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Phenethyl caffeic acid, the magic substance in propolis

    Propolis has rich and prominent biological activities, and is currently used in food and health products to prevent diseases. Phenethyl caffeic acid is the main active component of propolis, and has attracted much attention because of its antioxidant, anti-inflammatory, anti-tumor, antibacterial and immunomodulatory effects. The content of phenethyl caffeic acid is low in nature, and the traditional extraction method is time-consuming and costly, and the efficient and large-scale preparation of phenethyl caffeic acid has become a research focus.
    As an important source of drug discovery, most natural products have the characteristics of good curative effect and few side effects, and are a huge resource base for new drug research. Propolis is a kind of aromatic resin substance. It is a sticky solid gel formed by mixing plant resin collected by worker bees with secretions such as mandibular gland and wax gland. The color is yellowish-green, red or dark brown, depending on the source and season. Hard and brittle in the cold, pliable and sticky in the warm.
    Propolis has a long history of application, as early as 300 BC, the ancient Egyptians used it as a preservative and a medicine to prevent and treat diseases. Propolis has many biological activities, such as antioxidant, antibacterial, antiviral, anti-inflammatory, anti-tumor, liver protection, immune regulation, etc. At present, it is widely used in medicine, health care products, beauty and other fields, and has high research value.
    At present, more than 200 compounds have been found from propolis, such as flavonoids, aromatic acids, terpenoids, aldehydes, alcohols, fatty acids and esters, amino acids, steroids and sugars, etc. Caffeic acid phenyl ethyl ester (phenethyl caffeic acid) is one of the main active ingredients in propolis. Affected by the propolis origin, the content of phenethyl caffeic acid differs greatly. For example, most of the propolis samples in the northern temperate zone contain phenethyl caffeic acid, while the propolis from South America, Brazil and other southern and tropical regions basically do not contain this component.
    China is located in the north temperate zone, taking propolis of Hebei Province as an example, the content of phenethyl caffeic acid is the most abundant (29.2 mg/g). GRUNBERGER et al. isolated phenethyl caffeic acid from propolis and confirmed that it has a significant inhibitory effect on tumor cells. NATARAJAN et al. proposed that phenethyl caffeic acid in propolis can selectively kill tumor cells and inhibit their growth, marking a major breakthrough in laboratory research on phenethyl caffeic acid in the treatment of cancer. With the development of modern medical technology, the antioxidant, anti-inflammatory, anti-tumor and immunomodulatory effects of phenethyl caffeic acid have been revealed.
    Phenethyl caffeic acid has many biological activities, such as antioxidant, antibacterial, antiviral, anti-inflammatory, anti-tumor, liver protection, immune regulation, etc. In recent years, the research on phenethyl caffeic acid mainly focuses on antioxidant, anti-inflammatory, anti-tumor, detoxification and so on.
    Phenethyl caffeic acid, the magic substance in propolis
    Antioxidant and anti-inflammatory effects
    The structure of caffeic acid phenyl ethyl ester contains catechol structural units, and the electron-rich benzene ring region can remove free radicals to achieve the purpose of antioxidant. By studying the effects of phenethyl caffeate on lipid peroxides in the serum of burned rats, SUDINA et al. found that phenethyl caffeate could remove active oxidizing substances, inhibit the activities of xanthine oxidase and nitric oxide synthetase, thereby reducing the consumption of superoxide dismutase (SOD) and play an antioxidant role. Phenethyl caffeic acid can remove excess free radicals produced by oxidative stress reaction, and upregulate glutathione, catalase (CAT), SOD and glutathione peroxidase in hepatic tissue in a dose-dependent manner, so as to achieve the purpose of antioxidant protection of liver. Some domestic researchers have established a diabetes model by streptozotocin, and found that phenethyl caffeic acid has a great effect on the peroxidation of the heart of mice and the activity of antioxidant enzymes in the liver and kidney of rats, significantly increasing the contents of SOD and CAT, and having a significant antioxidant effect.
    MICHALUART et al. reported that phenethyl caffeate can inhibit the synthesis of prostaglandins (PG) and leukotrienes. PG is produced by arachidonic acid under the catalytic action of cycoperoxidase (COX), which is crucial in the formation of inflammation. Phenethyl caffeate inhibits the release of arachidonic acid on cell membranes and inhibits COX activity. Prevent the synthesis of PG and thus play an anti-inflammatory role.
    Antitumor effect
    Cancer is one of the main causes of human death, and the study of various anticancer drugs has become a hot spot in the field of drug research. In 1988, GRUNBERGER et al. conducted a study on the cell inhibitory activity of phenethyl cafeate, and found for the first time that it had inhibitory effects on breast cancer (MCF-7), melanoma (SK-MEL-28 and SK-MEL-170) and colon cancer (HT-29), but had no effect on normal cells.
    Breast cancer
    In 2004, WATABE et al. found that in breast cancer cells MCF-7, phenethyl caffeate can activate Fas through Fas ligand-independent mechanism, and induce the activation of pro-apoptotic factor B lymphoblastoma-2 gene (Bcl-2) related protein X and caspase. Phenethyl caffeate also activates both P38 and C-Jun amino-terminal kinase (JNK) in the mitogen-activated protein kinase (MAPK) family. In 2011, WU et al. studied the inhibitory effect of phenethyl caffeate on breast cancer cells MCF-7 and MDA-MB231 and found that phenethyl caffeate could inhibit the growth of tumor cells, but had almost no effect on normal breast cells, and had an inhibitory effect on the transcription factor NF-κB. It can induce MCF-7 and MDA-MB231 breast cancer cell cycle arrest and apoptosis.
    Colorectal cancer and colon cancer
    Studies have shown that the occurrence of colorectal cancer is related to the abnormal activation of Wnt/ β-catenin signaling pathway, and the key to carcinogenesis is the accumulation of free β-catenin in the cytoplasm. The function of β-catenin mainly mediates intercellular adhesion, and plays an important regulatory role in cell proliferation, differentiation and apoptosis. It was found that phenethyl caffeate can affect the Wnt/β-catenin signaling pathway in colorectal cancer cells HCT116 and SW480 in a dose – and time-dependent manner, reducing the expression level of β-catenin protein, indicating that phenethyl caffeate is an inhibitor of Wnt pathway. It can block the growth cycle of colorectal cancer cells and induce cell apoptosis.
    In addition, phenethyl caffeate can also treat colon cancer through a variety of signaling pathways, as shown in Figure 9. Xue Wen et al. found that the mechanism of action of phenethyl caffeate in the treatment of colon cancer may be related to the decrease of the activity of JNK-paxillin signaling pathway, thus leading to cell apoptosis. JNK is the only kinase that can activate serine at paxillin78 site through phosphorylation. Therefore, phenethyl caffeate can inhibit nuclear translocation of JNK signaling pathway in cancer cells and block the activation of downstream paxillin, thus inhibiting the proliferation and migration of cancer cells, and the therapeutic effect of colon cancer is dose and time dependent.
    caspase-3 is an effective factor mediating tumor cell apoptosis. FAK-Ras-ERK is an important pathway to promote cell proliferation. Over-activated tyrosine kinases can activate downstream signaling pathways, fight cell apoptosis, promote cell proliferation, and ultimately promote the occurrence and development of tumors. In 2015, Liang Luchang et al. found that the therapeutic mechanism of phenylethyl caffeate may be to block the abnormal proliferation of FAK-Ras-MAPK, enhance the expression of caspase, inhibit the proliferation of colon cancer cells and induce their apoptosis, and the effect of phenylethyl caffeate is dose-dependent.
    In 2013, Yang Kun found that phenethyl caffeate inhibited the proliferation of human colon cancer lovo cells in a concentration and time dependent manner, and the mechanism of action may be that phenethyl caffeate inhibited the growth of colon cancer cells by down-regulating the proteins of PI3K/AKT signaling pathway and then up-regulating the apoptosis-related proteins caspase-3 and caspase-9.
    Liver cancer
    Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) is an important cytokine that preferentially induces apoptosis in cancer cells with negligible toxicity to normal cells. Studies have shown that phenethyl caffeate can induce TRAIL-mediated cell death in Hep3B liver cancer cells, while stimulating the expression of death receptor 5(DR5). However, after DR5 was treated with chimeric protein, the apoptosis induced by phenethyl caffeate /TRAIL was significantly blocked, suggesting that phenethyl caffeate /TRAIL stimulated apoptosis through the binding of TRAIL to DR5.
    These results suggest that phenethyl caffeinate may play a role in the prevention of liver cancer. Phagocytotic migration protein-1 (ELMO1) is a highly conserved transmembrane protein involved in the regulation of cytophagocytosis and cytoskeletal rearrangement. ELMO1 can inhibit the expression of fibronectin in liver cancer cells, resulting in reduced cell adhesion, easy separation between cancer cells, and the formation of metastatic nodules, resulting in metastasis of liver cancer cells. Wang Ziyan et al. found that phenethyl caffeic acid can down-regulate the expression of ELMO1, inhibit hepatocyte growth factor (HGF), and reduce the invasion and migration ability of human liver cancer cell line (HepG2).
    Prostate cancer
    It has been found that phenethyl caffeinate can inhibit the growth of prostate cancer cells by inhibiting phosphatidylinositol-3-kinase/protein kinase B(PI3K/Akt) signal transduction pathways, and reduce organ damage and toxicity caused by chemotherapy or radiotherapy. In human prostate cancer cells PC-3, DU145, phenethyl cafeate induces the expression of receptor tyrosine kinase-like orphan receptor 2(ROR2) signaling pathway in the non-classical Wnt pathway, inhibits β-catenin expression and NF-κB activity, while overexpression or knockout of ROR2 inhibits or enhances PC-3 cell migration, respectively.
    Protective effect of phenethyl caffeic acid on cadmium induced toxicity
    Cadmium pollution and poisoning are serious environmental and health problems. Cadmium is a highly accumulative and toxic non-essential heavy metal with a biological half-life of up to 38 years in human kidneys. Multiple evidence shows that even low levels of cadmium, if long-term exposure, can cause damage to the liver, kidneys, testicles, eyes and other organs. Therefore, it is very urgent to clarify the mechanism of cadmium toxicity and provide effective drugs or supplements to reduce or counteract the toxicity caused by cadmium pollution. As a hydrophobic polyphenol ester, phenethyl caffeic acid has the function of alleviating cadmium damage and regulating autophagy.
    In 2018, DALEL et al. found that cadmium chloride (CdCl2) can induce HepG2 cell toxicity and significantly reduce cell viability. HAO et al. found that phenethyl caffeate can inhibit autophagy of HepG2 cells, showing a protective effect on CDCl2-induced toxicology.
    Other pharmacological activities of phenethyl caffeic acid
    Phenethyl caffeinate also showed other pharmacological activities. For example, phenethyl caffeate can improve insulin resistance by regulating JNK and NF-κB signaling pathways in mice and HepG2 cells, significantly improve glucose consumption, glucose uptake, glycogen content and oxidative stress, and reduce the expression of glucose-6-phosphatase (G6Pase)mRNA in cells. Phenethyl caffeate has a protective effect on 6-hydroxydopamine (6-OHDA) -induced SH-SY5Y cells, and has the potential to be a candidate drug for prevention of Parkinson’s disease. Phenethylcaffeate protects PC12 cells from cisplatin induced neurotoxicity by activating AMPK/SIRT1, MAPK/ERK, and PI3K/Akt signaling pathways. Tang found that phenylethyl caffeate could inhibit the over-activation and proliferation of mouse T cells, and had a certain inhibitory effect on LPS-induced RAW264.7 macrophages, and biactively regulated the phagocytosis function of macrophages, indicating that phenylethyl caffeate had a certain immunomodulatory effect.
    In summary, phenethyl caffeic acid showed extensive pharmacological activities, especially in the anti-tumor aspect has high research value and significance. In the later stage, it can strengthen the research of anti-tumor mechanism of phenethyl caffeate and broaden the scope of anti-tumor therapy. It can also be developed on the basis of existing research and combined with other anti-tumor drugs to achieve strong anti-tumor effects and reduce the toxicity of anti-tumor drugs.
    articulation
    Natural products are important sources for the development of modern drugs, which have the advantages of biological correlation and structural diversity. Phenethyl caffeic acid is one of the main components of propolis extract, and it has a wide application prospect because of its many exact pharmacological effects. Phenethyl caffeic acid can be extracted from natural sources, the method is simple, low pollution, but time-consuming and low efficiency. Chemical synthesis can alleviate the problem of large-scale preparation of phenethyl caffeic acid, but its energy consumption is high and the environment is polluted.
    Phenethyl caffeic acid has a variety of different synthesis paths, researchers have been committed to seeking practical and versatile, relatively simple preparation methods, synthesis strategies still need to be improved, such as reaction raw materials, solvents and catalysts can be further optimized, green, efficient methods still need to be explored.
    Phenethyl caffeic acid can act on a variety of signaling pathways and molecular targets, and has been proved to have strong free radical scavenging ability, antioxidant, anti-inflammatory, anti-cancer and other pharmacological effects, indicating its application potential in inflammatory response, cardiovascular disease, brain tissue injury, tumor prevention and treatment, immune regulation and other aspects. Although phenethyl caffeic acid has extensive physiological activities, studies on the mechanism of phenethyl caffeic acid mainly focus on in vitro, and many mechanisms in the study of signaling pathways are not very clear, and there are not many studies on the influence of upstream signaling molecules in apoptosis signaling pathways, so more in-depth and detailed exploration is needed. In addition, the solubility of phenethyl caffeic acid ester is very low, which has an impact on its bioavailability, limiting its application in treatment and prevention, and future research can be strengthened in the preparation.

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