A pharmacological review and further research of chlorogenic acid

Wang Qing-hua, Du Ting-ting, Zhang Zhi-hui, Ji Ming, Hu Hai-yu, Chen Xiao-guang*

(State Key Laboratory of Small Molecular Tumor Immunotherapy Drug Research, Chinese Academy of Medical Sciences, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China)

Abstract: In recent years, the research on chlorogenic acid (CGA) has developed rapidly, and has a wide range of applications in the fields of medicine, chemical industry and food. It has potential and broad application prospects. As a water-soluble phenolic compound, it is widely distributed in the plant kingdom. It has strong biological activity and a wide range of pharmacological effects. This article intends to review the pharmacological effects and mechanisms of chlorogenic acid from several aspects such as antibacterial, antiviral, antitumor, antioxidant and anti-inflammatory and treatment of metabolic diseases. The purpose is to provide important theoretical basis for the in-depth research on the mechanism of chlorogenic acid and confirming the action target.

Key words: chlorogenic acid; pharmacological action; mechanism

Chlorogenic acid is a phenolic acid synthesized by the carboxyl group of caffeic acid and the hydroxyl group of quinic acid. It is a phenylpropanoid substance synthesized by plant cells through the shikimic acid pathway. Its molecular structure contains ester bond, unsaturated double bond, polyphenol and o-diphenol hydroxyl group [1, 2]. Chlorogenic acid has a high content in Eucommia, honeysuckle, green coffee beans, potatoes, apples, tea and other plants [3-5]. It has many pharmacological effects such as antioxidant, antibacterial, antiviral, anti-tumor, hypolipidemic, hypoglycemic and immune regulation [6-8], and has been widely used in food, medicine and chemical industry [9] (FIG. 1). With the advancement of science and technology and the deepening of research, the pharmacological mechanism of chlorogenic acid has been paid more and more attention. The pharmacological action and mechanism of chlorogenic acid were reviewed in order to provide reference for the research and development of chlorogenic acid.

Figure 1 The application of chlorogenic acid from green coffee beans in weight loss

1 Pharmacological action and mechanism of chlorogenic acid 1.1 Antibiosis

 A large number of studies have proved that chlorogenic acid has broad-spectrum antifungal and bacterial effects [7]. Martine et al. [10] reported in 2017 that chlorogenic acid has antifungal activity against a variety of plant pathogenic fungi and has the potential of biological fungicide. The mechanism is to control the growth of different plant pathogenic fungi by inhibiting the early membrane penetration of fungal spores. It has been extensively reported that chlorogenic acid works by damaging the cell membranes of Streptococcus pneumoniae, Staphylococcus aureus and Shigella dysenteriae. The permeability of outer and plasma membranes is increased, resulting in the loss of barrier function of bacteria, and then exerting their antibacterial activity [11, 12]. Ren et al. [13] coated chlorogenic acid on the surface of polydimethylsiloxane (silicone oil) to disinfect silicone oil. The new mechanism of its antibacterial effect is to reduce the hardness of bacterial cell wall, slow down the migration of bacteria and affect the stability of bacterial cell membrane. Lee's research group [14] clarified that the mechanism of inhibitory effect of chlorogenic acid is to induce the depletion of active oxygen species and then induce the apoptosis-like death of Escherichia coli. In summary, the in-depth study of the antibacterial mechanism of chlorogenic acid has laid a solid foundation for the research and development of new antibiotics.

1.2 Antivirus

      Chlorogenic acid and its derivatives have been well documented as natural compounds that inhibit a wide range of different types of viruses, including Human immunodeficiency virus (HIV), influenza A virus (H1N1/H3N2), Herpes simplex virus (HSVs), Hepatitis B virus (HBV), etc. [15, 16]. In 1997, Robinson et al. [17] reported that chlorogenic acid could inhibit HIV-1 integrase. In 2006, Tamura et al. [18] verified that chlorogenic acid can effectively inhibit HIV virus on human lymphoma cell line MT-2, providing a new lead compound for HIV drug design. Nikolai's research group [19] first reported in 2016 that chlorogenic acid and its derivatives could inhibit the neuraminidase activity of viruses. Ding et al. [20] also proved that chlorogenic acid could effectively inhibit the infection of influenza A virus (H1N1/H3N2) in the later stage of infection. Through indirect immunofluorescence analysis, chlorogenic acid has been shown to down-regulate the expression of Nucleoprotein (NP) of the virus, and has been shown to inhibit viral infection by inhibiting neuraminidase activity at the cellular and animal levels. The Zhao research group [21] proved that the addition of chlorogenic acid can significantly improve the survival rate of HSV-1 infected microglia (BV2), and at the same time inhibit TLR2 (Toll-like receptor, toll-like receptor, toll-like receptor) in infected cells. necrosis factor-α (TNF-α) and IL-6 (interleukin, Myeloid differentiation factor88 (Myd88) increased and decreased necrosis factor-α (TLR), TLR9, and myeloid differentiation Factor88 (MYD88). Interleukin, IL) release. Therefore, chlorogenic acid has been shown to treat viral infection by effectively inhibiting viral infection production and inflammatory response. In 2009, Wang et al. [22] demonstrated that chlorogenic acid could inhibit HBV-DNA replication and Hepatitis B surface antigen (HBsAg) production using HepG2.2.15 cells and duck hepatitis B virus infection model. Therefore, chlorogenic acid is expected to be a potential broad-spectrum antiviral drug.

1.3Anti-tumor

In the 1980s, chlorogenic acid was found to have an inhibitory effect on tumors, thus attracting widespread attention [23]. Since then, more and more studies have been conducted on its inhibition of different types of tumors and its mechanisms. In 2017, our research group reported for the first time that chlorogenic acid inhibited the growth of brain glioma by affecting the M1/M2 polarization typing of macrophages (i.e. promoting M1 macrophages and inhibiting M2 phenotype macrophages) [24]. Jiang's research group [25] reported that chlorogenic acid has obvious inhibitory effect on liver cancer, lung cancer and glioma, and its mechanism is not through direct killing effect, but through influencing the induction of tumor cell differentiation to inhibit tumor, and pointed out that chlorogenic acid is expected to become a safe and effective inducer of tumor differentiation. Hou et al. [26] found that chlorogenic acid inhibits colon cancer by inducing the production of reactive oxygen species. Sapio et al. [27] reported that chlorogenic acid inhibits the proliferation of osteosarcoma cells by activating Extracellular regulated protein kinases 1/2 (ERK1/2). Motoki Tagami's research group [28] reported that chlorogenic acid can inhibit lung cancer cells by affecting the expression of apoptosis-related genes. Although the antitumor mechanism of chlorogenic acid has been reported in a large number of literatures, the views are not consistent. Therefore, the search and mechanism of potential targets need to be further explored.

1.4 Antioxidant and anti-inflammatory

 Chlorogenic acid is a secondary metabolite of polyphenols widely found in plants with strong antioxidant and anti-inflammatory properties. The presence of catechol structure provides binding sites for free radicals [29, 30]. Chlorogenic acid can chelate metal ions and scavenge free radicals (superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (•OH), hypochlorous acid (HOCl), hydrochloric acid (H2O2), and hydrochloric acid (HOCL). Peroxynitrite anion (ONOO-) and nitric oxide (NO) [31-33]. Lu et al. [34] reported that chlorogenic acid showed strong antioxidant activity, its scavenging activity of DPPH free radicals was 2-3 times that of vitamins C and E, and its scavenging activity of superoxide anion free radicals was 10-30 times that of vitamins C and E. In recent years, the anti-inflammatory effect of chlorogenic acid has also attracted much attention. In 2006, Dos Santos et al. [35] reported for the first time the anti-inflammatory activity of chlorogenic acid in a rat inflammation model induced by lipopolysaccharide. Subsequently, a lot of literature on its anti-inflammatory mechanism has been deeply discussed. In 2018, Hee, etc. [36] found that chlorogenic acid can inhibit the intestinal epithelial cells induced by oxidative stress in the production of IL - 8 to have anti-inflammatory effect, and to clarify its mechanism of action is by eliminating intracellular Reactive oxygen species (Reactive oxygen species, ROS inhibits IL-8 production through activation of Protein kinase D-Nuclear factor kappa-B (PKD-NF-κB) signaling pathway. In the same year, Liang et al. [37] also pointed out that chlorogenic acid and its isomers could inhibit IL-8 production in Caco-2 epithelial cells by inhibiting p38 cascade phosphorylation and up-regulating NF-κB signaling pathway. Gao et al. [38] found in the mouse ulcerative colitis model induced by glucose-sulfate that chlorogenic acid regulates Mitogen-activated protein kinase. MAPK /ERK/c-Jun N-terminal kinase (JNK) signaling pathway to reduce tissue inflammation. The experiments of Fu et al. [39] prove that chlorogenic acid is a promising new therapeutic agent for Rheumatoid arthritis (RA) by reducing NF-κB and B cell-activating factor. The DNA-binding capacity of the BAFF promoter region inhibited the BAFF expression of the NF-κB pathway in TNF-α-stimulated MH7A cells. Shi et al. [40] proved that chlorogenic acid can effectively reduce the production of TNF-α, IL-6 and IL-1β inflammatory factors in CCL4-induced acute liver injury by activating Nuclear factor erythroid 2-related factor 2, Nrf2) signaling pathway and inhibition of nucleotide-binding oligomer domains, (Nucleotide- binding oligomerization domain, leucine- rich repeat and pyrin domain- containing 3, (Nucleotide- binding oligomerization domain, Leucine - rich repeat and pyrin domain- containing 3, NLRP3) inflammasome activation to protect against acute liver injury. Tsai et al. [41] treated HUVEC cells with oxidized low-density lipoprotein (oxLDL) under the condition of chlorogenic acid pretreatment. The results showed that pretreatment with chlorogenic acid increased the activity level of NAD-dependent Sirtuin 1 (SIRT1) and reversed oxLDL-impaired SIRT1 and AMP-activated protein kinase. AMPK)/Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) activity, Oxldl-induced oxidative stress and mitochondrial biogenic dysfunction were alleviated. Its mechanism is to inhibit oxLDL-induced endothelial cell apoptosis by regulating SIRT1 and AMPK/PGC-1 function. Therefore, silencing SIRT1, AMPK, and PGC-1 weakens the ability of chlorogenic acid to resist oxidative stress. Yang et al. [42] reported that chlorogenic acid prevents lipid toxicity induced by saturated Free fatty acid (FFA) by activating mitochondrial morphology regulated by SIRT1. The results show that. Chlorogenic acid alleviates oxidative stress and mitochondrial dysfunction by reducing ROS production and increasing mitochondrial mass and mitochondrial membrane potential; The expression of pro-apoptotic protein Bax (Bcl2 associated X, Bax) was significantly decreased, thereby reducing the mitochondria-mediated Caspase-dependent apoptosis. In terms of mechanism, ROS-induced mitochondrial fragmentation was reduced by inhibiting the expression of dynamin-relatedprotein 1 (Drp1) and enhancing the expression of Mitofusin 2 (Mfn2). Activation of SIRT1 prevented chlorogenic acid from inhibiting mitochondrial ROS and Drp1. Ali, etc. [43] studies have shown that chlorogenic acid has liver protective effect, its mechanism by increasing inhibit apoptosis Bcl2 (2, B lymphocyte tumor B - cell lymphoma 2, Bcl2) - 2 expression and inhibiting ring oxidase (Cyclooxygenase 2, Cox-2), Inducible nitric oxide synthase (iNOS), Bax and Caspases 3, 9 mediated inflammatory response and apoptosis to reduce the hepatotoxicity induced by Methotrexate (MTX). Wang et al. [44] showed that chlorogenic acid inhibited schistosomiasis induced liver fibrosis by affecting IL-13/microRNA-21 (miR-21) /Smad7 signaling interaction in hepatic stellate LX2 cell line. Therefore, chlorogenic acid is expected to be an anti-hepatic fibrosis drug for the treatment of schistosomiasis liver fibrosis. Pathological studies of neurodegenerative diseases (Alzheimer's disease (AD) and Parkinson's disease (PD)) have shown that chronic oxidative stress and pro-inflammatory mechanisms can lead to neuronal damage [45]. Based on the strong antioxidant and anti-inflammatory effects of chlorogenic acid, many scholars have found that it has a good nervous system protection [46]. Some clinical and preclinical studies have shown that coffee extract (the main component chlorogenic acid) has a good effect on AD and PD [47, 48]. Hermawati et al. [49] found that chlorogenic acid can improve memory loss and death of hippohippoal cells after transient global ischemia, and the mechanism is through increasing Bcl2, Superoxide dismutase 2, superoxide dismutase 2, superoxide dismutase 2. SOD2) and Platelet endothelial cell adhesion molecule CD31 (Platelet endothelial cell adhesion molecule - 1, PECAM 1 / CD31) expression and reduce Endothelin (Endothelin - 1, ET-1) expression to improve spatial memory and prevent CA1 pyramidal cell death after bilateral common carotid artery occlusion. Fang research group [50] showed that chlorogenic acid, as an effective free radical scavenger, could significantly protect PC12 cells from oxidative damage. The mechanisms include direct ROS quenching activity and induction of endogenous antioxidant enzymes through activation of Nrf2. Therefore, chlorogenic acid can be used as a potential neuroprotective agent.

1.5 Treatment of metabolic disease

 With the progress of society and the improvement of human material living standard, metabolic related diseases have become an important problem affecting human health worldwide. These include dyslipidemia, hypertension, high fasting blood glucose level, insulin resistance, chronic inflammation and thrombosis [51]. With the gradual development of the advantages of natural products in the treatment of metabolic diseases, people have renewed their interest in natural products. Many studies have evaluated the effects of chlorogenic acid on metabolic diseases, including obesity, dyslipidemia, diabetes, hypertension, metabolic syndrome, and cardiovascular protection [52].

In the treatment of obesity, Wang et al. [53] fed mice on a High fat diet (HFD) and treated them with chlorogenic acid for 6 weeks. The results showed that administration of chlorogenic acid significantly reduced body weight in mice, reduced plasma lipid levels, and altered mRNA expression of genes associated with adipogenesis and lipolysis in adipose tissue. In addition, chlorogenic acid improves HFD-induced intestinal flora disorders and also helps to improve HFD-induced obesity. Han et al. [54] showed that chlorogenic acid can stimulate the thermogenesis of brown fat cells by promoting glucose uptake and mitochondrial function. The mechanism enhances thermogenesis and proton leakage in brown fat cells, upregates Glucose transporter type 2 (GLUT2) and Phosphofructokinase (PFK) to promote glucose absorption, Increases the number and function of mitochondria. In 2019, Xu et al. [55] studied the combined mechanism of chlorogenic acid and caffeine on lipid metabolism in obese mice induced by high fat diet. Feeding chlorogenic acid and caffeine in combination effectively reduced increased body weight, intraperitoneal adipose tissue weight, serum LDL-c, FFA, Totalcholesterol (TC), Triglyceride (TG), leptin, IL-6 concentrations, and liver TG and TC levels. It also increased serum adiponectin levels, promoted AMPKα phosphorylation, and inhibited transcription regulatory factor Sterol regulatory element-binding protein-1c (Sterol regulatory element-binding protein-1c). SREBP-1c) and Liver X receptor α (LXRα) expression, and decreased Fatty acid synthesis (FAS) and 3-hydroxy-3-methylglutaryl CoA Reductase (HMG-CoA reductase), The expression of HMGR. In addition, the expression of Adipose triglyceride lipase (ATGL) and Hormone-sensitive lipase (HSL) in adipose tissue was increased. The results showed that the combination of chlorogenic acid and caffeine can activate AMPKα-LXRα/ SREBP-1c signaling pathway, which has anti-obesity effect and regulation of lipid metabolism in obese mice induced by high fat diet. In the same year, Kumar et al. [56] also reported that chlorogenic acid controlled obesity by activating AMPK, inhibiting HMGR and enhancing the activity of Carnitine palmitoyltransferase 1 (CPT1). Cho et al. [57] studied the effects of chlorogenic acid on weight, body fat and obesity-related hormones of obese mice induced by high fat diet. Both chlorogenic acid and caffeic acid significantly reduced body weight, visceral fat mass, plasma leptin and insulin levels, triglycerides in the liver and heart, and cholesterol in adipose tissue and heart compared to the high-fat diet control group. Huang et al. [58] obtained similar results in rat experiments, where chlorogenic acid inhibited the increase of internal and visceral fat and free fatty acids induced by high fat diet in a dose-dependent manner. Similarly, human studies have shown that foods rich in chlorogenic acid have anti-obesity effects. Thom[59] gave 30 overweight subjects five cups of regular instant Coffee or Coffee Slender® (rich in chlorogenic acid) per day for 12 weeks. Participants who drank Coffee Slender® had a significant weight loss, 80% of which was due to body fat, while the effects of weight loss and body fat loss were not significant in participants who drank regular instant coffee. In addition, Soga et al. [60] studied the effect of chlorogenic acid on human energy metabolism. In 18 healthy male subjects who consumed 185 ml of test beverages (329 mg) with or without chlorogenic acid daily for 4 weeks, indirect calorimetry showed that beverages containing chlorogenic acid significantly improved postprandial energy utilization compared to control beverages, and subjects who consumed beverages containing chlorogenic acid had higher postprandial fat utilization.

In terms of controlling dyslipidemia, Cho et al. [57] observed that both chlorogenic acid and caffeic acid significantly reduced free fatty acids, triglycerides and cholesterol in mouse plasma, and significantly increased the ratio of HDL cholesterol to total cholesterol compared with the high-fat control group. Huang et al. [58] found that chlorogenic acid inhibited serum lipid levels induced by high fat diet in a dose-dependent manner. Wan et al. [61] studied the effect of chlorogenic acid on hypercholesterolemia in rats. Chlorogenic acid significantly decreased total cholesterol and low density lipoprotein cholesterol, and increased high density lipoprotein cholesterol; In addition, atherosclerosis index and cardiac risk factors were improved.

In the treatment of diabetes, Ong et al. [62] observed that chlorogenic acid inhibited the expression and activity of glucose-6-phosphatase (G-6-P) in the liver of Leprdb/db diabetic mice, reduced hepatic steatosis, improved lipid distribution and skeletal muscle Glucose uptake. Thereby improving fasting blood glucose levels, glucose tolerance, insulin sensitivity and dyslipidemia. Attila et al. [63] studied the anti-diabetic activity of the leaf extract of white mulberry and its three main components (chlorogenic acid, rutin and isoquercetin). In a streptomycin-induced diabetic rat model, non-fasting glucose levels of leaf extract, chlorogenic acid and rutin of white mulberry were found to decrease dose-dependent, but not isoquercetin. Jin et al. [64] studied the effects of chlorogenic acid on glucose and lipid metabolism in mice with advanced diabetes. Body fat, fasting blood glucose, and percentage of glycosylated Hemoglobin (HbA1c) were significantly lower in the chlorogenic acid group compared to the control group. Kim et al. [65] determined the effect of chlorogenic acid on sugar-induced cataract through a rat galactose-induced cataract model. Experiments have shown that oral chlorogenic acid for two weeks can effectively prevent the development of sugar cataracts. Bagdas et al. [66] studied the effect of chlorogenic acid treatment on wound healing in rats with diabetes. Streptomycin was used to induce a diabetic rat model and wound was formed on its back. By observing the time of wound healing, chlorogenic acid was found to accelerate wound healing. Johnston et al. [67] evaluated the antidiabetic effect of chlorogenic acid in coffee. The experimental results showed that chlorogenic acid could significantly reduce glucagon-dependent insulinotropic polypeptide (GIP) and significantly increase Glucagon-like peptide-1, Glucagon-like peptide-1, glucagon-dependent insulinotropic polypeptide (GIP) and glucagon-dependent insulinotropic polypeptide (GIP). The results showed that chlorogenic acid effectively reduced the intestinal glucose absorption rate and had antagonistic effect on glucose transport. Similarly, Iwai et al. [68] evaluated the hypoglycemic effect of caffeine-free green coffee bean extract rich in chlorogenic acid on 45 subjects. A significant decrease in plasma glucose was found after consumption of beverages containing chlorogenic acid, but no significant change in plasma insulin profile was observed. Ahrens[69] studied the anti-diabetic effects of Emulin™, a patented mixture of chlorogenic acid, myricetin, and quercetin. Forty patients with type 2 diabetes were treated. The results show that if taken regularly, EmulinTM not only has the acute effect of reducing food blood sugar, but also can reduce the blood sugar level in type 2 diabetes patients in the long term. Based on the regulatory effect of chlorogenic acid on glucose metabolism disorders in humans, Gao et al. [70] identified the target of chlorogenic acid as Protein kinase B (AKT) through the functionalized magnetic microglobulin modified by chlorogenic acid. The co-localization of chlorogenic acid and AKT was further demonstrated by immunofluorescence of chlorogenic acid molecular probe. At the same time, we elucidate its mechanism of action by directly targeting the PH domain of AKT, activating AKT phosphorylation on Ser-473, and inducing phosphorylation of downstream molecules. Glycogen synthase kinase 3 (GSK3) and Forkhead box O1 (FOXO1) regulate glucose metabolism.

In the treatment of metabolic syndrome, Ma et al. [71] evaluated the role of chlorogenic acid in metabolic syndrome and found that the prevention and treatment of chlorogenic acid had a good effect on obesity and obesity-related liver steatosis and insulin resistance in mice. Chlorogenic acid is effective in preventing weight gain, inhibiting the development of hepatic steatosis, and reducing insulin resistance induced by high fat diet. Patti et al. [52] evaluated the effect of a natural supplement containing chlorogenic acid on patients with metabolic syndrome. In 78 patients with metabolic syndrome who continued taking the drug for 4 months, significant reductions in body weight, body mass index, waist circumference, fasting blood glucose, and body weight were observed, and effective reductions in total cholesterol were also observed.

Chlorogenic acid has shown good efficacy in the treatment of cardiovascular system and thromboembolic diseases. At the cellular level, Sancheza et al. [72] showed that after treating 3T3-L1 adipocytes with 200 mM chlorogenic acid, the intracellular calcium concentration increased by 9 times compared with the control, and the secretion of insulin was also promoted. At the same time, it significantly improves PPARg (Peroxisome proliferator-activated receptor), peroxisome proliferator-activated receptor, mRNA expression of PPAR (150 %) and GLUT4 (220 %), PPARa (40 %) and Fatty acid transporters (FATP) (25 %). Therefore, it can be used as a sensitizer and lipid-lowering agent to stimulate insulin. In overall animals, Suzuki et al. [73] reported that chlorogenic acid reduced blood pressure and improved vascular function in spontaneously hypertensive rats. Its mechanism reduces oxidative stress and improves nitric oxide bioavailability by inhibiting the excessive production of reactive oxygen species in the vascular system, thereby alleviating endothelial dysfunction, vascular hypertrophy and hypertension in spontaneously hypertensive rats. In humans, foods high in pure chlorogenic acid and chlorogenic acid can have a positive effect on blood pressure. Kozuma et al. [74] targeted 117 healthy men with mild hypertension. Groups were given chlorogenic acid at different concentrations for 28 days, and it was found that chlorogenic acid could effectively reduce Systolic blood pressure (SBP) and Diastolic blood pressure (DBP), because chlorogenic acid has antioxidant properties. Improves endothelial dysfunction and lowers blood pressure. Watanabe et al. [75] also proved that chlorogenic acid can effectively reduce blood pressure in patients with hypertension. Mubarak et al. [76] studied the acute effects of chlorogenic acid on nitric oxide status, endothelial function and blood pressure. The results showed that both systolic and diastolic blood pressure of the subjects given chlorogenic acid were significantly reduced, and no status and endothelial function were not significantly affected. Chlorogenic acid can be used to prevent cardiovascular damage caused by diabetes [77]. Stefanello et al. [78] showed that chlorogenic acid as an anticoagulant can significantly reduce platelet aggregation in diabetic rats after 30 days of chlorogenic acid treatment under the stimulation of Adenosine diphosphate (ADP). In addition, Fuentes et al. [79] demonstrated that chlorogenic acid inhibited platelet A2A receptor/Cyclic adenosine phosphate (cAMP)/Protein kinase A (Kinase A). PKA signal activation pathway inhibited arterial thrombosis in mice. In this review, the mechanism of action of chlorogenic acid in the treatment of metabolic diseases is summarized (Figure 2).

Figure 2 Mechanisms of action of chlorogenic acid over metabolic diseases.

Abbreviations: AMPK = AMP-activated protein kinase, CPT1 = Carnitine palmitoyltransferase 1, FAS = Fatty acid synthase, FFA = Free fatty acid, GLUT2=Glucose transporter type 2, G-6-P = Glucose-6-phosphatase, GIP = Glucose-dependent insulinotropic polypeptide, GLP-1=Glucagon-like peptide-1, HMGCR = 3-hydroxy-3-methylglutaryl CoA reductase, LXR = Liver X receptor, NO = Nitric oxide, PFK = Phosphofructokinase, PPAR = Peroxisome proliferator-activated receptor, ROS = Reactive oxygen species, SREBP-1c = Sterol regulatory element-binding protein 1c

2 Summary

        In recent years, there are more and more reports on chlorogenic acid, which has become one of the research hotspots in the field of natural products. Chlorogenic acid, as one of the main active components of many Chinese herbal medicines such as honeysuckle, Eucommia, coffee and wormwood, has been used more and more widely with the in-depth study of its biological activity. Chlorogenic acid has been sold as a health care product for weight loss in foreign countries. In our country, chlorogenic acid is also being used as an antitumor agent in Phase II clinical studies of advanced recurrent glioblastoma. However, it is worth noting that although China has a long history of the use of traditional Chinese medicine containing chlorogenic acid and its derivatives, there are still great deficiencies in the exploration of the molecular mechanism of chlorogenic acid and the verification of targets, which is also a problem that we will focus on solving in the future.

References

[1] Kühnl T, Koch U, Heller W, et al. Chlorogenic acid biosynthesis: characterization of a light-induced microsomal 5-O-(4-coumaroyl)-D-quinate/shikimate 3'-hydroxylase from carrot (Daucus carota L.) cell suspension cultures [J]. Arch Biochem Biophys, 1987, 258(1): 226-232.

[2] Lallemand L A, Zubieta C, Lee S G, et al. A structural basis for the biosynthesis of the major chlorogenic acids found in coffee [J]. Plant Physiol, 2012, 160(1):249-260.

[3] Lepelley M, Cheminade G, Tremillon N, et al. Chlorogenic acid synthesis in coffee: An analysis of CGA content and real-time RT-PCR expression of HCT, HQT, C3H1, and CCoAOMT1 genes during grain development in C. canephora [J]. Plant Sci, 2007, 172(5): 978-996.

[4] Duarte G S, Pereira A A, Farah A. Chlorogenic acids and other relevant compounds in Brazilian coffees processed by semi-dry and wet post-harvesting methods [J]. Food Chem, 2010, 118(3):851-855.

[5] Wang Z, Clifford M N. Comparison of the profiles of chlorogenic acids and their derivatives from three Chinese traditional herbs by LC-MSn [J]. Acta Pharm Sin, 2008, 43(2):185-190.

[6] Naveed M, Hejazi V, Abbas M, et al. Chlorogenic acid (CGA): A pharmacological review and call for further research [J]. Biomed Pharmacother, 2018, 97:67-74.

[7] Bagdas D, Gul Z, Meade J A, et al. Pharmacologic Overview of Chlorogenic Acid and its Metabolites in Chronic Pain and Inflammation [J]. Curr Neuropharmacol, 2020, 18(3):216-228.

[8] Li Y, Wang Q, Yao X, et al. Induction of CYP3A4 and MDR1 gene expression by baicalin, baicalein, chlorogenic acid, and ginsenoside Rf through constitutive androstane receptor- and pregnane X receptor-mediated pathways [J]. Eur J Pharmacol, 2010, 640(1-3):46-54.

[9] Santana-Gálvez Jesús, Luis C Z, Jacobo-Velázquez Daniel. Chlorogenic acid: recent advances on its dual role as a food additive and a nutraceutical against metabolic syndrome [J]. Molecules, 2017, 22(3):358.

[10] Martínez G, Regente M, Jacobi S, et al. Chlorogenic acid is a fungicide active against phytopathogenic fungi [J]. Pestic Biochem Physiol, 2017, 140:30-35.

[11] Lou Z, Wang H, Zhu S, et al. Antibacterial activity and mechanism of action of chlorogenic acid [J]. J Food Sci, 2011, 76:M398-M403.

[12] Li G, Wang X, Xu Y, et al. Antimicrobial effect and mode of action of chlorogenic acid on Staphylococcus aureus [J]. Eur Food Res Technol, 2014, 238:589-596.

[13] Ren S, Wu M, Guo J, et al. Sterilization of polydimethylsiloxane surface with Chinese herb extract: a new antibiotic mechanism of chlorogenic acid [J]. Sci Rep, 2015, 5:10464.

[14] Lee B, Lee D G. Depletion of reactive oxygen species induced by chlorogenic acid triggers apoptosis-like death in Escherichia coli [J]. Free Radic Res, 2018, 52(5):1-11.

[15] Neamati N, Hong H, Sunder S, et al. Potent inhibitors of human Immunodeficiency virus type 1 integrase: identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors [J]. Mol Pharmacol, 1997, 52(6):1041.

[16] Utsunomiya H, Ichinose M, Uozaki M, et al. Antiviral activities of coffee extracts in vitro [J]. Food Chem Toxicol, 2008, 46(6):1919-1924.

[17] Robinson W E, Cordeiro M, Abdel-Malek S, et al. Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: Inhibition of the core catalytic domain of human immunodeficiency virus integrase [J]. Mol Pharmacol, 1996, 50(4):846-855.

[18] Tamura H, Akioka T, Ueno K, et al. Anti-human immunodeficiency virus activity of 3,4,5-tricaffeoylquinic acid in cultured cells of lettuce leaves [J]. Mol Nutr Food Res, 2006, 50(4-5): 396-400.

[19] Karar M G E, Matei M F, Jaiswal R, et al. Neuraminidase inhibition of dietary chlorogenic acids and derivatives-potential antivirals from dietary sources [J]. Food Funct, 2016, 7: 2052-2059.

[20] Ding Y, Cao Z, Cao L, et al. Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase [J]. Sci Rep, 2017, 7:45723.

[21] Guo Y J, Luo T, Wu F, et al. Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia [J]. Life Sciences, 2015, 127:12-18.

[22] Wang G F, Shi L P, Ren Y D, et al. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro [J]. Antiviral Res, 2009, 83(2):186-190.

[23] Huang M T, Smart R C, Wong C Q, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate[J]. Cancer Res. 1988, 48(21):5941-5946.

[24] Xue N, Zhou Q, Ji M, et al. Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype [J]. Sci Rep, 2017, 7:39011.

[25] Huang S, Wang L L, Xue N N, et al. Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation [J]. Theranostics. 2019, 9(23): 6745-6763.

[26] Hou N, Liu N, Han J, et al. Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells [J]. Anti-Cancer Drugs, 2016, 28(1):1.

[27] Sapio L, Salzillo A, Illiano M, et al. Chlorogenic acid activates ERK1/2 and inhibits proliferation of osteosarcoma cells [J]. J Cell Physiol. 2020, 235:3741-3752.

[28] Yamagata K, Izawa Y, Onodera D, et al. Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells [J]. Mol and Cell Biochem, 2018, 441: 9-19.

[29] Kono Y, Kobayashi K, Tagawa S, et al. Antioxidant activity of polyphenolics in diets. Rate constants of reactions of chlorogenic acid and caffeic acid with reactive species of oxygen and nitrogen [J]. Biochim Biophys Acta, 1997, 1335(3): 335-342.

[30] Riceevans C A, Miller N J, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids [J]. Free Radic Biol Med, 1996, 20(7): 933-956.

[31] Sato, Y, Itagaki, S, Kurokawa, T, et al. In vitro and in vivo antioxidant properties of chlorogenic acid and caeic acid [J]. Int J Pharm, 2011, 403: 136-138.

[32] Kono Y, Kobayashi K, Tagawa S, et al. Antioxidant activity of polyphenolics in diets. Rate constants of reactions of chlorogenic acid and caffeic acid with reactive species of oxygen and nitrogen [J]. Biochim Biophys Acta, 1997, 1335(3): 335.

[33] Zhang L Y, Cosma G, Gardner H, et al. Effect of chlorogenic acid on hydroxyl radical [J]. Mol Cell Biochem, 2003, 247: 205–210.

[34] Lu Y, Foo L Y. Antioxidant and radical scavenging activities of polyphenols from apple pomace [J]. Food Chem, 68(1): p81-85.

[35] Dos Santos M D, Almeida M C, Lopes N P, et al. Evaluation of the Anti-inflammatory, Analgesic and Antipyretic Activities of the Natural Polyphenol Chlorogenic Acid [J]. Biol Pharm Bull, 2006, 29(11): 2236-2240.

[36] Hee S, Hideo S, Min-Jung B, et al. Catechol groups enable reactive oxygen species scavenging-mediated suppression of PKD-NFkappaB-IL-8 signaling pathway by chlorogenic and caffeic acids in human intestinal cells [J]. Nutrients, 2017, 9(2): 165.

[37] Liang N, D. Kitts D. Chlorogenic acid (CGA) isomers alleviate interleukin 8 (IL-8) production in Caco-2 cells by decreasing phosphorylation of p38 and increasing cell integrity[J]. Int J Mol Sci, 2018, 19: 3873.

[38] Gao W, Wang C, Yu L, et al. Chlorogenic Acid Attenuates Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice through MAPK/ERK/JNK Pathway [J]. BioMed Res Internat, 2019, 6769789.

[39] Fu X, Lyu X, Liu H, et al. Chlorogenic acid inhibits BAFF expression in collagen-induced arthritis and human synoviocyte MH7A cells by modulating the activation of the NF-κB signaling pathway [J]. J Immunol Res, 2019, 8042097.

[40] Shi A, Shi H, Wang Y, et al. Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury [J]. Int Immunopharmacol, 2018, 54:125-130.

[41] Tsai K L, Hung C H, Chan S H, et al. Chlorogenic acid protects against oxLDL-induced oxidative damage and mitochondrial dysfunction by modulating SIRT1 in endothelial cells [J]. Mol Nutr Food Res, 2018, 1700928.

[42] Yang L, Wei J, Sheng F, et al. Attenuation of palmitic acid-Induced lipotoxicity by chlorogenic acid through activation of SIRT1 in hepatocytes [J]. Mol Nutr Food Res, 2019, 63 (14): 1801432.

[43] Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress inflammation and apoptosis in rat liver: An experimental approach [J]. Chem Biol Interact, 2017, 272: 80-91.

[44] Wang Y, Yang A F, Xue B J, et al. Antischistosomiasis liver fibrosis effects of chlorogenic acid through IL-13/miR-21/Smad7 signaling interactions in vivo and in vitro [J]. Antimicrob Agents Chemother, 2016, 61(2): e01347-16.

[45] Nabavi S M, Manayi A, Daglia M, et al. Chlorogenic acid and mental diseases: from chemistry to medicine [J]. Curr Neuropharmacol, 2017, 15(4): 471-479.

[46] Lin M T, Beal M F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases [J]. Nature, 2006, 443(7113): 787-795.

[47] Ascherio A, Chen H, Schwarzschild M A, et al. Caffeine, postmenopausal estrogen, and risk of Parkinsons disease. Neurology, 2003, 60(5), 790-795.

[48] Arendash G W, Schleif W, Rezai-Zadeh K, et al. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production [J]. Neuroscience, 2006, 142(4): 941-952.

[49] Hermawati E, Arfian N, Mustofa, et al. Chlorogenic acid ameliorates memory loss and hippocampal cell death after transient global ischemia [J]. Eur J Neurosci, 2020, 51: 651–669.

[50] Juan Y, Peng S, Xu J, et al. Reversing ROS-mediated neurotoxicity by chlorogenic acid involves its direct antioxidant activity and activation of Nrf2-ARE signaling pathway [J]. Biofactors, 2019, 45(4):616-626.

[51] Gregory K, Panagiota P, Eva K, et al. Metabolic syndrome: definitions and controversies [J]. BMC Med, 2011, 9(1):48-48.

[52] Patti A M, Al-Rasadi K, Katsiki N, et al. Effect of a natural supplement containing Curcuma longa, Guggul, and chlorogenic acid in patients with metabolic syndrome [J]. Angiology, 2015, 66, 856-861.

[53] Wang Z, Lam K L, Hu J, et al. Chlorogenic acid alleviates obesity and modulates gut microbiota in high-fat-fed mice [J]. Food Sci Nutr, 2019, 7(2): 579-588.

[54] Han X, Zhang Y, Guo J, et al. Chlorogenic acid stimulates the thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria [J]. J Food Sci, 2019, 84 (12): 3815-3824.

[55] Xu M, Yang L, Zhu Y, et al. Collaborative effects of chlorogenic acid and caffeine on lipid metabolism via the AMPKα-LXRα/SREBP-1c pathway in high-fat diet-induced obese mice [J]. Food Funct, 2019, 10: 7489-7497.

[56] Kumar R, Sharma A, Iqbal M S, et al. Therapeutic promises of Chlorogenic acid with special emphasis on its anti-obesity property [J]. Curr Mol Pharmacol, 2020, 13(1):7-16

[57] Cho A S, Jeon S M, Kim M J, et al. Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice [J]. Food Chem Toxicol, 2010, 48(3): 937-943.

[58] Huang K, Liang X C, Zhong Y L, et al. 5-Caffeoylquinic acid decreases diet-induced obesity in rats by modulating PPARα and LXRα transcription [J]. Journal of the Science of Food and Agriculture, 2015, 95(9):1903-1910.

[59] Thom, E. The effect of chlorogenic acid enriched coffee on glucose absorption in healthy volunteers and its effect on body mass when used long-term in overweight and obese people [J]. J Int Med Res, 2007, 35(6): 900–908.

[60] Soga S, Ota N, Shimotoyodome A. Stimulation of postprandial fat utilization in healthy humans by daily consumption of chlorogenic acids [J]. Biosci Biotechnol Biochem, 2013, 77, 1633-1636.

[61] Wan, C W, Wong C N, Pin W K, et al. Chlorogenic acid exhibits cholesterol lowering and fatty liver attenuating properties by up-regulating the gene expression of PPAR-α in hypercholesterolemic rats induced with a high-cholesterol diet [J]. Phytother Res, 2013, 27, 545–551.

[62] Ong K W, Hsu A, Tan B K H. Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation [J]. Biochemn Pharmacol, 2013, 85(9):1341-1351.

[63] Attila H, Ana M, Tusty-Jiuan H, et al. Chlorogenic acid and rutin play a major role in the in vivo antidiabetic activity of Morus alba leaf extract on type II diabetic rats [J]. PloS One, 2012, 7(11): e50619.

[64] Jin S, Chang C, Zhang L, et al. Chlorogenic acid improves late diabetes through adiponectin receptor signaling pathways in db/db mice[J]. PloS One, 2015, 10(4): e0120842.

[65] Kim C S, Kim J, Lee Y M, et al. Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats[J]. Arch Pharm Res, 2011, 34(5):847-852.

[66] Bagdas D, Etoz B C, Gul Z, et al. In vivo systemic chlorogenic acid therapy under diabetic conditions: Wound healing effects and cytotoxicity/genotoxicity profile [J]. Food Chem Toxicol, 2015, 81:54-61.

[67] Johnston K L, Clifford M N, Morgan L M. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine [J]. Am J Clin Nutr, 2003, 78(4):728-733.

[68] Iwai K, Narita Y, Fukunaga T, et al. Study on the postprandial glucose responses to a chlorogenic acid-rich extract of decaffeinated green coffee beans in rats and healthy human subjects [J]. Food Sci Technol Res. 2012, 18: 849-860.

[69] Ahrens, M J, Thompson D L, et al. Effect of emulin on blood glucose in type 2 diabetics [J]. J Med Food, 2013, 16:1-6.

[70] Gao J, He X, Ma Y, et al. Chlorogenic acid targeting of the AKT PH domain activates AKT/GSK3β/FOXO1 signaling and improves glucose metabolism[J]. Nutrients, 2018, 10(10). 10(10): 1366.

[71] Ma Y, Gao M, Liu D. Chlorogenic acid improves high fat diet-induced hepatic steatosis and insulin resistance in mice [J]. Pharm Res, 2015, 32, 1200-1209.

[72] Sancheza M B, Miranda-Pereza E, Gomez J C, et al. Potential of the chlorogenic acid as multitarget agent: Insulin-secretagogue and PPAR a/g dual agonist [J]. Biomed Pharmacother, 2017, 94:169.

[73] Suzuki A, Yamamoto N, Jokura H, et al. Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats [J]. J Hypertens, 2006, 24:1065-1073.

[74] Kozuma K, Tsuchiya S, Kohori J, et al. Antihypertensive effect of green coffee bean extract on mildly hypertensive subjects [J]. Hypertens Res, 2005, 28, 711–718.

[75] Watanabe T, Arai Y, Mitsui Y, et al. The blood pressure-lowering effect and safety of chlorogenic acid from green coffee bean extract in essential hypertension [J]. Clin Exp Hypertens, 2006, 28: 439-449.

[76] Mubarak A, Bondonno C P, Liu A H, et al. Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: A randomized trial [J]. J Agric Food Chem, 2012, 60, 9130-9136

[77] Stefanelloa N, Spanevellob R M, Passamontic S, et al. Coffee, caffeine, chlorogenic acid, and the purinergic system [J]. Food and Chem Toxicol, 2019, 123: 298-313.

[78] Stefanello N, Schmatz R, Pereira L B, et al. Effects of chlorogenic acid, caffeine and coffee on components of the purinergic system of streptozotocin-induced diabetic rats [J]. J Nutr Biochem, 2016, 38,145-153.

[79] Fuentes E, Caballero J, Alarcón M, et al. Chlorogenic acid inhibits human platelet activation and thrombus formation [J]. PLoS One, 2014, 9e: 90699.