1/2 and -serine/
by these cells and ultimately prevents neurodegenerative disor- threonine kinases (Yu et al., 2011).
ders such as PD (Ren & Chen, 2020). The fundamental framework
of new adenosine receptor antagonists is frequently derived from
the core structure of caffeine. Acute and chronic caffeine interven- 5.1.3 | Caffeine and hepatocellular carcinoma
tion can alter the expression of a number of receptors, including the
5-hydroxytryptamine (5-HT) receptor, the cholinergic receptor, the Consuming coffee is indicated to have a preventative effect on the
opioid receptor, and the GABA receptor (Hu et al., 2019). The mech- onset and progression of liver disease. These effects occur in both
anism of action of antagonistic interactions between adenosine A2A the presence and absence of the chronic hepatitis B and C virus and
and dopamine D2 receptors is shown below in Figure 9. are associated with low levels of the liver enzymes such as alanine
aminotransferase, aspartate aminotransferase, and gamma-glutamyl
transferase as well as hepatocellular carcinoma (HCC; DePaula &
5.1.2 | Anticancer effect of caffeine Farah, 2019; Saab et al., 2014). Coffee's hepatoprotective effects
are thought to be caused by several processes. In the absence of
Procarcinogens or reactive oxygen species (ROS) damage DNA, cellular DNA, oxidized bases accumulate, which is the reason for
which results in the development of cancer. This process involves the link between coffee and HCC. Chromosome instability is a
several steps, such as additional DNA mutations and/or genetic condition caused by oxidative DNA to DNA shortening telomeres
imprints, and is typically accompanied by the activation of (Rudolph et al., 2009). Consuming coffee regularly causes telomere
|

lengthening, which stabilizes chromosomal DNA and stops the In comparison with fast metabolizers, such adverse effects can
evolution of cancer. The presence of caffeine, phenolic metabolites be observed in slow metabolizers at much lower doses, as low as
(CGA), as well as other substances such as the diterpenes kahweol 50 mg or less (Yang et al., 2010). Nevertheless, after repeated con-
and cafestol, all have a role in the mediation of epidemiological sumption, a tolerance to the general effects of caffeine is frequently
research on food (Gressner et al., 2009; Lv et al., 2010). The inverse seen. Upregulation of adenosine receptors has been suggested as
relationship between coffee consumption and HCC is thought to the cause of the poorly understood and highly variable mechanism
be due to caffeine's alteration of liver signaling and inflammatory that increases tolerance in the population (Addicott et al., 2009).
pathways, which lowers circulating levels of inflammatory biomarkers Conversely, even in those who are genetically predisposed, toler-
such as interferon-gamma (IFN-γ), CX3CL1-fractalkine, CCL4, FGF- ance to such an anxiety-inducing impact develops in adults who use
2, and sTNFRII (de Melo Pereira et al., 2020; Loftfield et al., 2015). caffeine frequently. A single nucleotide polymorphism in the gene
encoding the adenosine A2A receptor has been hypothesized to
be the origin of the interindividual heterogeneity in the anxiogenic
5.1.4 | Anti-inflammatory effect of caffeine response to caffeine ingestion (ADORA2A; Erblang et al., 2019). In
any case, only a small percentage of caffeine users ingest such large
Inflammation is connected with and regulated by a variety of cy- levels, and those who are sensitive to caffeine's effects in general
tokines and chemokines; therefore, lowering these markers should or who experience its anxiogenic effects are likely to abstain from
lower the level of total inflammation. Caffeine's ability to reduce in- using it (Bertasi et al., 2021; DePaula & Farah, 2019). As a result, caf-
flammation is assumed to be a result of its ability to inhibit phospho- feine's capacity to cause anxiety in adults is reduced by its self-lim-
diesterase or to work against adenosine receptors (Lee et al., 2014; iting nature.
Monteiro et al., 2016). Additionally, alterations in the synthesis of In terms of sleep, single doses of caffeine in adults of roughly
cell signaling molecules have been related to caffeine's anti-inflam- 100 mg or more (1.5 mg/kg bw/day in a 70 kg adult) have been shown
matory properties (DePaula & Farah, 2019). Studies portrayed that to shorten sleep duration and increase sleep latency in a dose-de-
caffeine enhanced the release of anti-inflammatory cytokines, such pendent way (DePaula & Farah, 2019; Rodak et al., 2021). This may
as interleukin 10 (IL-10; Ouyang et al., 2010; Tauler et al., 2015). be followed by a reduction in sleep quality, as seen by a rise in the
Moreover, caffeine mediates immune suppression of proinflam- frequency of unplanned awakenings and movements. Most people
matory cytokine production, including tumor necrosis factor-alpha appear to not be affected in this way by doses lower than 100 mg.
(TNF-α), interleukin 2 (IL-2), and interferon-gamma (IFN-γ), which However, people who regularly drink large amounts of caffeine are
are crucial for the onset and progression of autoimmune diseases less likely to report sleep problems than people who only sometimes
(DePaula & Farah, 2019). Caffeine has an effect that lowers levels of consume caffeine, which further suggests that people can become
inflammatory cytokines, which are linked to the immune system. In tolerant to the effects of caffeine on this parameter (DePaula &
this respect, a study found that mice's macrophage cells exposed to Farah, 2019).
0.1–1.2 mM caffeine for 24 h had lower levels of IL-6, IL-3, IL-13, and
ROS (Samieirad et al., 2017).
5.2 | Chlorogenic acid

5.1.5 | Potential adverse effects of caffeine on On average, the stomach or upper gastrointestinal tract absorbs
mood, behavior, and sleep one-third of the CGA consumed by drinking coffee. However, this
absorption is partially dependent on hydrolysis, and some of the
Various studies have been conducted on the impact of caffeine on CGA is broken down by the intestinal microbiota before entering
adult mood, and it has been found that the stimulant effects of the blood again and being reabsorbed and converted by the liver
caffeine are related to the release of neurotransmitters like norepi- into ferulic acid, dihydrocaffeic acid, 3-hydroxyphenylpropionic
nephrine, dopamine, and serotonin as well as its stimulating effects acid, and coumaric acid (Farah & de Paula Lima, 2019; Nwafor
(Alasmari, 2020). Although ingesting small to moderate amounts of et al., 2022). Additionally, CGA is further conjugated with sulfate,
caffeine usually results in pleasant feelings, larger amounts taken glucuronic acid, or other compounds following hydrolysis or a lack
all at once or within a short period of time can cause or aggravate thereof and is absorbed in the colon and other organs (Mateos
jitteriness, insomnia (especially in caffeine abstainers), nervous- et al., 2006; Sadeghi et al., 2018). Moreover, in mammals, phase II
ness, and anxiety (Bertasi et al., 2021; Chaudhary et al., 2016). This metabolism or resorption of the metabolites generated by the in-
is especially true for people who already have psychiatric anxiety testinal flora by the intestine occurs (Clifford et al., 2020; Farah &
disorders, but it can also happen to healthy adults who are not de Paula Lima, 2019). Finally, the liver absorbs metabolites through
regular caffeine users. Between 400 and 2000 mg of caffeine per blood circulation (Farah & de Paula Lima, 2019; Zeng et al., 2022).
day, the range of doses thought to cause anxiety and mood changes CGA is one of the bioactive components of coffee with an anti-
differs greatly among writers and government standards (DePaula oxidant property that is frequently linked to anti-inflammatory,
& Farah, 2019). antibacterial, antihypertensive, neurodegenerative diseases, and
|

F I G U R E 1 0 Antioxidant activity
mechanism of action of CGA (Rashidi
et al., 2022).

antioxidant activities. In addition, it inhibits the buildup of fat and effects on gut health and the microbiota (Ludwig et al., 2013; Mills
modifies the metabolism of glucose (Acikalin & Sanlier, 2021; Hu et al., 2015). Intestinal inflammation frequently results in impaired
et al., 2019; Zeng et al., 2022). intestinal barrier performance and elevated permeability, which
encourages the development of illnesses. There are three basic
ways that CGA enhances gut barrier performance. First, CGA
5.2.1 | Antioxidant activity works by inhibiting mucosal inflammation and the expression
of inflammatory factors, including the inhibition of the toll-like
Numerous experiments have been done to assess the antioxi- receptor (TLR4)/nuclear factor kappa-B (NF-κB) pathway or the
dant activity of CGAs, both in vitro and in vivo (Cha et al., 2014; phosphorylation of the extracellular regulated protein kinases
Liang & Kitts, 2015; Rojas-Gonz et al., 2022; Xu et al., 2012). (ERK1/2)-signal transducer and activator of antioxidant capacity. It
CGAs have a comparable free radical-scavenging effect as ascor- also increases glutathione peroxidase (GSH)-Px and catalase (CAT;
bic acid. Additionally, CGAs have the ability to chelate transi- Chen, Xie, et al., 2018; Chen, Yu, et al., 2018; Liang & Kitts, 2018;
tion metals like Fe 2+ to neutralize free radicals and stop chain Qader et al., 2020). Lastly, it encourages intestinal cells to express
reactions (Rojas-Gonz et al., 2022). According to in vitro studies, the tight junction proteins occludin and zonula occludens (ZO)-1
CGAs may protect against DNA damage as well as the oxidation (Wu et al., 2018; Zeng et al., 2022). Figure 11 depicts proposed
of low-density lipoproteins (LDL) brought on by various oxidiz- mechanism of CGA-attenuated intestinal inflammation and injury
ing agents (Cinkilic et al., 2013; Gordon & Wishart, 2010). The induced by oxidative stress.
most significant CGA in coffee, 5-CQA, has the ability to neu-
tralize peroxynitrite (ONOO-), superoxide anions (O2•-), hydroxyl
radicals (•OH), and 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH; 5.2.3 | Neurodegenerative disease protection
Cha et al., 2014; Rojas-Gonz et al., 2022), and protect DNA
from oxidative stress damage (Liang & Kitts, 2018; Rojas-Gonz Inflammation and oxidative stress are significant contributors to
et al., 2022; Xu et al., 2012). Antioxidant activity mechanism of the incidence and progression of neurodegenerative illnesses like
action of CGA is indicated in Figure 10. AD and PD (Li et al., 2021). Inflammatory variables cause excessive
microglial activation, an overabundance of ROS, glutamate toxicity,
and nerve cell injury. CGA reduces oxidative damage brought on by
5.2.2 | CGA and gut health microglia and encourages the inactivation of c-Src tyrosine kinase in
these cells (Socodato et al., 2015). One of the ways CGA controls the
The intestine is home to tens of thousands of bacteria. They abnormal microglia function may be by preventing activation of the
are the primary areas of host–microbiota interactions, cohabit NF-κB/P38 MAPK inflammatory axis and by suppressing the release
harmoniously with each other's advantages, and support intestine of inflammatory proteins like TNF-α and IL-1β. Additionally, in BV2
digestion, immunity, and neuronal functions (Zhou et al., 2020). microglia, CGA suppresses the expression of nitric oxide synthase
CGA plays a significant “probiotic” role in the gut under the (NOS) and COX-2 in a dose-dependent way and prevents the pro-
influence of the stomach and gut bacteria, with particular regulatory duction of nitric oxide (Kim et al., 2015).
|

F I G U R E 1 1 A model of the proposed

mechanism of chlorogenic acid (CGA)-
attenuated intestinal inflammation
and injury induced by oxidative stress
CGA protects the intestinal epithelium
against oxidative stress-induced injury
via regulating the phosphatidylinositol-
3-kinase (PI3K)/protein kinase B (Akt)/
nuclear factor erythroid-derived-related
factor 2 (Nrf2) signaling pathway; CGA
attenuates the intestinal inflammation
by coregulating the PI3K/Akt/heme
oxygenase-1 (HO-1) and NF-kappa-B
inhibitor alpha (Iκ-Bα)/nuclear factor-κB
(NF-κB) signaling pathway (Chen et al.,
2021).

F I G U R E 1 2 Cardiovascular vascular
disease prevention mechanism of action
of CGA (Li et al., 2020).

5.2.4 | Role of CGA in type-2 diabetes and It also contributes to the metabolism of lipids by lowering serum
cardiovascular disease and hepatic triglyceride, LDL cholesterol, and LDL oxidation levels,
activating lipid metabolism in the liver, and inhibiting lipid absorption
CGA contributes to the metabolism of glucose by promoting glu- in the small intestine (Gökcen & Şanlier, 2019) and encourages lipid
cose uptake in both insulin-sensitive and noninsulin-sensitive adi- metabolism to prevent obesity and heart disease. For example, a sig-
posity (Gökcen & Şanlier, 2019) and also increases insulin secretion, nificant risk factor in the pathogenesis of arteriosclerosis is the oxi-
decreases insulin tolerance, and activates or inhibits the body's dative alteration of LDLs, and an in vivo study with 11 healthy male
enzyme activity to promote glucose metabolism, lowering blood students indicated that CGAs can protect cardiovascular disorders
glucose levels, and treating diabetes by reducing insulin tolerance by reducing the body's level of LDL cholesterol (Yukawa et al., 2004).
(Jin et al., 2015). It is believed that one of the most significant met- Foam cell production and oxidative stress are the two main
abolic routes blocks the glucose-6-phosphate system, delaying causes of the multifactorial inflammatory illness atherosclerosis.
the absorption of glucose in the intestine (Habtemariam, 2019). By causing cholesterol outflow to lipid-poor apolipoproteins, such
Additionally, a rat model research revealed that CGAs can directly as ApoA1, foam cell development can be prevented. Cholesterol
block blood glucose levels to lower them and by inhibiting the en- transporters ABCG1 and ABCA1 are crucial in mediating choles-
zyme glucose-6-phosphatase involved in hepatic gluconeogenesis terol efflux to high-density lipoprotein. Nuclear transcriptional
(Hu et al., 2019). factors LXRα and PPARc control the expression of these molecules
|

(Bobryshev et al., 2016). It has been demonstrated that CGA dramat- of NF-κB. The effectiveness of CGA, caffeic acid, and kahweol is via
ically raises the mRNA levels of PPAR, LXRα, ABCA1, and ABCG1, preventing NF-κB-induced activation of proinflammatory biomark-
as well as PPAR's transcriptional activity. Additionally, a cholesterol ers (de Melo Pereira et al., 2020), As a result, they manage numer-
efflux assay revealed that the main metabolites caffeic, ferulic, and ous inflammatory diseases, such as acute liver injury, gastrointestinal
gallic acids greatly increased cholesterol efflux from RAW264.7 disease, and endothelial dysfunction (de Melo Pereira et al., 2020; Di
cells. According to these findings, CGA significantly slows the devel- Paola et al., 2010; Xu & Chen, 2010). The anticancer effect mecha-
opment of atherosclerosis in ApoE/E mice and increases cholesterol nism of action of CGA is shown below in Figure 13.
efflux from RAW264.7 macrophages (Lukitasari et al., 2021; Wu
et al., 2014). CGA cardiovascular vascular disease prevention mech-
anism of action is indicated in Figure 12. 5.3 | Trigonelline

The amount of trigonelline synthesized in the pericarp is significantly

5.2.5 | Anticancer effect of CGA and diterpenes higher than that in the seeds, but part of the pericarp-produced trig-
onelline can be transferred to the seeds, resulting in a higher level
In combination with diterpenes, CGAs, particularly 5-CQA, have a of trigonelline in seeds than in the pericarp. Quinolinic acid, an inter-
significant role in the production of enzymes in phase II metabo- mediate formed from the pyrimidine nucleotide, enters the pyridine
lism that are responsible for the endogenous antioxidant defenses nucleotide cycle, where it undergoes the following steps: nicotina-
and anticarcinogenic action by inhibiting DNA methyltransferase (de mide → nicotinic acid → nicotinic acid mononucleotide (NaMN) → nic-
Melo Pereira et al., 2020). Moreover, CGA, caffeic acid, and kahweol otinic acid → adenine dinucleotide (NaAD) → NAD → nicotinamide
manage inflammatory reactions in the body by preventing the re- mononucleotide (Zheng et al., 2004).
lease of specific inflammatory mediators like TNF-α, IL-6, and IL-1 Trigonelline reported to prevent cardiovascular disease, neuro-
(Nwafor et al., 2022). These proinflammatory biomarkers are acti- protection, and anticarcinogen effects. In diabetic rats, trigonelline
vated by the inflammation of tissue induced by signaling activation controls key enzymes involved in the metabolism of glucose and

F I G U R E 1 3 Anticancer effect mechanism of action of CGA (Wang, Pan, et al., 2022; Wang, Wang, et al., 2022).
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lipids, including glucokinase, glucose-6-phosphatase, fatty acid syn- downregulating the crystal receptors on the apical membranes of
thase, and carnitine palmitoyl transferase. This action results in a re- renal tubular cells. Trigonelline may have a higher inhibitory effect
duction in blood sugar, cholesterol, and blood lipid levels (Yoshinari on crystallization than coffee since it has the potential to decrease
et al., 2009; Zhou et al., 2011). crystal mass, a more important crystallization index than crystal size
(Peerapen et al., 2022).

5.3.1 | Anticancer effect of trigonelline

5.4 | Diterpenes
Trigonelline has two primary anticancer effects that it achieves
without directly killing cancer cells through cytotoxicity. One is Small intestine absorbs about 70% of the amount of cafestol and
to stop cell invasion, which is a key factor in the proliferation of kahweol consumed (Ren et al., 2019; Socala et al., 2021). Various
cancer cells (Hirakawa et al., 2005). The other is to control tran- researches have focused on diterpenes, particularly those describ-
scription factor Nrf2 expression. In response to cell invasion, the ing connections to human health. There have been both positive
transcription factor Nrf2 is activated to defend cells from damage. and negative consequences (Acikalin & Sanlier, 2021). In association
Nevertheless, because cancer cells also have the Nrf2 factor, chem- with caffeine, the diterpene compounds such as kahweol and cafes-
otherapy frequently inhibits its activity. Trigonelline can decrease tol are reported to lower the risk of colon cancer (Lee et al., 2012).
the expression of Nrf2 in cancer cells and enhance the effects of However, the diterpenes kahweol and cafestol can have harmful ef-
chemotherapy, according to an investigation employed on H6c7 fects on health, such as raising LDL and total cholesterol, and maybe
pancreatic duct cells and pancreatic carcinoma cell lines as mod- a potential risk of inducing some cardiovascular disease (Godos
els (Arlt et al., 2013). In addition, trigonelline has been proven to et al., 2014; Penson et al., 2018; Ren et al., 2019).
cross the blood–brain barrier and enter the brain, which can help Among the diterpene compounds, cafestol exhibits a choles-
rats with their memory and have neuroprotective effects but does terol-increasing impact by lowering the expression and activity of
not fully explain how it works. cholesterol 7-alpha-hydroxylase, the rate-limiting enzyme in the for-
mation of bile acids (Acikalin & Sanlier, 2021; Karabudak et al., 2015).
Fortunately, the filtration procedure considerably lowers the
5.3.2 | Trigonelline in minimizing oxidative stress amounts of kahweol and cafestol in coffee (Zhang et al., 2012). By
removing the foreign elements from the body, filtered coffee can
Moreover, trigonelline was found to minimize oxidative stress by assist the human body defends itself against the damaging effects
boosting antioxidant enzyme activity and have a scavenging effect these compounds have on blood lipids and boost the immune sys-
on ROS in a study conducted on rats (Zhou et al., 2013). The activa- tem (Acikalin & Sanlier, 2021). Moreover, numerous researches have
tion of the Nrf2 pathway, on the other hand, has been proposed as shown that cafestol and kahweol have a variety of pharmacological
one of the most crucial defense mechanisms against oxidative stress, effects, such as anti-inflammatory, antiangiogenic, and antitumori-
and trigonelline defends the organism from oxidative stress by acting genic properties (Acikalin & Sanlier, 2021; Ren et al., 2019; Socala
as an inhibitor of nuclear factor erythroid 2-related factor 2 (Nrf2; et al., 2021). Figure 14 shows the bioactivities and targets of cafestol
Boettler et al., 2011). These characteristics explain why trigonelline and kahweol.
not only has a favorable impact on immune system cells but also low-
ers the likelihood of autoimmune disease (Acikalin & Sanlier, 2021).
5.4.1 | Anticancer effect of diterpenes

5.3.3 | Trigonelline in inhibition of kidney The growth and migration of prostate cancer cells were decreased
stone formation by kahweol acetate and cafestol in a dose-dependent manner. The
treatment combination using kahweol acetate and cafestol syner-
A recent study finding depicts the function of trigonelline in inhibi- gistically inhibited proliferation and migration of cancer cells in
tion of kidney stone formation. Trigonelline significantly decreased mice. The inhibition is via the induction of apoptosis, prevention of
the size, number, and mass of calcium oxalate monohydrate (COM) the epithelial–mesenchymal transition, and a decline in androgen
crystals during crystallization. The smaller number of COM crystal receptor. This reduced nuclear androgen receptor in androgen re-
receptors on the apical membranes of the trigonelline-treated cells ceptor-positive cells (Iwamoto et al., 2019; Izumi & Mizokami, 2019).
affirmed the downregulation of some of these crystal receptors by Additionally, cafestol and kahweol acetate decreased chemokine re-
trigonelline. Trigonelline also dose dependently inhibited crystal ceptors (CCR2 and CCR5) without changing their ligands, CCL2 and
growth and crystal-cell adhesion. These findings demonstrate how CCL5. Furthermore, oral treatment of kahweol acetate and cafestol
trigonelline inhibits the formation of kidney stones by preventing considerably slowed the growth of tumors, according to the results
COM crystallization, crystal growth, and crystal-cell adhesion via of the xenograft trial (Iwamoto et al., 2019).
|

F I G U R E 1 4 Diagram showing bioactivities and targets of cafestol and kahweol. Cafestol and kahweol raise human serum lipid level and
show extensive anti-inflammatory, anticancer, and potential antidiabetic activities (Ren et al., 2019).

5.4.2 | Anti-inflammatory effect of diterpenes cytotoxicity tests performed on RAW 264.7 macrophages (>90%
cell viability; Kim et al., 2004; Rajapakse et al., 2008). By decreasing
Activated inflammatory corpuscles play a major role in mediating the expression of COX-2 and iNOS protein as well as the mRNA lev-
inflammation, which is a protective response of bodies to stimu- els of these enzymes, cafestol and kahweol were found to suppress
lus. When a pathogen invades, macrophages release proinflamma- the production of PGE2 and NO. This was shown by RT-PCR and
tory cytokines like IL-1 and TNF-α or inflammatory mediators such WB. They verified that kahweol also showed a sizable anti-inflamma-
as NO and PGE2, which are essential for enhancing the body's first tion effect in vivo using a rat model of acute air pouch inflammation
response. Although this immune response is a protective defense brought on by carrageenan (El-Huneidi et al., 2021; Kim et al., 2006;
mechanism, excessive inflammation is unmistakably linked to a num- Ren et al., 2019).
ber of immunological disorders, including cancer, cardiovascular dis-
ease, atherosclerosis, autoimmune diseases, allergic reactions, and
infectious diseases (El-Huneidi et al., 2021; Ren et al., 2019). 5.5 | Melanoids
The activation of various inflammatory signaling pathways by
lipopolysaccharide (LPS)-induced macrophages can be utilized to The high MW products of the Maillard reaction often have low
assess the anti-inflammatory effects of various medications. LPS- bioavailability (Aljahdali & Carbonero, 2019). Melanoidins have
induced macrophages produce the essential inflammatory modula- been detected in rat urine in both in vitro and in vivo experiments,
tors NO and PGE2 and the stimulation of iNOS and COX-2 amplifies indicating that melanoidins with lower MW are only partially
their synthesis to a large degree (Rajapakse et al., 2008). In a dose-de- absorbed (Iriondo-dehond et al., 2021). However, the majority of
pendent manner, cafestol and kahweol can considerably reduce the melanoidins bypass superior digestion, make it to the colon intact,
production of PGE2 and NO in LPS-activated macrophages. Cafestol and are then retrieved in feces (Pastoriza & Rufián-Henares, 2014;
and kahweol demonstrated no negative impact on cell viability in Pérez-Burillo et al., 2020). Melanoidins can enter the colon intact
|

and serve as substrates for the gut flora, producing chemicals that Furthermore, melanoidins have been shown to reduce blood
are connected to antioxidant activity (Alves et al., 2021; Castaldo pressure by regulating the in vitro activity of the angiotensin-I-con-
et al., 2021; Iriondo-dehond et al., 2021; Pérez-Burillo et al., 2020; verting enzyme and to prevent colon cancer by inhibiting the in vitro
Wang et al., 2011). Before being metabolized by the intestinal activity of the family of endo-peptidases known as matrix metal-
microbiota during the digestion of coffee brew melanoidins, loproteases (MMPs), which is essential for the development and
polyphenolic compounds can be liberated, leading to the creation metastasis of tumors (Rufian-Henares & Morales, 2009). In living
of metabolites with improved biological properties relative to the organisms, coffee melanoidins have a variety of biological activ-
parental molecule (Castaldo et al., 2021). ities. However, the complexity of their structures significantly re-
stricts our understanding of their biological activities, thus it would
be worthwhile to carry out more systematic research studies in the
5.5.1 | Antioxidant effect of melanoidins future (Hu et al., 2019).

Melanoidins have been shown to have antioxidant effects on the

body in studies using animal models. Their capacity for metal chela- 6 | DISCUSSION
tion and free radical scavenging may be the mechanism. Additionally,
it has been discovered that the copolymerization of phenolic com- Various chemical compounds of coffee are reported to have an im-
pounds like CGAs accounts for a major portion of their antioxidant pact on the perceived aroma of the coffee. Both C. arabica and C.
effect (Iriondo-dehond et al., 2021). The maximum antioxidant activ- canephora vary in their biochemical compositions, and they exhibit
ity was exhibited by low molecular weight compounds that were lib- different flavor profiles. As a result, consumer preferences for cof-
erated from melanoidins following gastrointestinal digestion, even fee types may differ. One of the primary coffee qualities that af-
more so than by substances that were ionically linked to melanoidins fect consumers' acceptability is its bitterness. Caffeine is the major
(Rufian-Henares & Morales, 2009). aromatic compound of coffee that contributes to its bitterness. The
Colon cancer, atherosclerosis, and liver damage are among free amount of caffeine in roasted Robusta beans doubles that of roasted
radical-induced disorders that melanoidins effectively protect; this Arabica beans. This explains a significant percentage of the stronger
action may be attributed to the bonded CGAs (Daglia et al., 2008; bitterness often present in coffee brews made with Robusta beans
Itzkowitz, 2011). By preventing the release of inflammatory factors, (Seninde & Chambers IV, 2020). Due to this characteristic of the cof-
melanoidins can help prevent disorders brought on by bodily inflam- fee, Arabica coffee has dominated the world coffee market share
mation. Additionally, through activating Nrf2-regulated signaling and is preferred over Robusta. Even though, Arabica and Robusta
pathways in a variety of cell types, including intact gut tissue, mela- coffee have been shown to have different levels of biochemical com-
noidins may also boost the antioxidative capability within the cell position, and some studies revealed that their ability to reduce ROS
(Sauer et al., 2013). was comparable, but the level of roasting seemed to have the great-
Due to their antioxidant properties, melanoidins, both soluble est influence on the antioxidant impact (Henrique et al., 2022).
and insoluble, can serve as useful dietary fibers to squelch radical Numerous scientific study reports demonstrated the
species in the gastrointestinal system. In the upper gastrointestinal health-beneficial effects of coffee chemical compounds, particu-
tract, in which they can interact with the various microbial species larly those involved in coffee's perceived aroma (Table 4). They
found in the hindgut, melanoidins escape digestion and exhibit are shown to have a protective effect and reduce the risk of the
the characteristics of soluble dietary fibers. Moreover, a portion world's most common public health complications such as type
of the coffee melanoidins is also fermented by microbes in the gut 2 diabetes, cancer, and cardiovascular disease. Moderate intake
(Gniechwitz et al., 2008; Reichardt et al., 2009). (3–4 cups/day) of filtered coffee is recommended for a healthy
adult to benefit from coffee consumption. However, the amount
may vary depending on the physiological condition and health
5.5.2 | Antibacterial effect of melanoidins status of the consumer. The caffeine content of one cup of cof-
fee varies depending on geographical region and preparation
Melanoids reported to have an antibacterial effect and three distinct method. A cup of coffee contains 140 mg of caffeine in Northern
methods were discovered for how they might create antibacterial Europe and the United Kingdom, 85 mg of caffeine in the United
action through chelation with metal ions: (1) Melanoidins chelate States, and around 50 mg in Southern Europe (Coppi et al., 2023).
with ions in the medium at low concentrations to mediate antibacte- Consequently, the European Food Safety Authority (EFSA) has es-
rial activity. (2) Melanoidins chelate with the siderophore-Fe3+ com- tablished safe levels of caffeine consumption in the general popu-
plex in bacteria that can produce siderophores, lowering the activity lation. Adults should limit their caffeine consumption in one sitting
of the bacteria. (3) Higher levels of coffee melanoidin can destroy to 200 mg (about two regular 125 mL cups of coffee) and 400 mg
cell membranes, liberate intracellular molecules, and remove Mg2+ throughout the day. Pregnant women should not consume more
from the outer membrane (Rufian-Henares & de la Cueva, 2009). than 200 mg of caffeine per day, and children and adolescents
20

TA B L E 4 Overview of in vivo and in vitro study on the health benefits of coffee and their proposed mechanism of action.
|

Coffee bioactive
compound Study Study type Proposed mechanism of action References

Caffeine Caffeine inhibits cell proliferation and Both in vitro and Caffeine (1 mg/mL) treatment inhibited glioma cell proliferation via G0/G1 cell Ku et al. (2011)
regulates PKA/GSK3β pathways in in vivo cycle arrest by inhibiting Rb phosphorylation. Caffeine also caused apoptosis by
U87MG human glioma cells activating caspase-3 and cleaving poly(ADP-ribose) polymerase (PARP). Caffeine
also phosphorylated glycogen synthase kinase 3 beta (GSK3β) serine 9. Caffeine-
induced GSK3βser9 phosphorylation was inhibited by H89, a pharmacological
inhibitor of protein kinase A (PKA), suggesting that the mechanism may involve a
cAMP-dependent PKA-dependent pathway. Caffeine-treated tumors had lower
proliferation and higher apoptosis in vivo than vehicle-treated tumors
Caffeine Low concentration of caffeine inhibits the In vitro Caffeine (<412 μM) may slow the progression of HCC via the Akt signaling pathway Dong et al. (2015)
progression of hepatocellular carcinoma
Caffeine Caffeine suppresses the progression of In vitro Caffeine (0.1 and 0.5 mM) inhibited cell invasion in U-87MG, GBM8401, and Cheng et al. (2016)
human glioblastoma LN229 cultures. Caffeine reduced cathepsin B mRNA, protein expression, and
activity. Caffeine treatment also increased mRNA and protein expression of
tissue inhibitor of metalloproteinase-1 (TIMP-1) while decreasing mRNA and
protein expression of matrix metalloproteinase-2 (MMP-2). Caffeine reduced
the expression of Ki67, p-p38, phosphorylated extracellular regulated protein
kinases (p-ERK), and membranous integrins β1 and β3. The Rho-associated
protein kinase (ROCK) inhibitor Y27632 inhibited caffeine-mediated reductions
in cathepsin B, phosphorylated focal adhesion kinase (p-FAK), and p-ERK, as
well as invasion. Furthermore, caffeine reduced tumor size, cathepsin B, and
Ki67 expression in an animal model. Caffeine inhibited glioma cell invasion and
tumor growth in an orthotopic xenograft animal model, indicating that it has
anticancer potential in glioma therapy
Caffeine Caffeine prevents LPS-induced inflammatory Both in vitro and Caffeine (1000 and 1200 μM) reduced the inflammatory mediator nitric oxide Hwang et al. (2016)
responses in RAW264.7 cells and in vivo (NO) induced by LPS. Caffeine treatment also reduced the expression of
zebrafish proinflammatory genes such as inducible nitric oxide synthase (iNOS),
cyclooxygenase-2 (COX-2), interleukin (IL)-3, IL-6, and IL-12, as well as IL-6
secretion and phosphorylated p38MAPK expression in RAW264.7 cells treated
with LPS. Caffeine inhibited nuclear factor κB (NF-κB) translocation via κ-IBα
phosphorylation. Caffeine also inhibited LPS-induced NO production in zebrafish
Caffeine Caffeine shows an anti-inflammatory activity In vitro The key proinflammatory cytokines IL-6 and 1L-1β were reduced by caffeine treatment Almeida et al. (2021)
in Swiss mice (0.5 and 5 mg/kg). As a result of the low mRNA expression of iNOS in splenocytes,
the involvement of nitric oxide in the bactericidal action was ruled out
Caffeine Caffeine shows anti-inflammatory effect on In vivo Caffeine (6 mg/kg) pretreatment decreased the expression of Il1b, Il6, and Eichwald et al. (2023)
muscle under lipopolysaccharide-induced Tnfa while increasing the expression of Il10 and Il13. Caffeine's negative
inflammation modulation of the inflammatory response included a decrease in inflammasome
components, Asc and Casp1, promoting an anti-inflammatory scenario.
Caffeine treatment promoted the upregulation of adenosinergic receptors,
Adora1 and Adora2A, which was offset by LPS. Furthermore, there was a
significant increase in Adora2A promoter hypermethylation, which could be a
compensatory response to increased Adora2A expression
MAKISO et al.

Coffee bioactive
compound Study Study type Proposed mechanism of action References

Chlorogenic acid Chlorogenic acid shows an anticancer effect In vitro CGA (50 μM) significantly reduced HIF-1β and SPHK-1 expression as well as Lee et al. (2017)
SPHK-1 activity in hypoxia-induced DU145 cells. Furthermore, CGA inhibited
the phosphorylation of AKT and GSK-3, which are associated with HIF-1β
stabilization, and had a concentration-dependent effect on SPHK-1. SPHK-1
signaling pathway inhibition of HIF-1β by CGA using SPHK-1 siRNA and SPHK
inhibitor (SKI). CGA inhibited hypoxia-induced angiogenesis by decreasing VEGF
secretion and cellular expression
Chlorogenic acid Chlorogenic acid induces reactive oxygen In vitro CGA (1000 μmol/L) inhibited HCT116 and HT29 cell viability in a dose-dependent Hou et al. (2017)
species generation and inhibits the manner. ROS production was induced by CGA. Furthermore, CGA induced
viability of human colon cancer cells S phase cell cycle arrest and suppressed extracellular signal-related kinase
activation in both cell types, which likely contributes to the ROS-induced
viability inhibition caused by CGA treatment
Chlorogenic acid Chlorogenic acid improves intestinal In vivo CGA (1000 mg/kg) supplementation reduced serum tumor necrosis factor-α, Chen, Xie, et al. (2018,
development in weaned pigs interleukin-6, and interleukin-1IL-6 concentrations while increasing serum Chen, Yu,
immunoglobulin G and jejunal secretory immunoglobulin A concentrations in et al., 2018)
comparison to the control group. CGA, on the other hand, increased jejunal
villus height, duodenal and jejunal villus width, and jejunal and ileal villus height/
crypt depth. CGA not only reduced the number of duodenal and jejunal cells
in the G0G1 phase, but also increased the number of jejunal and ileal cells
in the S phase. CGA supplementation reduced the percentages of late and
total apoptotic cells in the jejunum, as well as the ratio of B-cell lymphoma-2-
associated X protein to B-cell lymphoma-2 (Bcl-2) in the duodenum and jejunum.
Finally, CGA increased Bcl-2 expression in the duodenum and jejunum while
decreasing caspase-3, caspase-9, and Fas expression in the jejunum and ileum
Chlorogenic acid Chlorogenic acid inhibits growth of 4 T1 In vitro Chlorogenic acid (200 μM) increased Bax expression while decreasing Bcl2 Changizi et al. (2020)
breast cancer cells expression in 4 T1 cells. P53 and caspase3 expression increased in 4 T1 cells
Chlorogenic acid Chlorogenic acid shows antitumor activity In vitro and CGA (80 μM) inhibits the phosphorylation of p-protein kinase C alpha (PKCα), Akt, Tan et al. (2019)
in vivo and the expression of Rictor and F-Actin, all of which are known to activate cell
growth and organize the Actin cytoskeleton
Chlorogenic acid Chlorogenic acid inhibits the proliferation of Both in vitro and Chlorogenic acid (400 μM) inhibits the binding of annexin A2 to the p50 subunit, Wang et al. (2020)
human lung cancer A549 cell lines in vivo thereby inhibiting the expression of downstream antiapoptotic genes cIAP1 and
cIAP2 of the NF-B signaling pathway in A549 cells. Furthermore, chlorogenic
acid inhibited the binding of annexin A2 to Actin, potentially inhibiting tumor
cell cycle and migration
Chlorogenic acid Chlorogenic acid inhibits proliferation in In vitro CGA (300 μM) effectively suppressed the noncanonical NF-B signaling pathway Jiang et al. (2021)
human hepatoma cells while activating HCC mitochondrial apoptosis via upregulation of the BH3-only
protein Bcl-2 binding component 3 (BBC3)
|

(Continues)
21

TA B L E 4 (Continued)

Coffee bioactive
compound Study Study type Proposed mechanism of action References

Trigonelline Trigonelline protects the cardiocyte from In vitro The addition of TG (25–100 μM) to cells reduced H2O2-induced cell death and Ilavenil et al. (2015)
hydrogen peroxide-induced apoptosis in increased antioxidant activity. Furthermore, during H2O2-induced oxidative
H9c2 cells stress, TG regulated the apoptotic genes caspase-3 and caspase-9, as well as the
antiapoptotic genes Bcl-2 and Bcl-XL
Trigonelline Trigonelline reduced diabetic nephropathy In vivo In T2DM rats, trigonelline (40 mg/kg/day) induced the protein expression of Li et al. (2019)
and insulin resistance in type 2 diabetic peroxisome proliferator-activated receptor (PPAR) and suppressed the protein
rats expression of glucose transporter 4, but suppressed the protein expression of
tumor necrosis factor and leptin
Trigonelline Trigonelline-loaded micelles on Nrf2 In vitro Trigonelline micelles (500 nM) reduced Nrf2 mRNA expression in resistant colon Pirpour Tazehkand
suppression to overcome oxaliplatin cancer cells by nearly twofold. Furthermore, trigonelline reduced Ho-1 mRNA et al. (2020)
resistance in colon cancer cells expression threefold
Trigonelline Trigonelline induces autophagy to protect In vitro In HMCs induced by high glucose, TG (800 μM) improved proliferation, increased Chen, Luo, et al. (2021),
mesangial cells in response to high the expression of miR-5189-5p, decreased HIF1AN, and restored autophagy Chen, Ma,
glucose inhibition. HIF1AN expression was inhibited by miR-5189-5p mimics, while et al. (2021)
HIF1AN expression was increased by miR-5189-5p inhibitor. MiR-5189-5p
mimics significantly improved HMC proliferation induced by high glucose,
reduced p-AMPK, SIRT1, LC3B, and Beclin-1 relative protein expression, and
significantly increased p62 relative protein expression
Trigonelline Trigonelline inhibits Nrf2 via EGFR signaling In vitro In both A549 and NCIH460 cells, trigonelline (50 μM) reduced nuclear accumulation Fouzder et al. (2021)
pathway and augments efficacy of of pNrf2 by fourfold and downregulated Nrf2 targeted genes. Trigonelline
Cisplatin and Etoposide in NSCLC cells inhibited Nrf2 by reducing EGFR signaling pathway activation and its
downstream effector ERK 1/2 kinase. Trigonelline in combination with Cisplatin/
Etoposide inhibited NSCLC cell proliferation (A549, NCIH460, and NCIH1299)
without causing cytotoxicity in normal lung epithelial cells (L132)
Trigonelline Trigonelline prevents kidney stone formation In vitro Trigonelline (100 μM)) significantly reduced COM crystal size, number, and mass Peerapen et al. (2022)
processes during crystallization by inhibiting calcium oxalate crystallization, growth,
and crystal-cell adhesion and downregulating crystal receptors. Furthermore,
trigonelline inhibited crystal growth and crystal-cell adhesion in a dose-
dependent manner
Trigonelline Trigonelline prevents ultraviolet-B-induced Both in vitro and TG (50 μM) protects HDF cells and BALB/c mice from UV-B-induced DNA damage Tanveer et al. (2023)
oxidative DNA damage in primary human in vivo by regulating the expression of key DNA damage protein markers such as P53,
dermal fibroblasts and BALB/c mice ATM, ATR, H2AX, Chk1, and Chk2. In immunocytochemistry, TG provides
geno-protection to UV-B-irradiated HDFs by alleviating CPD induction, reducing
the number of TUNEL-positive cells, and decreasing the expression levels of
the DNA damage marker protein H2AX. TG also protects against UVB-induced
oxidative stress by activating the PI3K-AKT-Nrf2 signaling pathway. TG protects
the genome from UV-B irradiation via the PI3K-AKT-Nrf2 signaling pathway
MAKISO et al.

Coffee bioactive
compound Study Study type Proposed mechanism of action References
MAKISO et al.

Diterpene Coffee diterpene kahweol protect In vitro Kahweol (10 μM) significantly reduced 6-OHDA-induced ROS production, caspase-3 Hwang and
kahweol human dopaminergic neurons from 6 activation, and cell death. Kahweol also increased heme oxygenase-1 (HO-1) Jeong (2008)
hydroxydopamine-derived oxidative expression, which protected neurons from 6-OHDA-induced oxidative injury. In
stress addition, kahweol activated PI3K and p38, which are involved in the induction
of Nrf2, HO-1 expression, and neuroprotection. These findings suggest that the
PI3K and p38/Nrf2 signaling pathways control the intracellular levels of ROS by
regulating the antioxidant enzyme HO-1
Cafestol and Coffee, cafestol, and kahweol induce In vitro In MSTO-211H cells, cafestol (60 and 90 μM) and kahweol (40 and 60 μM) increased Lee et al. (2012)
kahweol apoptosis through regulation of sub-G1 population and nuclear condensation. Sp1 inhibitor Mithramycin A
specificity protein 1 expression in human previously confirmed Sp1 roles in cell proliferation and apoptosis of MSTO-
malignant pleural mesothelioma 211H cells. Sp1 protein levels were significantly suppressed by cafestol and
kahweol. In MSTO-211H cells, kahweol slightly reduced Sp1 mRNA, whereas
cafestol had no effect. In mesothelioma cells, cafestol and kahweol modulated
the promoter activity and protein expression levels of Sp1 regulatory genes such
as cyclin D1, Mcl-1, and survivin. Cafestol-induced cleavages of Bid, caspase-3,
and PARP, as well as kahweol-induced upregulation of Bax and downregulation
of Bcl-xl, activated the apoptosis signaling cascade
Diterpene Coffee diterpene kahweol suppresses cell In vitro Kahweol (50 μM) reduced the protein level of cyclin D1 in HCT116 and SW480 Park et al. (2016)
kahweol proliferation in human colorectal cancer cells. MG132 treatment reduced kahweol-mediated cyclin D1 downregulation,
cells and cyclin D1 half-life was reduced in kahweol-treated cells. Kahweol
increased cyclin D1 phosphorylation at threonine-286, and a point mutation
of threonine-286 to alanine reduced kahweol-induced cyclin D1 degradation.
PD98059, SP600125, or LiCl inhibition of ERK1/2, JNK, or GSK3b inhibited
cyclin D1 phosphorylation and downregulation by kahweol
Diterpenes Coffee diterpenes kahweol acetate and In vivo Cafestol (30 μM) and kahweol (30 μM) acetate inhibited proliferation and migration Iwamoto et al. (2019)
kahweol cafestol synergistically inhibit the by inducing apoptosis, inhibiting epithelial–mesenchymal transition, and
acetate and proliferation and migration of prostate decreasing androgen receptor, resulting in a decrease in nuclear androgen
cafestol cancer cells receptor in androgen receptor-positive cells. Furthermore, kahweol acetate
and cafestol inhibited CCR2 and CCR5 while increasing their ligands, CCL2
and CCL5. The xenograft study found that taking kahweol acetate and cafestol
orally significantly reduced tumor growth
Diterpene, Coffee Diterpene, Kahweol, Ameliorates In vitro Kahweol (5 μM) downregulated STZ-induced nuclear factor kappa B (NF-κB), and El-Huneidi et al. (2021)
Kahweol Pancreatic β-Cell the antioxidant proteins, heme oxygenase-1 (HMOX-1), and inhibitor of DNA
Function binding and cell differentiation (Id) proteins (ID1, ID3) while upregulated protein
expression of insulin (INS), p-AKT, and B-cell lymphoma 2 (BCL-2)
Melanoids Melanoidins from coffee, scavenge In vitro Caffeic acid (CA) and 3-caffeoylquinic acid (1 mg/mL) had DC-scavenging kinetic Zhang et al. (2019)
α-dicarbonyl compounds under simulated profiles similar to HMW-CM, and mass spectrometry data confirmed that
physiological conditions hydroxyalkylation and aromatic substitution reactions resulted in the formation
of a stable adduct between CA and MGO
|

(Continues)
23

should not consume more than 3 mg/kg body weight for a 70 kg not only the volume of coffee consumed, but also the caffeine con-
adult pose no safety concerns. Pregnant women and others who centration of the coffee, and the consumption of caffeine from
need to limit caffeine consumption can safely drink four cups of sources other than coffee.
some coffees per day without exceeding the recommended caf- Another possible explanation for discrepancies in study findings
feine intake; however, drinking even one cup of espresso at the is the presence of certain disease risk factors that are linked to both
higher end of the scale will exceed the recommended limit of coffee or caffeine consumption and the disease under investigation.
200 mg/day (Coppi et al., 2023; Nehlig, 2018). In addition, there was no control for the effects of confounding vari-
Quinic acid is a type of phenolic acid found in a variety of plants ables, and most studies simply asked study participants to report
and microorganisms. It is impossible for mammals, including hu- how many cups of caffeinated coffee they drank on a daily basis.
mans, to synthesize (Dong et al., 2022). The natural isomer is 1 L-(−)- Any dose–response relationships that may have existed could have
quinic acid; despite this, it is ambiguously named 1D-quinic acid in been obscured by the imprecision of such estimates. Furthermore,
some scientific literature (Abrankó & Clifford, 2017). Consumption coffee consumption epidemiological studies often fail to include in-
of acyl-quinic acid sources, such as coffee, has been linked to im- formation on the genetic type and source of coffee beans, the type
proved cardiovascular and metabolic health (Domínguez-Fernández and brand of coffee, the blend and mode of preparation, the caffeine
et al., 2022). 5-O-CQA, a known dietary precursor of this metabo- or another physiologically active or toxic component concentration,
lite (3′-methoxycinnamic acid-4′-sulfate), has been shown in clinical and the volume of coffee per serving.
studies to reduce diastolic and systolic blood pressure, and bever-
ages containing acyl-quinic acids have produced an acute improve-
ment in flow-mediated dilatation, implying that many people who 7 | CO N C LU S I O N S
drink such beverages regularly may gain at least a modest health
benefit long term (Rubió et al., 2021). Furthermore, epidemiologi- Bioactive compounds in coffee and their role in lowering the risk of
cal and intervention research suggests that they may lower the risk major public health problems, as well as their mechanisms of action,
of developing type 2 diabetes and cardiovascular disease (Clifford are addressed in this article. Coffee Arabica and Robusta are the two
et al., 2020). Additionally, 1 L-(−)-quinic acid has been shown to have most widely consumed coffee species for their pleasant aroma and
antioxidant and anti-inflammatory properties. It stimulates the pro- flavor. They contain different mixtures of aroma-impact compounds,
duction of tryptophan and nicotinamide in the intestine, which raises such as caffeine, CGA, trigonelline, melanoidins, and diterpenes that
the concentrations of all lipoproteins (Dong et al., 2022). significantly determine the perceived quality of coffee. Study find-
Despite the positive health impacts of consuming coffee, too ings show that these bioactive compounds are associated with a low
much/excessive intake from the recommended daily intake is di- risk of type-2 diabetes, cardiovascular disease, neurodegenerative
rectly associated with potential health risks. It may increase the pos- diseases, and various types of cancer. Moreover, they were reported
sibility of cardiovascular disease, lung cancer, interaction of some to enhance lipid and glucose metabolism, block the production of
coffee bioactive components with drugs and nutrients, and adverse inflammatory mediators, and avoid damage from free radicals. Based
pregnancy-related complications. Furthermore, intake of unfiltered on an individual's physiological condition and health status, three
coffee may also be prone to a considerable amount of diterpenes to four cups of filtered coffee per day have been associated with
such as cafestol and kahweol. They are known to raise the blood cardiovascular protection and other health benefits. However, the
LDL, the total cholesterol level, and the potential risk for cardio- amount of caffeine and other bioactive compounds in a cup of cof-
vascular disease. In another way, some epidemiological study find- fee varies depending on the geographical origin and method of prep-
ings on the health benefits of coffee consumption have limitations, aration. As a result, the EFSA recommends 400 mg of caffeine per
particularly the doses used in animal and in vitro studies to benefit day for adults. Caffeine consumption should be limited to no more
from coffee consumption, which are not easily achievable in normal than 200 mg per day for pregnant women. However, even one cup of
human consumption. espresso at the higher end of the scale exceeds the recommended
Epidemiological studies conducted in the 1980s and 1990s daily limit of 200 mg. In general, exceeding the recommended daily
linked coffee consumption with poor health, heart disease, cancer, allowance, calcium and vitamin D deficiency, and drinking unfiltered
infertility, and other issues. The degree of association between cof- coffee all increase the risk of potential health risks, including cardio-
fee consumption and the occurrence of each of these diseases and vascular disease. Moderate coffee consumption is advised to reduce
conditions has been low and inconsistent. The inconsistencies in the the risk of a variety of noncommunicable diseases.
relationship between coffee or caffeine consumption and the occur-
rence of various diseases may be due to methodological differences AU T H O R C O N T R I B U T I O N S
between studies. The precision of the various instruments used to Markos Urugo Makiso: Conceptualization (equal); methodology
assess coffee and caffeine intake could be a significant difference. (equal); writing – original draft (equal). Yetenayet Bekele Tola:
Coffee intake estimation only requires precise measurement of the Investigation (equal); supervision (equal); writing – review and
volume of coffee consumed in a given time period, whereas caffeine editing (equal). Onwuchekwa Ogah: Conceptualization (equal);
intake measurements are much more complex because they include investigation (equal); methodology (equal); supervision (equal);
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Anastasiadi, R. M., Berti, F., Colomban, S., Tavagnacco, C., Navarini, L., &
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G E M E N T S
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The authors declare that they do not have any conflict of interest. line, caffeine, chlorogenic acid and their related compounds in in-
stant coffee samples by HPLC using an acidic mobile phase contain-
DATA AVA I L A B I L I T Y S TAT E M E N T ing octanesulfonate. Analytical Science, 31(August), 831–835.
Arlt, A., Sebens, S., Krebs, S., & Schafer, H. (2013). Inhibition of the Nrf2
The data that support the findings of this study are available from
transcription factor by the alkaloid trigonelline renders pancreatic
the corresponding author upon reasonable request. cancer cells more susceptible to apoptosis through decreased pro-
teasomal gene expression and proteasome activity. Oncogene, 32,
E T H I C S S TAT E M E N T 4825–4835.
Arnaud, M. J. (2011). Pharmacokinetics and metabolism of natural
This study does not involve any human or animal testing.
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ORCID Ashihara, H., Ludwig, I. A., Katahira, R., Yokota, T., Fujimura, T., & Crozier,
Markos Urugo Makiso https://orcid.org/0000-0002-6241-1417 A. (2015). Trigonelline and related nicotinic acid metabolites:
Occurrence, biosynthesis, taxonomic considerations, and their
Yetenayet Bekele Tola https://orcid.org/0000-0002-8247-4546
roles in planta and in human health. Phytochemistry Reviews, 14(5),
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How to cite this article: Makiso, M. U., Tola, Y. B., Ogah, O.,
112831. https://doi.org/10.1016/j.biopha.2022.112831
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different coffee brew mechanisms. Food Research International, their role in lowering the risk of major public health
49(1), 27–31. consequences: A review. Food Science & Nutrition, 00, 1–31.
Zhang, D., Vega, F. E., Infante, F., Solano, W., Johnson, E. S., & Meinhardt,
https://doi.org/10.1002/fsn3.3848
L. W. (2020). Accurate differentiation of green beans of Arabica
and Robusta coffee using nanofluidic array of single nucleotide

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Bioactive Compounds in Coffee and Their Role in Lowering

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Bioactive Compounds in Coffee and Their Role in Lowering

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Received: 9 December 2022 | Revised: 4 November 2023 | Accepted: 7 November 2023

Bioactive compounds in coffee and their role in lowering the

Markos Urugo Makiso1,2 | Yetenayet Bekele Tola2 | Onwuchekwa Ogah3 |

Food Sci Nutr. 2023;00:1–31. ﻿ wileyonlinelibrary.com/journal/fsn3 | 1

Total articles gathered by the team members on coffee

Eligibility Total full

Total studies included in the qualitative and

Articles included in this review article development (n=193)

4 | CO FFE E A RO M A I M PAC T 4.1 | Nonvolatile components of coffee

Nonvolatile compounds Coffea arabica Coffea canephora Role on perceived sensation

F I G U R E 7 Chemical structure of melanoids (Moreira et al., 2012).

TA B L E 2 Volatile aroma compounds of roasted coffee.

Key odorants Volatile compounds Aroma descriptor

Aldehyde 2-methylbutanal Rancid, almond-like, toasty

Key odorants Volatile compounds Aroma descriptor

Norisoprenoid (E)-β-damascenone Honey-like, fruity, apple, rose, honey, tobacco, sweet

Source: Yeretzian et al. (2019).

TA B L E 3 Key compounds responsible

Source: Yeretzian et al. (2019).

F I G U R E 1 1 A model of the proposed

The amount of trigonelline synthesized in the pericarp is significantly

5.3.1 | Anticancer effect of trigonelline

Melanoidins have been shown to have antioxidant effects on the

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Food Sci Nutr. 2023;00:1–31. wileyonlinelibrary.com/journal/fsn3 | 1