An Insight Into the Therapeutic Potential of Major Coffee Components

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REVIEWARTICLE An Insight into the Therapeutic Potential of Major Coffee Components

Muhammad Torequl Islam1,2, Shams Tabrez3,*, Nasimudeen R Jabir3, Murtaza Ali4, Mohammad Amjad Kamal3, Lidiane da Silva Araújo5, Jose Victor de Oliveira Santos5, Ana Maria Oliveira Ferreira da Mata5, Rai Pablo Sousa de Aguiar5 and Ana Amélia de Carvalho Melo Cavalcante5

1Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 2Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 3King Fahd Medical Research Center, King Abdu- laziz University, Jeddah, Saudi Arabia; 4Department of Biosciences Jamia Millia Islamia, New Delhi, India; 5Post-Graduate Pro- gram in Pharmaceutical Science, Federal University of Piauí, Teresina, Brazil

Abstract: Background: The popular drink, coffee (Coffea arabica) is under the great attention of late because of its promising pharmacological potential. Caffeine (the major constituent of coffee) is known for its prominent psychoactive impact. A R T I C L E H I S T O R Y Methods: This review aims at highlighting the therapeutic potentials of caffeine and other five coffee components

Received: October 02, 2017 viz. caffeic acid, chlorogenic acids, cafestol, ferulic acid and kahweol and their mechanisms of action. Revised: December 27, 2017 Results: A number of pharmacological activities are attributed to these components that include anti-oxidant, anti- Accepted: January 19, 2018 inflammatory, immunomodulatory, anti-microbial, anti-cancer, cardioprotective and neuroprotective effects. In addi- DOI: tion, osteogenesis (kahweol), anti-diabetic (caffeine, chlorogenic acid and ferulic acid) and hepatoprotective (chloro- 10.2174/1389200219666180302154551 genic acid) activities have also been reported by some of these components in the scientific literature. Caffeine has also been noted for adverse effect on the development of the brain at early stages and reproductive systems. Conclusion: A more advanced pre-clinical and clinical trials are recommended to investigate the safety profiles of these coffee components before their use as possible therapeutics. Keywords: Anti-oxidant, anti-inflammation, Coffea arabica, coffee components, metabolism, organo-protection.

1. INTRODUCTION CAA phenethyl ester takes place by direct esterification of CAA The widely consumed beverage, coffee gained increased at- and phenethyl alcohol, which greatly influence the transformation tention lately because of its popularity all around the world. The reaction rate [6] and biological activities [7]. biological resource of coffee is the Coffea arabica (Family- Ru- 2.2. Caffeine [C H N O ] biaceae), cultivated in most of the countries across the globe [1]. 8 10 4 2 It is a complex beverage that contains several biologically active Caffeine (1,3,7-trimethylxanthine) is a substance shown in a components. Among them, caffeine is by far the most studied wide assortment of drinks like espresso, tea, cola and in chocolate- compound and to a great extent represents the inherent habit- based nourishment items [8]. Fundamentally, it is demethylated by forming nature of coffee [2]. It is a natural alkaloid and psychoac- the hepatic cytochrome P4501A2 (CYP1A2) into 1,7- tive agent, isolated from coffee beans [3]. Along with caffeine, dimethylxanthine (1,7-X) and to a lesser extent into 3,7- the diterpenes, cafestol, kahweol, chlorogenic acids and hydroxy- dimethylxanthine (3,7-X) and 1,3-dimethylxanthine (1,3-X) in hu- cinnamic acids are the important components of coffee which mans. Besides, demethylation of 1,7-X is trailed by the same have been noted to possess different pharmacological potential. CYP1A2 enzyme which brings about the development of 1- These coffee components have undergone a number of non- methylxanthine (1-X) and 1-methyluric corrosive (1-U) [9]. clinical and pre-clinical investigations in different animal models. In this review, we have highlighted the therapeutic potentials of 2.3. Chlorogenic Acid (CGA) [C16H18O9] the caffeine, caffeic acid, chlorogenic acid, cafestol, ferulic acid Chlorogenic acids are the phenolic compounds formed by the and kahweol. The mechanisms of action of these constituents esterification of cinnamic acids [10]. These are the abundant poly- have also been covered. phenols in the human diets, with coffee, fruits and vegetables being some of the main sources. The major part of the CGA is not ab- 2. PHARMACO-CHEMISTRY OF DIFFERENT COFFEE sorbed in the proximal part of the gut and it is hydrolyzed by the COMPONENTS microflora after reaching in the large intestine which exhibits es-

2.1. Caffeic Acid (CAA) [C9H8O4] terase activity [11]. Finally, the formation of CAA and quinic acid takes place which gets further metabolized [12]. The aromatization Caffeic acid (3,4-dihydroxycinnamic acid) is well known for its of quinic acid leads to the formation of hippuric acid which then strong antioxidant potential [4]. CAA and its derivatives are good turns into benzoic acid and subsequently conjugated with glycine in substrates of polyphenol oxidases, and under specific conditions the liver and kidney [12, 13]. may experience oxidation in plant tissues [5]. The synthesis of

2.4. Cafestol [C20H28O3] and Kahweol [C20H26O3] *Address correspondence to this author at the King Fahd Medical Research Cafestol and kahweol are very close structural diterpenes, dif- Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi ferentiated only by the presence of a double bond in a ring of the Arabia; E-mail: [email protected] cafestol molecule [14]. They are present only in the non-saponified

1389-2002/18 $58.00+.00 © 2018 Bentham Science Publishers 2 Current Drug Metabolism, 2018, Vol. 19, No. 00 Islam et al. lipid fraction of coffee. Moreover, approx 0.4-0.7% cafestol are sickness [29]. The excess consumption of caffeine may increase present in C. arabica. blood pressure and could lead to vasoconstriction [30], affect gas- Cafestol carries a furan moiety and their epoxidation is an im- trointestinal motility and gastric acid secretion [31], bone loss [32], portant biotransformation step for their biological effects. It has dehydration [33], anxiety and panic disorder [34], low birth weight also been noted to produce epoxy-glutathione and glucuronide con- [35], colorectal cancer [36], intraocular pressure in glaucoma [37], jugates in mice model. caffeinism and caffeine dependency [38]. Additionally, nervous- ness, irritability, restlessness, insomnia, headaches, palpitations, 2.5. Feluric Acid [C10H10O4] fidgeting, anxiety and excitement are also associated with caffeine Ferulic acid [(E)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-enoic overdose [38, 39]. Massive overdose can also lead to the death of acid] is a phenolic compound present in several plants. It is an im- the individual [40]. The estimated LD50 of caffeine in humans is portant pharmaceutically active agent used in the treatment of car- 150-200 mg/kg [41]. It should also be mentioned that individuals diovascular and cerebrovascular diseases [15]. Their antioxidant with intricacy to metabolize caffeine may encounter chronic liver activity is due to its capability of forming a resonance-stabilized diseases [42]. Caffeine has also been reported to impact male sper- phenoxy radical [16]. matogenesis [43] and fetal survival [44]. On the other hand, the alteration in the hormonal level during pregnancy may slow down 2.6. Caffeine the metabolic clearance of caffeine, which might lead to some complications in this category of patients [45]. The biosynthetic [46] The prominent psychoactive drug, caffeine is mainly used to and laboratory synthesis [47] pathways of caffeine are presented in treat bronchopulmonary dysplasia, apnea [17], Parkinson’s disease Fig. (1). [18] and cardiovascular complications (e.g. coronary artery disease and stroke) [19], weight gain [20], cerebral palsy, language and 3. METABOLISM OF COFFEE COMPONENTS cognitive delay [21], orthostatic hypotension [22], fatigue (both from muscle and central) [23, 24], drowsiness [25], type 2 diabetes The caffeine is mainly absorbed in small intestine and stomach (T2D) [26], liver cirrhosis [27], headaches [28] and acute mountain [48]. After their absorption, they are rapidly distributed in the plasma. Their occurrence has been detected in breast milk, umbilical cord

A O B

HN N H C H 3 N O NC O N N H + O OCH3 H O CH3 Ethyl-2-cyanoacetate HO 1,3-dimethylurea EtOH NaOEt HO OH

Xanthosine O D-riboside H C NO 7-methylxanthosine 3 synthase H2O O CH3 O NH2 N-methyl N CH O CH3 HN 3 + nucleosidase HN N O N N 1,3-dimethyl-4-amino- H 5-nitrosouracil O N N H 7-methylxanthine Pd(C) HCO H/H O O 2 2 HO Theobromine syhthease O HO OH O CH3 H3C NH2 7-methylxanthosine HN N O NH2 N O N CH3

H3C 1,3-dimethyl-4,5- Caffeine syhthease 3,7-dimethylxanthine diaminouracil (Theobromine)

O O O CH3 H H3C H3C NH2 H3C N (CH )SO N N N 3 4 CHO N O NH O N N O N CH H C 3 H3C 3 1,3-dimethyl-4-amino 1,3,7-trimethylxanthine Theophylline -5-formalinouracil (Caffeine) Fig. (1). (a) biosynthesis and (b) laboratory synthesis pathways of caffeine. [(a) 7-methylxanthosine synthase causes a methylation at N7 position of the xanthosine to get the first methylation product, 7-methylxanthosine, which with the help of N-methyl nucleosidase grounds a hydrolytic cleavage of the D-ribose to 7-methylxanthine. Further addition of a second methyl group occurs in the N3 position of 7-methylxanthine in the presence of theobromine synthase. Finally, the second methylation product, 3,7-dimethylxanthine or theobromine is formed in the presence of caffeine synthase after the addition of a third methyl group at its N1 position (1,3,7-trimethylxanthine). (b) 1,3-dimethyl-4-amino-5- nitrosouracil is the first product in the occasion, which results in an alcoholic medium (EtOH) by the presence of sodium ethanoyet (NaOEt) from 1,3- dimethylurea and ethyl-2-cyanoacetate. A formalin-aminoation occurs in the presence of formaldehyde and the metal catalyst, Pd, turn it into the theophylline in the presence of methyl sulphate. Further methylation at N7 position causes the occurrence of caffeine]. An Insight into the Therapeutic Potential of Major Coffee Components Current Drug Metabolism, 2018, Vol. 19, No. 00 3 blood, bile, saliva and semen [49]. The plasma concentration peaks and produces a sleepiness effect. Caffeine can promptly cross the between 15 and 120 minutes after oral ingestion [50]. Lack of hepatic blood-brain and placenta barrier [67]. Caffeine counteracts adeno- first-pass effect has been reported in human and animal models [51]. sine to tie up with its receptors, which causes the sluggishness and Caffeine could readily crosses cell membranes and a significant level reestablishes the readiness. of caffeine are detected in the brain within 5 minutes of oral intake Caffeine can control the binding of dopamine with its receptor [52]. Almost, 98% of caffeine could be reabsorbed by renal tubules in the striatum through adenosine receptors, prompting the devel- and in humans, only 0.5% to 2% of urinary excretion of absorbed opment of GPCR heteromers, particularly the A1-D1 and A2A-D2 caffeine have been reported [53]. Minor urinary excretion of caffeine heterotetramers. Moreover, chronic usage of caffeine may reduce explains the rate-limiting plasma clearance of its metabolites. dopamine release via A1-A2A heterodimer stimulation in the axon The metabolism of caffeine takes place primarily in the liver by terminal of glutamate neurons and could lead to caffeine tolerance. hepatic microsomal enzyme systems [51]. Impaired clearance of In addition, caffeine could also antagonize A2A receptor in the ven- caffeine has been reported in patients with liver disease [54]. In the trolateral preoptic area and diminishes inhibition of GABA neuro- liver, it experiences a complicated series of reactions involving sev- transmission to the tuberomammillary nucleus [68, 69]. Caffeine eral enzyme systems, basically N-demethylations and C-8- has also been reported to augment the intracellular cAMP and acti- hydroxylation, to yield a mixture of di and trimethylated xanthines, vates protein kinase A through their phosphodiesterase inhibition. It uric acids, and acetylated uracil derivative. These metabolites are could downregulate TNF- and leukotriene synthesis and reduce principally formed by cytochrome P450 1A2 and are in charge of the inflammation and innate immunity. It has also been reported to oxidative metabolism of exogenous substances in humans [55]. Other inhibit AChE enzyme [70]. P450 enzymatic systems, as well as N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), also play a role in the metabolism of 4. MAJOR PHARMACOLOGICAL POTENTIAL OF VARI- caffeine and/or its metabolites [56]. In fact, caffeine has been consid- OUS COFFEE COMPONENTS ered as a metabolic probe for the enzymes CYP1A2, NAT2 and XO. 4.1. Antioxidant Activity These enzymes are also involved in the detoxification of various The use of natural antioxidant compounds to combat oxidative xenobiotic compounds [56, 57]. Caffeine and its metabolites act stress-related diseases has gained a great attention lately. In this through different systems that include action on receptors and chan- context, dietary antioxidants are the imperative agents with their nels on the cell membrane and additional intracellular action on potential to serve as an anti-inflammatory and immune enhance- calcium and cyclic adenosine monophosphate phosphodiesterase ment agent [71]. (cAMP) pathways [58]. Caffeine can competitively inhibit cAMP which is their central pharmacological effect in peripheral tissues Antioxidant enzymes play a crucial role in the cellular defense against reactive oxygen species (ROS) (such as superoxide anion [58]. Paraxanthine (1,7-dimethylxanthine) is the major metabolite • • • (70-80%) of caffeine and is reported to be an equipotent cAMP in- radical (O2 ), hydroxyl radical ( OH) and peroxyl radical (ROO ). hibitor [57]. The long-term exposure of caffeine leads to a substantial These radicals are continually generated in the cells from a number accumulation of paraxanthine which could ultimately contribute to of exogenous and endogenous sources and cause oxidization of bio- the tolerance and withdrawal symptoms [59]. An amplified occur- macromolecules viz. membrane lipids, proteins and nucleic acids rence of paraxanthine has been associated with increasing age, and it [72, 73]. could be attributed to the maturation of CYP1A2 activity augmenta- Ferulic acid has been reported to significantly inhibit LPS- tion by caffeine exposure [60]. Paraxanthine contributes towards the induced NO production in RAW264.7 cells [74]. The antioxidative moderate rise in intracellular cytosolic free calcium through the acti- potential of ferulic acid has also been noted in rodents [75]. On the vation of ryanodine receptor calcium release channels which provide other hand, cafestol has exhibited ROS scavenging potential in potential benefits against neurodegeneration [61]. In addition, caf- NIH3T3 cells and ICR mice [76]. The other coffee component, feine clearance rates are also influenced by both natural and physio- CAA is a strong scavenger of 5,5-dimethyl-1-pyrroline N-oxide logical components, for example, utilization of oral contraceptives, (DMPO) [77], ROS and nitric oxide (NO•) radical [78]. Similarly, smoking, and pregnancy [62]. kahweol has been reported to augment the GSH content in several organs of male rats [79]. According to Lee and Jeong [76] kahweol 3.1. Pharmacokinetics has been noted to induce a protective effect against hydrogen per- The pharmacokinetic data of caffeine suggests bioavailability oxide (H2O2)-induced oxidative stress and DNA damage in up to 99%, protein binding: 25-36%; metabolism: primary- NIH3T3 cells. It could regulate antioxidant enzyme HO-1 via PI3K CYP1A2, minor- CYP2E1, CYP2C8, CYP2C9, CYP3A4; biologi- and p38/Nrf2 signaling pathways which control the intracellular cal half-life (t1/2): adults- 3 to 7 hours, neonates- 65 to 130 hours; ROS levels [80]. CGA has also been reported for their DPPH and onset of action: ~ 1 hour; duration of action: 3-4 hours and excre- ROS scavenging activity [81, 82]. Furthermore, caffeine, which is a tion: urine (100%) [63]. It is eliminated by first-order kinetics [64]. well-known nerve stimulator is believed to inhibit oxidative stress- Nicotine could decrease t1/2 of caffeine by 30 to 50%, while oral induced tissue damage in a number of neoplastic transforming cells, contraceptives can double it [45]. thus confirming its therapeutic relevance as a cytoprotective agent. Caffeine is metabolized by the liver cytochrome P450 oxidase 4.2. Anti-inflammatory Activity enzyme system mostly into the three dimethylxanthines: paraxanthine, theobromine and theophylline. Paraxanthine increases lipoly- Inflammatory reactions are the defensive biological procedures sis, prompting a rise of glycerol and free fatty acid levels in the carried out by endogenous mediators to dispose of harmful stimuli. blood. On the other hand, theobromine dilates blood vessels and The oxidants, eicosanoids, cytokines, chemokines and lytic enzymes increases the volume of urine. Theophylline relaxes smooth mus- are the most common inflammatory mediators, often secreted by cles of the bronchi [65]. We would also like to mention here that macrophages, neutrophils as well as by the injured tissues [83-87]. 1,3,7-trimethyluric acid is a minor metabolite of caffeine whose In the inflammatory process, cyclooxygenase (COX) and actual activity is still unexplored [66]. lipoxygenase (LO) are two important enzymes involved in the biosynthesis of prostaglandins (PGs) and leukotrienes [88]. 3.2. Pharmacodynamics Caffeine has been reported to inhibit some pro-inflammatory In an attentive state, after some time adenosine amasses in the cytokines viz. TNF-, IL-1 IL-2 and IL-4 in mice model [89, 90]. neuronal neurotransmitter and leads to the activation of the adeno- Ullah et al. [91] reported significant inhibition in neuro-inflammation sine receptors (particularly A1, A2A, A2B, and A3) in CNS neurons by caffeine in rats. A similar activity was also noted by Yang and Jou 4 Current Drug Metabolism, 2018, Vol. 19, No. 00 Islam et al.

[92] in the male Sprague-Dawley rats. In the RAW264.7 cells, caf- 1/Nrf2 system, probably via carbon monoxide and bilirubin produc- feine has been suggested to suppress LPS-induced inflammatory tion [122]. In one study, Xu et al. [123] reported significant analgesic responses via regulation of NF-B and MAPK phosphorylation [93]. potential of ferulic acid, which is mediated by its modulatory effect Chlorogenic acids has also been attributed for anti-inflammatory on 2- adrenoceptor and 5-HT1A receptors along with a decrease in effect in various cell lines and mice model [94-96]. In a clinical study, monoaminergic system and -opioid receptor. CGA has been noted to inhibit COXs enzymes in humans [97]. On Kahweol has been attributed to a neuro-protection activity via the other hand, the strong inhibition of COX-2, PGE2 and NO pro- regulation of the anti-oxidant enzyme HO-1 through PI3K and duction has also been noted by cafestol [98, 99]. Ferulic acid has also p38/Nrf2 signaling pathways in human neuroblastoma cells [80]. It been reported for prominent anti-inflammatory and inhibitory effect has also been noted to induce a peripheral anti-nociceptive effect on the upregulation of IL-6, TNF- and iNOS expression [74, 100, along with the release of endogenous noradrenaline in rats [118]. 101]. The other important coffee component, kahweol has also been One study reported an analgesic action of kahweol by modulating reported to be an effective inhibitor of PGE2 and COX-2 [102-104]. acid-sensing ion channels (ASICs) in the primary afferent neurons Accumulated data suggest that above mentioned coffee components in rat dorsal root ganglion (DRG) [124]. Moreover, Mikami and have anti-inflammatory potential, which may be linked with their Yamazawa [125] exhibited a significant neuro-protection from promising antioxidative capacities. glutamate-induced Ca2 + efflux into neurons by chlorogenic acids. A recent report highlighted the inhibitory potential of AChE, BChE, 4.3. Immunomodulatory Effects tyrosine and oxidative stress by chlorogenic acids [126]. There are some available literatures on the immunomodulatory Several studies also highlighted neuro-protective potential of potential of the coffee components. Caffeine has been noted to sig- caffeine in rodents and humans [92, 127, 128] apnea child [129], nificantly reduce the number of immunopositive cells and pro- AD [130] and PD [131] patients. Caffeine has also been noted to inflammatory cytokines viz. TNF- and IL-1 [89]. It has also been produce an antagonizing effect in ketamine/xylazine anesthetized reported to suppress tumor via alternative splicing of the target rats [132]. In addition, caffeine could also significantly reduce the genes of serine/arginine-rich splicing factor 3 in HeLa cells [105]. spike-and-wave discharge expression on the motor activity without However, more research is required in this field to insight the po- affecting the expression of epilepsy in rats [133]. Interference in tential of coffee components on the immune system. cholinergic neurotransmission during brain development with caf- 4.4. Anti-microbial Activity feine has also been reported [134]. Caffeine has been reported to potentiate GAT-1-mediated d-asp-induced GABA release, via The uses of antibiotics are difficult to sustain for longer time inhibition of A receptor and activation of PKA pathway in chick because of their less effectivity, high resistance and side effects. In 1A embryo [135] and A2A receptor in rats [136]. Moreover, caffeine this context, the searches for natural anti-microbial agents have could acts as anti-depressive agent [137], memory enhancer [138- gained considerable pace lately. In one study, chlorogenic acids 140], anxiolytic agent [141, 142], nuclear maturator and develop- have been reported to act against Escherichia coli in LPS-induced ment facilitator [143], arousal enhancer [144], motivator [145] and mice [106]. In another study, chalcones (synthesized from caffeine- improver of endurance performance [146]. A study by Acevedo et based aldehyde) has been suggested to exhibit a significant anti- al. [147] reported a stimulatory effect on the lumbar spinal system malarial, anti-trypanosomal and anti-leishmanial activities [107]. by caffeine controlling rear limb locomotion through a restraint A CGA has also been reported to act against hepatitis B and herpes 1 receptor and subsequent activation of D1 receptors by means of the simplex viruses-1 via TLR2/TLR9-Myd88 signaling pathway [108, PKA-dependent intracellular mechanism. In addition, perpetual 109]. Similarly, caffeic acid has been also noted to strongly inhibit exposure of caffeine amid pre-adolescence and puberty has addi- the growth of type A and B influenza virus [110-112]. On the other tionally been accounted for the change in the learning and memory hand, ferulic acid has been suggested to inhibit a number of food- in male mice [148]. During brain developmental stage, caffeine borne pathogens [113]. In addition, ferulic acid has also been re- could produce an impaired memory function in female rats [149]. ported to act against Candida albicans and Microcystis aeruginosa infection [114, 115]. Moreover, caffeine has also been noted for These results indicate that caffeine could serve as a promising anti-microbial activity [116]. The above-mentioned findings sug- agent such as neurostimulator and for the treatment of a variety of gest that coffee components may be served as natural anti-microbial nervous disorders such as neuroinflammation, oxidative stress, stress- agents. However, the exact mechanism of their action is yet to be induced complications, depression, seizure, apnea, AD, and PD. In identified. addition, other coffee components viz. chlorogenic acids, ferulic acid have also been noted for their neuro-protective potential. 4.5. Effects on Nervous System 4.6. Effect on Lung The impacts of caffeine on the nervous system are tremen- dously studied in various animal models. This might be because of Research data related to the effect of coffee components on the their promising cytoprotectve capabilities as they are good antioxi- respiratory system is insufficient. Caffeine has been noted to have no dant and anti-inflammatory agents. relation with the chronic obstructive pulmonary disease in humans [150]. However, adequate studies are recommended to envisage the Cafestol has been reported to exhibit a significant Nrf2-mediated effect of different coffee components on the respiratory system. neuroprotective effect in Drosophila strains [117]. It has also been noted to induce a peripheral anti-nociceptive effect with the release of 4.7. Effects on Heart, Blood Pressure and Cholesterol Level endogenous noradrenaline [118]. On the other hand, ferulic acid has The cardiovascular diseases remained one of the leading causes been suggested to significantly reduce MDA contents and AChE, + + of death worldwide [151-153]. A number of studies highlighted the BChE, MAO, and Na /K -ATPase activities [119]. A rotenone- therapeutic potential of coffee components against cardiovascular induced dopaminergic neurodegeneration of ferulic acid has also been complications. Chlorogenic acids have been reported to inhibit Iso- demonstrated by Ojha et al. [75] which is linked with its antioxidant induced cardiac hypertrophy by attenuating NF-B signaling path- and anti-inflammatory potentials. In addition, the chronic ferulic acid way in neonatal rat myocytes [154]. It has also been observed to administration has been noted to exert an anti-depressant-like effect reduce the hypoxia-induced pulmonary arterial hypertension in rats [120]. Moreover, Zhang et al. [121] suggested that ferulic acid ame- [155]. Additionally, chlorogenic acids have also been suggested to liorate nerve injury induced by cerebral ischemia in a rat model. exert cardiovascular protective effect through an increased produc- Ferulic acid has also been reported to exhibit a neuro-protection in tion of NO and induction of HO-1 [156]. On the other hand, caf- human neuroblastoma cell line through an activation of the HO- feine has been accounted to induce a cardiomyocyte hypertrophy An Insight into the Therapeutic Potential of Major Coffee Components Current Drug Metabolism, 2018, Vol. 19, No. 00 5 alongside the release of Ca2+ from the sarcoplasmic reticulum and [174]. Moreover, caffeine has been suggested to reduce birth weight cytosol, prompting the activation of CaMKII and p300, which im- of the baby in a pregnant woman [175], and lower the level of fetal proves the expression of MEF2 [157]. Caffeine has also been noted blood leptin in pregnant rats [176]. In addition, it could also signifi- to increase the heart beats [158]. Moreover, ferulic acid has been cantly decrease the scavenger receptor class B type I expression, reported to decrease the serum and hepatic lipids in high fat diet- cholesterol uptake and restrained steroidogenesis in the fetal adre- induced obese mice [159]. It is believed that ferulic acid leads to the nal cells [176]. Caffeine has also been suggested to act against tes- downregulation of lipogenic genes (mainly- SREBP1c, FAS, ACC) ticular general architecture and sperm death or testicular damage and an upregulation of -oxidation genes, CPT1a and PPAR. The [177]. High caffeine consumption is linked to a risk of abnormal administration of ferulic acid exhibited a significant anti-thrombotic fetal development [178], abnormal spermatogenesis [43], preterm activity through an inhibition of p38 and ERK2 phosphorylation birth [179] and brain development anomaly [180]. The above- pathways with the activation of PKA and PKG via inhibition of mentioned data clearly highlights the concern about the use of cof- PDE, leading to an inhibition of intracellular calcium and platelet fee components, as it produces sex-dependent effects in experimen- aggregation [160]. Additionally, ferulic acid has also been noted to tal animals. On the other hand, a large amount of caffeine intake decrease the production of inflammatory cytokines via the inhibi- cause reproductive abnormality in both genders of the test animals. tion of IKK/IB/NF- B pathway [161]. Similarly, cafestol has In addition, low birth weight and malnourishment phenomena have been suggested to augment the levels of LDL-c [162]. The ferulic also been noted with high caffeine exposure. acid along with caffeic acid has been noted to exert a vasorelaxation effect in rats [163], while kahweol has been noted to produce an 4.11. Effects on Absorption and Metabolism anti-atherosclerotic effect in humans [104]. The gastrointestinal complications and metabolic systems are The above-mentioned literature reveals the cardiovascular pro- also crucial considerations during drug formulation. Drug interac- tection potential of coffee components because of their ability to tion with ingested food and other drugs could affects the control BP, LDL-c, genes associated with lipogenesis, thrombous metabolism of food materials and xenobiotics. formation inside the vessels, along with antioxidant and anti- Chlorogenic acids have been reported to decrease protein absorp- inflammatory activities. tion from soymilk in the digestive tract in human [181]. It could also control the blood glucose levels in rats and human [182, 183]. 4.8. Effects on Liver Moreover, chlorogenic acids have also been attributed to decrease the In the last one decade, there has been great attention on the use metabolism of CYP1A1, CYP1A2, CYP2B1 and CYP2B2 in male of natural compounds for the treatment of liver disorders. The rats [171] and CYP2E1 in mice [76]. One study showed a region- above-mentioned coffee components have also demonstrated the dependent rise or decline in brain function by caffeine intake which ability to serve as hepatoprotective agents. results in an unaltered average brain metabolic rate [184]. Moreover, Caffeic acid has been reported for hepatoprotectivity via caffeic acid has also been noted to increase the liver pressing for su- antioxidant-mediated mechanism [164]. It has also been noted to crose in male rats [185]. Ferulic acid has been reported for a protec- serve against OXT-induced liver injury [111]. On the other hand, tive effect against intestinal epithelial barrier dysfunction in rats chlorogenic acids have been suggested to reduce oxidative stress- [186]. In addition, a significant prevention in the multiple aspects of mediated liver toxicity in mouse and rat models [165]. It also pro- metabolic syndrome in the high-fat diet mice has also been reported tects liver against cholestasis [166], tetrachlorobenzoquinone [167], in response to combined use of ferulic acid and CAA [187]. The above-mentioned literature clearly suggests that coffee components CCl4 toxicity [168] and acetaminophen toxicity [169]. In addition, caffeine has been reported for hepatoprotection without affecting have some important effects on metabolic systems. hepatic performance [170]. Cafestol along with kahweol has been 4.12. Effects on Blood Glucose Level and Diabetes reported to downregulate the levels of CYP1A1, CYP1A2, CYP2B1 and CYP2B2 (metabolic enzymes of a wide variety of Diabetes mellitus is usually associated with many complica- substances including liver toxicants) [171]. In one study, cafestol tions such as cardiovascular complications, nephropathy and neu- and kahweol co-treatment have been reported to inhibit CYP450 ropathy [188]. Fortunately, more than 1200 species of plants have and SULT that highlight their hepatoprotective and chemopreven- been reported to possess anti-diabetic activities [189]. tive potentials [171]. Moreover, ferulic acid has also been suggested Chlorogenic acids have been reported to significantly control to reduce the oxidative stress in hepatocytes and cardiomyocytes the blood glucose and insulin levels in rats and humans [182, 190]. via Keap1-Nrf2-ARE signaling pathway [172]. The above- On the other hand, caffeine has been suggested to lower the blood mentioned studies point towards the potential of the coffee compo- glucose level in rodents [191]. It has also been noted to exhibit AA1 nents against hepatic oxidative stress, inflammation and carcino- and AA2B mediated insulin resistance in Wistar rats [192]. Simi- genesis, along with some other health benefits. However, further larly, ferulic acid has been reported to improve the glucose homeo- research is required to determine their effects on liver enzymes, stasis in high-fat diet-induced obese mice by decreasing insulin histological alterations and risk/benefit ratio. resistance through the suppression of phosphoenolpyruvate carboxykinase and G6Pase expression [159]. These findings clearly 4.9. Effects on Kidney suggest the hypoglycemic and insulin-sensitizing capabilities of There is limited research available on the effect of coffee com- coffee components especifically caffeine, chlorogenic acids and ponents on the renal system. Coffee components may impart pro- ferulic acid. tective effects on the nephritic system because of their antioxidant and anti-inflammatory potentials. Chlorogenic acids have been 4.13. Effects on Bone noted to attenuate cisplatin-induced kidney injury through suppres- The effects of coffee components on bone have been noted in sion of oxidative stress, inflammation, apoptosis and autophagy the scientific literature. In a study, in BALB/c mice and bone mar- [94]. However, more research is required on various coffee compo- row-derived macrophages have been noted to prevent the osteoclas- nents related to their effect on the nephritic system. togenesis via an impairment of NFATc1 expression and blockage of ERK phosphorylation pathway [193]. Caffeine has been reported to 4.10. Effects on Reproductive System enhance an orthodontic tooth movement via increase in osteoclas- There are several studies related to the effect of caffeine on the togenesis in male Wistar rats [194]. However, more research is reproductive system in various animal models. Caffeine has been required to establish the clear effect of coffee components on the reported to reduce the co-ordination in neonatal developmental bone. The molecular mechanisms of action underlying the different [173]. It could also exert a sex-dependent stimulatory effect in rats coffee components are listed in Table 1.

6 Current Drug Metabolism, 2018, Vol. 19, No. 00 Islam et al.

Table 1. Molecular mechanisms underlying activities of different coffee components (: increase; : decrease).

Processes Components Targets/Pathways Models/Cell Types References

Oxidation CAA : DMPO levels In vitro [77] : ROS and NO levels [78] : LP levels

CGA : DPPH scavenging In vitro [82, 97] : ROS levels

CSL : ROS levels NIH3T3 cells [76]

FRA : NO levels LPS-treated RAW264.7 cells [74]

KWL : GSH content Male F344 rats [79, 80] : ROS levels (regulation of HO-1) Human neuroblastoma SH-SY5Y cells

Inflammation CFE : IL-1 and TNF- activity Mice [89, 90, 93] : IL-2 and IL-4 activity Mice : NF-B activation and MAPK phosphorylation LPS-treated RAW264.7 cells

CGA : pro-inflamatory mediators BALB/cN mice [94] : COXs activity Human

CSL : COX-2 and PGE2 levels LPS-treated mouse macrophage cells [98, 102] : NO levels

FRA : IL6, TNF- and iNOS expression LPS-treated RAW264.7 cells [74, 101] : iNOS expression Human cancer cell lines

KWL : COX-2 and PGE2 levels RAW 264.7 cells [98, 102]

Viral infection CGA : TLR2/TLR9–Myd88 signaling pathway Herpes simplex virus (HSV)-1 [109]

Hepatic injury CAA : oxidative stress Rats [111, 164]

CFE : oxidative stress Rats [170, 171]

CGA : cholestasis Sprague- Dawley rats [166]

CSL : CYP1A1, CYP1A2, CYP2B1, CYP2B2 Male F344 rats [171]

FRA : Keap1-Nrf2-ARE expression Hepatocytes exposed to HG [172]

KWL : CYP450, SULT Male F344 rats [171]

Cardiac complica- CAA : vasorelaxation with FRA Rats [163] tion CFE : MEF2 via activation of CaMKII and p300 Human [157, 158] : heart beats

CGA : NF-B expression and ROS production Iso-treated rat myocytes [154-156] : BP Hypoxial rats : NO, HO-1 C57BL mice

CSL : LDL-c levels Rats [162]

FRA : serum and hepatic lipids, and SREBP1c, FAS, HFD mice [159] ACC expression; : CPT1a and PPAR expression [160] : p38 and ERK2 phosphorylation; : PKA and PKG Mice and rats via PDE inhibition (inhibition of intracellular Ca+2

and platelet aggregation) [161] : inflammatory cytokines via IKK/IB/NF- B- CP-treated mice dependent pathway

Table (1) contd…. An Insight into the Therapeutic Potential of Major Coffee Components Current Drug Metabolism, 2018, Vol. 19, No. 00 7

Processes Components Targets/Pathways Models/Cell Types References

Urinary complica- CGA : oxidative stress Cisplatin-treated BALB/cN mice [94] tion

Metabolic syn- CAA : sucrose levels Male Sprague–Dawley rats [185] dromes CGA : blood glucose levels Sprague-Dawley rats and human [181, 182] : dietary protein absorption Human

CSL : CYP1A1, CYP1A2, CYP2B1, CYP2B2 Male F344 rats [171]

Osteogenesis KWL : NFATc1 expression and ERK phosphorylation RAW-D cells [192]

CFE : osteoclastogenesis Male Wistar rats [194]

Complications in CFE : cholinergic neurotransmission Rats [134, 136, nervous system : GAT-1; : A1A expression via PKA pathway Chick embryo 147, 195] : A2A expression Rats : synaptophysin and synapsin I protein expression Rats

: A1; : D1 receptors expression via PKA-dependent ICR mice pathway

CGA : Ca2 + efflux in cortical neurons Cell culture [125, 126] : AChE, BChE and TYR levels as well as oxidative In vitro stress

CSL : Nrf2 expression Drosophila strains [117]

FRA : MDA contents and AChE, BChE, MAO, and Cd-treated rats [75, 119, 122, Na+/K+-ATPase activities 123] : dopaminergic activity, oxidative stress, inflammation ROT-treated rats : HO- 1/Nrf2 expression via CO and BR production SH-SY5Y cell line : spinal beta2- adrenoceptor and 5-HT1A, mono- In vivo aminergic system and -opioid receptor expression

KWL : HO- 1 expression via PI3K and p38/Nrf2 signaling SH-SY5Y cells [80, 118] pathways : endogenous noradrenaline secretion Rats

Diabetes CFE : A1 and A2B mediated insulin resistance CFE Wister rats [177, 192] : blood glucose levels Alloxan-treated rats

CGA : insulin; : blood glucose levels Sprague-Dawley rats [182]

FRA : glucose homeostasis; : PEPCK and G6Pase ex- HFD-treated obese mice [159] pression

Reproduction CFE : steroidogenic factor-1 and associated steroidogenic Pregnant rats [43, 196] complication enzymes expression : spermatogenesis Human Sertoli cells

siderable amount of information about the molecular mechanism of CONCLUSION action of these compounds is known. However, their toxicological There is extensive research lately focusing herbal products, data needs to be considered before their advancement into clinical considering them as an alternative medicine. Coffee and its compo- trials. Hence, we recommend advanced pre-clinical trials to assess nents have attracted the scientific attention of late for their promis- their safety in different animal models prior to advancement to ing biological activities and comparatively low systemic toxicity clinical trials. that can make them alternative to conventional therapeutic drugs. Our article clearly indicates that five coffee components viz. caf- LIST OF ABBREVIATIONS feine, chlorogenic acids, ferulic acid, cafestol and kahweol have 5-HT1A = 5-hydroxytryptamine 1A important therapeutic potentials against a number of disorders in A1 Receptor = Alpha1-adrenergic Receptor various cell lines and animal models. However, the lack of clinical A = Adenosine A Receptor (ADORA1A) data is negatively impacting their possible use in humans. A con- 1A 1A 8 Current Drug Metabolism, 2018, Vol. 19, No. 00 Islam et al.

ACC = Acetyl-CoA Carboxylase SREBP1c = Sterol Regulatory Element-Binding AChE = Acetylcholinesterase Protein 1 AD = Alzheimer's disease TNF- = Tumor Necrosis Factor- Akt = Chromosomal Gene that Encodes Pro- TYR = Tyrosine tein Kinase B CONSENT FOR PUBLICATION AMPK = 5' Adenosine Monophosphate-activated Protein Kinase Not applicable. ASCIs = Acid-sensing Ion Channels CONFLICT OF INTEREST BChE = Butyrylcholinesterase The authors declare no conflict of interest, financial or other- Bcl-2 = Helper Gene to White Blood Cells wise. CaMKII = Ca2+ /Calmodulin-dependent Protein Kinase II ACKNOWLEDGEMENTS cAMP = Cyclic Adenosine Monophosphate The authors are grateful to the research facilities provided by c-FLIP = Cellular FLICE (FADD-like IL-1- Federal University of Piauí, Brazil and King Fahd Medical Re- converting Enzyme)-inhibitory Protein search Center (KFMRC), King Abdulaziz University, Jeddah, Saudi cMyc = Typical Genes Encoding DNA-binding Arabia. 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