Biological Activities of Chlorogenic Acids: Comparison
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Please note this is a comparison between Version 1 by Zorba J Hernández-Estrada and Version 2 by Conner Chen.

The chlorogenic acids (CGAs) are a class of phenolic compounds widely distributed in various plants sources such as fruits, vegetables, coffee beans, tea, apples, and wine. CGAs are esters of quinic acid (QA) and one trans-cinnamic acid residue such as caffeic acid (CA), p-coumaric acid (p-CoA), and ferulic acid (FA), which are known as caffeoylquinic acids (CQAs), p-coumaroylquinic acids (p-CoQAs) and feruloylquinic acid (FQAs).

  • chlorogenic acids
  • biological activity
  • antioxidant activity
  • Cardiovascular Protection Activity
  • Anti-Inflammatory Activity
  • Anticancer Activity
  • Antidiabetic Activity
  • Coffee CGAs

1. Biological Activities of CGAs

Several studies have associated CGAs with beneficial health properties, such as antioxidant, antiviral, antibacterial, anticancer, and anti-inflammatory activity [1][2][3][4]. It has also been shown that it can modulate the gene expression of antioxidant enzymes and reduce the risk of cardiovascular disease by suppressing the expression of P-selectin in platelets [4]. In addition, CGAs can reduce the relative risk of type 2 diabetes and Alzheimer’s disease [3][5][6][7][8][9]. The main biological activities attributed to CGAs are shown in Figure 1.
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Figure 1. Main biological activities attributed to CGAs.
Some of these properties are well recognized and demonstrated by in vitro and in vivo studies, such as antioxidant activity. However, other bioactivities of interest in recent years, although not yet well demonstrated, such as the potential anti-obesity [7][10][11][12][13][14][15] or prebiotic [16][17][18] properties of CGAs. In addition, it has also been shown that CGAs can modulate the activity of glucose-6-phosphatase, an enzyme involved in glucose metabolism, and therefore it may have a positive effect on diabetes management [19].
Furthermore, it is important to highlight that these biological activities are dependent on the CGA’s stability. CGAs are particularly susceptible to environmental conditions, such as solvent type, pH, temperature, and light. These factors must be considered during the CGAs extraction. Moreover, the concentration of these compounds in plants is low. For this reason, the methodologies used for the CGAs extraction from plant sources must be efficient to guarantee the necessary concentration of CGAs to exert their biological activity.

2. Antioxidant Activity

There is a strong correlation between oxidative stress and the development of various degenerative diseases such as cancer and other aging-related diseases [20][21]. Extensive in vitro and in vivo studies have been performed to evaluate the antioxidant activity of CGAs [22]. As a result, CGAs are known to exhibit a radical scavenging effect similar to ascorbic acid [23]. In addition, CGAs can chelate transition metals such as Fe2+ to scavenge free radicals and disrupt chain reactions [24]. Studies have shown that CGAs may prevent the oxidation of low-density lipoproteins (LDL) induced by different oxidizing agents [25][26], as well as prevent DNA damage in vitro [27]. 5-CQA, which is the most important CGA in coffee, can scavenge 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH), superoxide anions (O2•−), hydroxyl radicals (• OH), and peroxynitrite (ONOO−) [28][29][30], and protect DNA from damage caused by oxidative stress in different studies [22][31].
Therefore, there is enough evidence to support that CGAS can inhibit the formation of reactive oxygen species and play a beneficial role in preventing oxidative and aging-related diseases [20][21]. However, studies indicate that these compounds may also act as potent pro-oxidants. Therefore, depending on their concentration, the presence of free transition metal ions, or their redox state, the antioxidant and pro-oxidant properties of CGAs can be modified [32][33][34].

3. Anti-Inflammatory Activity

Inflammation is a complex physiological process of tissue injury caused by exogenous or endogenous sources [22]. A prolonged unregulated inflammatory process can induce tissue damage and is the cause of many chronic pathologies, such as diabetes, alcoholic liver, chronic kidney disease, and cardiovascular and neurodegenerative diseases [35][36]. CGAs, mainly 5-CQA, have been shown anti-inflammatory activity by reducing pro-inflammatory cytokines, due to modulation of key transcription factors, such as tumor necrosis factor-alpha (TNF-α) and interleukins, such as IL-8 [22][37]. Another study performed in murine RAW264.7 macrophages showed that 5-CQA decreased lipopolysaccharide (LPS)-induced cyclooxygenase (COX-2) up-regulation at both the protein and mRNA levels, suggesting that 5-CQA might exert anti-inflammatory effects through inhibition of prostaglandin E2 (PGE2) production [38]. It has also been reported that CFA can enhance the wound healing process [22]. In a study with diabetic rats, oral administration of 5-CQA increased hydroxyproline concentrations and decreased malondialdehyde/nitric oxide levels in wound tissues. In addition, it allowed elevation of reduced glutathione [39][40]. Topical administration of 5-CQA-containing hydrogels to mouse skin wounds significantly reduced the size of the wound area in the inflammatory phase, improving the healing process [41].

4. Neuroprotective Activity

Alzheimer’s disease is a neurodegenerative disease characterized by progressive deterioration of learning, memory, and other cognitive deficits, along with the extracellular deposition of β-amyloid peptides into the brain leading to neuroinflammation, synaptic loss and neuronal death [42][43]. According to Alzheimer Association [44], in 2050, the number of people aged 65 and older with Alzheimer’s disease will reach 12.7 million. Several studies found an inverse relationship between coffee consumption and the development of Alzheimer’s disease, suggesting its possible use in managing treatments [42][45][46][47][48]. The neuroprotective mechanisms of coffee are suggested to be related to the anti-inflammatory effects of caffeine and CGAs on A1 and A2 receptors. In addition, it reduces toxic deposits of β-amyloid peptides in the brain, which is a distinctive feature in Alzheimer’s patients [3][46][48][49]. Furthermore, some coffee compounds could inhibit brain acetylcholinesterase and butyrylcholinesterase (causing a delay in the degradation of acetylcholine and butyrylcholine), resulting in the prevention of oxidative stress-induced neurodegeneration due to their high antioxidant activity [3][46][50].
On the other hand, murine model trials have shown a significant association between the consumption of CGAs and the prevention of the development of degenerative diseases and aging [3][51][52][53][54]. The effect of phenolic compounds from coffee on human cognitive function has not been well studied [55]. However, the number of in vitro studies concerning the neuroprotective effects of polyphenols is rapidly increasing. It has been demonstrated that intraperitoneal injections of 5-CQA reduced oxidative damage in the cerebellum of rats exposed to methotrexate, a drug with serious side effects used to treat some types of cancer, rheumatoid arthritis, and psoriasis [56]. In the same study, these researchers also observed that application of 5-CQA decreased lipopolysaccharide (LPS)-induced IL-1β and (TNF-α) release in the substantia nigra, indicating neuroprotective effects of 5-CQA on neurodegenerative diseases caused by proinflammatory cytokines [56]. Taram et al. [57] studied the neuroprotective effects of 5-CQA and caffeic and ferulic acids on rat cerebellar granule neuron cultures. This research proposed that caffeic acid showed enhanced neuroprotection against a wide range of stressors compared to the other compounds evaluated. Thus, the authors suggest that caffeic acid could be a promising candidate in preclinical models of neurodegeneration [57].

5. Anticancer Activity

The antimutagenic properties of CGAs was demonstrated decades ago [58]. This activity is partially related to the antioxidant activity of these compounds since the overproduction of oxygen free radicals leads to oxidative DNA damage. This damage is leading cause of the proliferation of several types of cancer, such as breast, colon, bladder, pancreatic, liver, skin, and prostate cancer [59]. Dietary polyphenols, including CGAs, can protect the initiation of tumor processes by inhibiting DNA lesions caused by both free radicals and carcinogens [60]. Indeed, some epidemiological studies demonstrated an inverse relationship between coffee consumption and the risk of certain types of cancer. This effect has been associated with the intake of CGAs [61][62][63]. Several mechanisms have suggested that CGAs may have a chemopreventive effect [36]. Among those, modulation of the expression of enzymes involved as endogenous antioxidant defenses, in DNA replication, as well as in cell differentiation and aging are prominent [60][64]. Moreover, metal chelation, inactivation of reactive compounds, and changes in metabolic pathways have been proposed to impact anticancer activity significantly [65]. Boettler et al. [66] demonstrated by in vitro and in vivo assays that coffee-derived CGAs can induce a cellular and tissue protection mechanism against carcinogenesis via the Nrf2/ARE pathway. This pathway regulates the expression of S-transferases (GST), γ-glutamate-cysteine ligase (γGCL), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase (H01). In another study by Feng et al. [64] using mouse epithelial JB6 cells, it was found that 5CQA had a protective effect against carcinogens. This effect was due to its ability to decrease the generation of free radicals and stimulate glutathione-S-transferase activity.

6. Antidiabetic Activity

According to International Diabetes Federation [67] diabetes (type 1 and 2) is one of the fastest-growing global health emergencies of the 21st century. It was estimated that 537 million adults aged 20–79 years are currently living with diabetes and type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for over 90% of all diabetes worldwide [67]. Several studies have demonstrated an association between moderate consumption of coffee and a lower risk of developing T2DM. This was observed in all sexes, obesity levels, and geographic locations [68][69][70][71][72][73][74][75]. This effect has been attributed to the bioactive compound 5-CQA. Through a meta-analysis, Huxley et al. [76] concluded that daily consumption of three to four cups of coffee decreased the risk of T2DM by 25%.
Furthermore, Bakuradze et al. [77] suggested that consumption of three to four cups of coffee per day could reduce oxidative damage, body fat mass, and energy/nutrient intake and that these effects were partially attributed to CGAs. Shearer et al. [78] studied the effects of regular and decaffeinated coffee (with CGAs) consumption for 28 days on insulin functions, in vivo using a rat model. They observed that the ingestion of decaffeinated coffee improves insulin-stimulated disposal in the high-fat-fed and insulin-resistant rats. Other suggested mechanisms of CGAs are related to the improvement of glucose and lipid metabolism by activating of AMP activated protein kinase (AMPK) [75], as shown in Figure 23. AMPK is a master sensor and regulator of cellular energy balance. This enzyme is activated by diverse pathological, metabolic, and pharmacological stressors such as hypoxia, exercise, thiazolidinediones, and metformin. This activation provokes the translocation of glucose transporter type 4 (GLUT4) from intracellular membranes to plasma and, therefore, the increase of glucose transport [75][79][80].
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Figure 23.
 5CQA-mediated regulation of glucose and lipid metabolism through activation of the AMPK pathway.

7. Cardiovascular Protection Activity

Currently, cardiovascular diseases (CVDs) comprise one of the leading causes of death and disability worldwide. The incidence of various chronic CVDs, including stroke, atherosclerosis, hypertension, ischemic heart disease, and heart failure, probably continues to increase [1]. Some risk factors, such as smoking, high blood pressure, hyperlipidemia, and hyperglycemia, have been reported to contribute, partially, to the development of CVDs [1]. According to the World Health Organization (WHO), ischemic heart disease is the leading cause of death worldwide, accounting for 16% of deaths worldwide (8.9 million people) [81]. Recently, many studies have shown that the consumption of CGAs-rich foods may be recommended to prevent CVDs [4][75][82][83][84]. The high antioxidant and anti-inflammatory activity of CGAs can improve endothelial dysfunction and reduce insulin resistance which could be critical mechanisms to enhance the cardiovascular protection attributed to these compounds, as shown in a large number of in vitro and in vivo studies [22]. Taguchi et al. [85] observed that CGAs could improve endothelial function through by releasing of vasoactive molecules such as nitric oxide. This effect was studied in streptozotocin-treated diabetic rats. On the other hand, CGAs could decrease blood pressure by the following proposed mechanisms: (i) stimulation of nitric oxide production through the endothelium-dependent pathway [86], (ii) reduction of free radicals through decreased expression and activity of NADPH oxidase [87], and (iii) through inhibition of the angiotensin-converting enzyme (ACE) [22].

8. Antibacterial, Antifungal, and Antiviral Activity

The antimicrobial (bacteriostatic and bactericidal) effects of 5-CQA and coffee extracts on various types of detrimental microorganisms that may grow in different parts of the body, from oral bacteria causative of caries to harmful intestinal bacteria, are well known. Roasted C. arabica and C. canephora extracts and brews exhibited antibacterial activity against Streptococcus mutans and other oral types of bacteria [88][89]. Furthermore, 5-CQA can have a positive affect against the adverse microbiota present in the colon. Therefore, this chlorogenic acid can be used as a preservative and food additive [90]. For this reason, CGAs, mainly 5-CQA, could be potential natural antibacterial, antifungal and antiviral agents [91]. For example, 5-CQA exhibited a broad-spectrum antimicrobial activity against Gram-positive (Streptococcus pneumoniae, Staphylococcus aureus, and Bacillus subtilis) and Gram-negative (Escherichia coli, Shigella dysenteriae, and Salmonella typhimurium) pathogenic bacteria by increasing the membrane permeability, leading to plasma membrane barrier dysfunction, as well as leakage of nucleotide [92][93]. The suggested mechanism by which 5-CQA provokes the membrane disruption could involve the perturbation of the membrane lipid bilayer, resulting in cell leakage and dissipation of the membrane electrical potential [1][93].
In addition, Sung and Lee [94] studied the antifungal properties of 5-CQA against Candida albicans, a pathogenic yeast. They suggested that this compound could exert antifungal activity by disrupting the cell membrane structure and consequently, it can be used as an option for fungal treatment. In several studies, both caffeic acid and 5-CQA have demonstrated multiviral activities against herpes simplex virus (HSV) types 1 and 2 [95], adenovirus [96], and HIV [97].

9. Other Bioactivities

9.1. Hepatoprotective Activity

The beneficial effects of coffee on liver diseases, in general, have been reported in several studies [98][99][100] for example, cirrhosis and hepatitis B and C [100]. Hepatic injury may be due to multiple factors, such as viral hepatitis, obesity, excessive alcohol consumption, and iron overload [22]. On the other hand, according to a meta-analysis of 16 human studies, coffee consumption (2 cups per day) decreased the risk of developing liver cancer by 40% compared to no coffee consumption [101][102]. The suggested mechanisms of hepatic protection were the prevention of cell apoptosis and oxidative stress damage due to the activation of natural antioxidant and anti-inflammatory systems [103][104]. These protective mechanisms have been mainly related to CGA [105] and caffeine [106], among other components of coffee.

9.2. Potential Prebiotic Activity

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), a prebiotic definition is “a substrate that is selectively utilized by host microorganisms conferring a health benefit” [107]. Usually, well-established prebiotics are carbohydrate-based, but other substances such as polyphenols and polyunsaturated fatty acids transformed into their respective conjugated fatty acids can potentially fit into this new prebiotic definition, provided there is sufficient evidence of their positive effect on the host [107]. The consumption of prebiotic foods or compounds selectively favors the growth of probiotic and other health-promoting microorganisms in the gut, especially Bifidobacterium and Lactobacillus [108][109][110]. Thus, indirectly, the health benefits of prebiotics are the following: (i) production of short-chain fatty acids that lower luminal pH, (ii) stimulation of the growth of beneficial intestinal bacteria and suppression of pathogenic bacteria [109][110], (iii) stimulation of the immune system [111][112], (iv) prevention of colon cancer [113], (v) decrease the prevalence to develop diabetes [114][115], and (vi) increased calcium absorption [116]. Furthermore, Kellow et al. [117] observed that dietary supplementation with prebiotics could reduce or delay the accumulation of advanced glycation end products (AGEs) formed through the Maillard reaction in individuals at high risk for type 2 diabetes and improve or restore the microbial balance within the gastrointestinal tract, potentially reducing AGE absorption.
Several studies have suggested that the non-absorbed part of 5-CQA and caffeic acid in the human gastrointestinal tract serves as a substrate for beneficial intestinal microbiota, thus stimulating their growth [118][119]. Whereas the bifidogenic effect of 5-CQA would seem consensus [16][17], the effect of 5-CQA on Lactobacillus growth remains debatable, as only selected strains can utilize it as a substrate [17][18]. Furthermore, Parkar et al. [16] reported an increase in short-chain fatty acids (butyric, acetic, and propionic acid) promoted by 5-CQA. Nevertheless, it has also been observed that 5-CQA promotes the growth of Firmicutes and Bacteroides, and Clostridium. Moreover, an inhibitory effect on the growth of E. coli has only been demonstrated in one study [93]. Therefore, more studies are needed to validate the effect of 5-CQA as a prebiotic.

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