. At present, the disease with the highest mortality rate in China is cardiovascular and cerebrovascular disease, and it shows a trend of younger age [1]. Oxidative stress is closely related to atherosclerosis, myocardial ischemia, essential hypertension and other cardiovascular and cerebrovascular diseases. The control of oxidative stress mainly depends on antioxidants, which is also one of the focuses of clinical work in the future. Although antioxidants are being widely used at this stage, the therapeutic effect is not outstanding, and research in this field still needs to be strengthened.

Plant polyphenols are a class of secondary metabolites that widely exist in plants and contain multiple phenolic hydroxyl groups, which have attracted increasing attention. Caffeoylquinic acid compounds exist in honeysuckle, honeysuckle, Inula, chrysanthemum and other plants. They have a wide range of biological activities, such as antioxidant, free radical scavenging, antiviral and so on, and have become a hot spot in drug research and development.

Dicaffeoylquinic acids (dcqas) are a kind of natural phenolic acids, which are synthesized by condensation of quinic acid and caffeic acid through esterification reaction. There are six common dcqas in plants, which are isomers of hydroxyl disubstituted on the mother nucleus of quinic acid, as shown in Figure 1, mainly including 1,3-dcqa（1,3-dicaffeoylquinic acid）、1,4-DCQA（1,4-dicaffeoylquinic acid）、1,5-DCQA（1,3-dicaffeoylquinic acid）、3,4-DCQA（Isochlorogenic acid B）、3,5-DCQA（Isochlorogenic acid A）、4,5-DCQA（Isochlorogenic acid C）[2]The targets of dcqas included in the traditional Chinese medicine systems pharmacology database and analysis platform (tcmsp) are only coagulation factor Xa and non receptor protein tyrosine phosphatase 1. Swiss target prediction suggested that protein kinase C (PKC) α / δ were potential targets of dcqas, see Table 1.

 

 

1 dcqas plant sources

Dcqas widely exist in honeysuckle, Eucommia ulmoides, Inula, Xanthium sibiricum, Apostichopus japonicus, tea, hawthorn, cherry, apple and other plants, and are also the main pharmacodynamic components of their clinical application. This paper uses three key words of "caffeoylquinic acid", "traditional Chinese medicine" and "plant" to search for the key words of "caffeoylquinic acid", "traditional Chinese medicine" and "plant" in 1995.The key words of "caffeoylquinic acid", "traditional Chinese medicine" and "plant—In 2022, for the retrieval period, the CNKI, Wanfang medicine and VIP databases were searched, and a total of 2432 relevant literatures were screened out. The non medicinal plant related literatures and duplicate literatures were eliminated, and 124 pharmaceutical literatures related to dcqas were finally screened out. The medicinal plants rich in dcqas are summarized in table 2, in which the sources of plants containing isochlorogenic acid (3,4-dcqa, 3,5-dcqa, 4,5-dcqa) are relatively more extensive.

 

2 pharmacokinetic characteristics of dcqas

Drug metabolism affects the efficacy and toxicity of drugs. Pharmacokinetic quantitative description of the dynamic changes of drugs entering the body is of great significance for guiding the development of new drugs and clinical medication. About 35% of the lead compounds stopped in preclinical research because the pharmacokinetic characteristics in vivo were not suitable for human body, and about 40% of the candidate drugs were eliminated in clinical research because of poor pharmacokinetic parameters[3]。

2.1 pharmacokinetic characteristics of dcqas in animals

1,5-dcqa is the earliest and most mature research on the kinetic characteristics of dcqas. Yang Bo[4]. When dogs and rats were treated with Ig 1,5-dcqa, there were double peaks in the drug time curve due to the presence of gastrointestinal double absorption sites. After 1,5-dcqa enters the rat body, it is mainly distributed in the liver, kidney and bladder, of which the liver and small intestine are the main metabolic sites, and the metabolic modes mainly include methylation, glucuronidation, and molecular lactone bond transfer. The enzymes involved in its methylation and glucuronidation reactions are mainly catechols-O-Methyltransferase and uridine diphosphate glucuronosyltransferase, the liver because of the expression of more Catechol-O-Methyltransferases are more likely to catalyze methylation of 1,5-dcqa than small intestinal mucosa. The ability of liver and small intestine to transform low concentration of 1,5-dcqa into glucuronidation products is similar, but the ability of small intestine to transform high concentration of 1,5-dcqa is stronger than that of liver. Glucuronidation metabolites can be hydrolyzed by β - glucosidase in the liver, and then exert drug efficacy.

1,5-dcqa can be catalyzed by rat intestinal flora to produce hydrolysis, reduction and isomerization products. Due to strong metabolism, bile excretion and rapid urinary excretion, dogs and rats excrete rapidly after IV or Ig 1,5-dcqa, 10% of which～20% were excreted by kidney and 70% were excreted with feces[5-6]The bioavailability of 1,5-dcqa in dogs and rats was 3.50% and 0.52%, respectively. It was not easy to accumulate in dogs and had no inducing effect on metabolic enzymes. The glucuronidated metabolites excreted by bile have higher water solubility and can be hydrolyzed by intestinal β - glucuronidase and reabsorbed into the intestinal hepatic circulation. Methylated metabolites can also be directly absorbed into the intestinal hepatic circulation. 1,5-dcqa mainly binds to human albumin and can interact with type I and II binding sites. These two types of site bound drugs (warfarin, diazepam, etc.) have potential drug interactions with 1,5-dcqa. Rat Ig 1,5-dcqa did not induce or inhibit liver microsomal enzymes[7]。

In addition, Takenaka et al [8] found that 3,5-dcqa was stable in the artificial digestive solution, and no prototype components were detected in the plasma of rats after ig administration, while 90% of the prototype components disappeared from the plasma within 30 min after IV administration. Heshuangfeng et al[9]. Three inhibitors (ferulic acid, benzoic acid, ibuprofen) can reduce the permeability of 3,5-dcqa in ileum, but have little effect on its jejunal permeability. The intestinal absorption of 3,5-dcqa belongs to the first-order kinetic process, and the absorption mechanism is passive diffusion. At the same time, there is active transport mediated by monocarboxylate transporters.

Wang can et al[10]A liquid chromatography-mass spectrometer (LC-MS) was used to simultaneously quantify 13 potential quality markers (including 3,5-dcqa, 4,5-dcqa, 3,4-dcqa, etc.) of Reduning Injection in rat plasma. Each compound has a short half-life in vivo and a fast elimination rate. All compounds are distributed in multiple tissues and have plasma tissue / target organ transmissibility. It can be used as a potential quality marker for the safety and efficacy evaluation of Reduning injection. Zhanmeirong et al[11]The changes of metabolites in plasma and urine of rats after ig 4,5-dcqa were determined by lc-ms/ms technology. 15 and 16 metabolites were detected respectively, involving methylation, hydration, reduction, glucuronidation, sulfation and other reactions. Wu Ting et al[12]The concentration of 3,4-dcqa in plasma of rats after IV Mailuoning injection at 4 ml / kg was determined. The results showed that the half-life of 3,4-dcqa in rats was (50.08 ± 13.78) min, and the area under the drug time curve was (278.34 ± 31.82) mg / (min)·mL)The clearance rate was (0.001 6 ± 0.000 2) l / min.

2.2 pharmacokinetic characteristics of dcqas in human body

Liujianglin et al[13-14]. In phase I clinical pharmacokinetic study, healthy subjects received a singlepoAfter 1,5-dcqa (200, 400 and 800 mg/ person), 1,5-dcqa and 1,5-diferoylquinic acid (dfqa) wereCmaxSimilar, showing dose correlation. After continuous oral administration, there was no time-dependent accumulation of 1,5-dcqa in human body and the metabolic phenomenon of inducing acceleration or inhibition. However, there was a time-dependent accumulation of the dimethyl metabolite 1,5-dfqa after continuous administration.IIIn the phase I clinical pharmacokinetics study, after the subjects took 1,5-dcqa orally twice a day for 14 consecutive days (200, 300 mg/ time), there was no time-dependent accumulation and induced accelerated or inhibited metabolism. However, its dimethyl metabolite 1,5-dfqa has a time-dependent accumulation. After oral administration of 1,5-dcqa, methylation, glucuronidation and methyl glucuronidation are the main metabolic pathways in human body.

With the continuous disclosure of the biological activities of dcqas, it is necessary to expand the pharmacokinetic study of dcqas with different structures with significant biological activities in the future.

3 biological activity of dcqas

Caffeoylquinic acid natural products widely exist in honeysuckle, Eucommia ulmoides, Inula, Xanthium sibiricum, Apostichopus japonicus and other plants, and are also the main pharmacodynamic components of their clinical application. In recent years, studies at home and abroad have found that caffeoylquinic acid natural products (including dcqas) have a wide range of biological activities, such as antioxidant, anti-inflammatory, hypoglycemic, blood lipid regulation, platelet inhibition, antimicrobial, anti-tumor and so on[15]。

3.1 oxidation resistance

Excessive reactive oxygen species in the human body will damage DNA, proteins and other cellular components, trigger lipid oxidation and other cytotoxic effects, and eventually lead to cardiovascular disease, aging, cancer, neurodegenerative diseases, etc[15]Ischemia reperfusion injury plays a major role in the occurrence and development of cardiovascular and cerebrovascular diseases. The main biological activity of dcqas is antioxidation, which is manifested in scavenging oxygen free radicals and inhibiting free radical producing related proteins.

El askary et al[16]Through in vitro enzyme inhibition test, it was found that 3,5-dcqa, 4,5-dcqa and 3,4-dcqa had better free radical scavenging ability than ascorbic acid in vitro, and 3,4-dcqa had the highest activity, which was related to the catechol group and three unsaturated ester groups in its structure. [17]. kamarauskaite et al[15] Through the total antioxidant capacity detection kit and measuring the absorbance spectrum of cytochrome c,It was found that 3,5-dcqa in mugwort has free radical scavenging, iron ion reduction, regulating mitochondrial function, antioxidant and cytochrome c reduction activities. Hyun et al[18].

Caoxu et al[19]1,5-dcqa was found to dose dependently attenuate 1-methyl-4-phenylpyridine ions（
1-methyl-4-phenyl-pyridiniuiodide，MPP＋）The oxidative stress damage of rat adrenal pheochromocytoma PC12 cells caused by 1,5-dcqa can reduce the production of reactive oxygen species and the depletion of glutathione. 1,5-dcqa 50 μ mol/l can significantly inhibit MPP＋Induced transcription and translation of cellular synuclein, exerting cytoprotective effects. Wu Ji et al[20] Determined by UV methodIn vitro scavenging activity of 1,1-diphenyl-2-trinitrophenylhydrazine free radical, found that3,5-DCQAAntioxidant activity is comparable to vitamin C.

Liu et al[21].

Xanthine oxidase (XOD) can catalyze the oxidation of xanthine to generate uric acid and reactive oxygen species in the presence of oxygen. Wan et al[22] through in vitro inhibition of XOD activity experiments,It was found that the inhibitory activity of dcqas on XOD was higher than that of caffeoylquinic acid. Dcqas had strong affinity with XOD through hydrophobic interaction and hydrogen bonding, which not only reduced the production of uric acid, but also weakened oxidative stress, and had potential preventive effect on hyperuricemia patients. Caoweiwei et al[23] by inhibiting XOD in vitro and inhibiting sodium urate inducedInterleukin-1 β (IL-1 β)The structure-activity relationship study,It was found that the inhibition of XOD activity by 1,4-dcqa, 1,5-dcqa, 3,4-dcqa, 3,5-dcqa and 4,5-dcqa in Artemisia selengensis leaves was positively correlated with the inhibition of sodium urate induced IL-1 β activity, revealing the structural characteristics of dcqas in preventing hyperuricemia and gout.

Lim et al[24]Through the corticosterone induced depression model in mice, it was found that 3,4-dcqa and 3,5-dcqa could significantly inhibit the activity of monoamine oxidase in neurons and astrocytes, thereby reducing reactive oxygen species and alleviating depressive symptoms such as memory loss in mice. Tian Xing[25] byAccording to the oxidative stress injury model of human neuroblastoma SH-SY5Y cells induced by hydrogen peroxide, it was found that dcqas could resist oxidative stress induced by hydrogen peroxide through extracellular regulated protein kinase (ERK), protein kinase B (Akt) / glycogen synthase kinase (GSK) -3 β signaling pathway and inhibiting the expression of mitochondrial apoptosis related proteins.

K ö NCZ ö l et al[26] study. Xu et al[27] through free radical scavenging activity experiments,. Marksa et al[28] studyIt was found that the antioxidant activities of 3,4-dcqa and 3,5-dcqa were stronger than those of caffeoylquinic acid under the same conditions. Bi et al[29]Using the rat myocardial h9c2apoptosis model induced by tert butyl hydroperoxide, it was found that 3,5-dcqa could inhibit myocardial apoptosis by activating phosphatidylinositide-3 kinase (PI3K) / aktsignaling pathway.

3.2 anti inflammatory

. Hong et al[30]Through this model, it was found that 3,5-dcqa could inhibitiNOS,COX-2）And tumor necrosis factor - α (TNF - α,TNF-α）Gene expression, effectively inhibit the production of nitric oxide and thus play an anti-inflammatory role. [31] study. Libisheng et al[32]It was found that 4,5-dcqa in Gardenia jasminoides Ellis had a good inhibitory effect on prostaglandin E2 secretion in RAW264.7 cells.

Wang et al[33]It was found that 4,5-dcqa in Xanthium sibiricum could significantly inhibit lipopolysaccharide induced apoptosis in RAW264.7 cellsTNF-α、IL-6andIL-8  MRNA expression, significantly improved the survival rate of mice with cecal ligation / puncture induced sepsis. Wan Peng et al[34]It was found that long-term intervention of dcqas could significantly reduce inflammatory factors in colon tissue of normal diet miceIL-1β、IL-6、TNF-α、 iNOSandCOX-2Gene expression, and reduce the level of inflammation in mice. [35] detected by Griess methodlipopolysaccharideStimulated RAW264.7 cells to secrete nitric oxide levels,It was found that 1,5-dcqa in the fruit of Acanthopanax scabra had certain nitric oxide inhibitory activity. Roh et al[36]It was found that 3,5-dcqa and 4,5-dcqa in Lavender leaves could regulate the activation of antimicrobial peptide LL-37 and inhibit the production of proinflammatory factors by inhibiting the activity of kallikrein 5.

De Campos facchin et al[37]It was found that Undaria pinnatifida extract and its isolate had significant anti-inflammatory effects on mouse pneumonia model, could inhibit the protein concentration in activated leukocytes and exudates, reduce the activities of adenosine deaminase and myeloperoxidase, and the levels of proinflammatory factors such as nitric oxide, tnf- α, IL-1 β, and IL-17A. These effects may be related to the effects of 3,5-dcqa and 4,5-dcqa on nuclear factor - κ B (nf- κ b) p65 and p38 mapksignaling pathway.

Liu Yang et al[38]It was found that 3,5-dcqa could inhibit the overexpression of nod like receptor thermal protein domain associated protein 3 (NLRP3), caspase-1, nf- κ B p65, receptor activator of nf- κ B ligand (RANKL), reduce the phosphorylation of nf- κ B inhibitory protein (inhibitor of nf- κ B, I κ b) - α and nf- κ B p65 proteins in the synovium of collagen induced arthritis rats, and inhibit the levels of plasma IL-1 β, IL-6, tnf- α, C-reactive protein, interferon gamma, IL-18, and then reduce the inflammatory response in rats.

Human neutrophil elastase plays a key role in the specific inflammatory response of acute lung injury (ALI). Chen et al[39]It was found that 3,5-dcqa has a strong selective inhibitory effect on neutrophil elastase in vitro and in vivo, which can reduce the level of inflammatory cytokines in bronchoalveolar lavage fluid of lipopolysaccharide induced Ali model, and produce the protective effect of Ali by inhibiting steroid receptor coactivator family kinase / guanine nucleotide exchange factor vavsignaling pathway to regulate neutrophil function. Wang et al[40]It was found that 3,5-dcqa could reverse lipopolysaccharide induced Ali by inhibiting the protein expression of nf- κ b/nlrp3signaling pathway.

Deng Yingying et al[41]It was found that the level of immunoglobulin E antibody in the serum of rabbits with SC 1,3-dcqa increased more than 2 times, indicating that 1,3-dcqa has potential sensitization. Niu Yixuan et al[42]It was found that 4,5-dcqa and 3,5-dcqa in Artemisia annua could significantly inhibit the degranulation of mouse mastocytoma P815 cells induced by C48 / 80, which had potential anti allergic activity.

3.3 hypoglycemia

Diabetes is a group of metabolic diseases characterized by hyperglycemia. Clinical hypoglycemic drugs include sulfonylureas, biguanides, α - glucosidase inhibitors, dipeptidyl peptidase (DPP) - Ⅳ inhibitors, etc. El askary et al[16]It was found that 3,4-dcqa and 3,5-dcqa had strong inhibitory activities on DPP - Ⅳ and α - glucosidase in vitro, and 3,4-dcqa also had significant inhibitory effects on α - amylase. ,It was found that 3,5-dcqa in honeysuckle bud had inhibitory effect on α - glucosidase except sucrase and Bacillus stearothermophilus α - glucosidase, and the inhibitory effect on rat small intestinal type II α - glucosidase was the strongest. Tong et al[44]It was found that 3,5-dcqa, the main component of chicory seed, could alleviate the hyperglycemic symptoms and partial damage of streptozotocin (STZ) - induced type I diabetes in mice, significantly improve glucose tolerance and reduce body weight, which was related to the increased circulating insulin level, islet volume retention, improved utilization of free fatty acids and α - glucosidase inhibition.

Etemadi tajbakhsh et al[45]findDorema ammoniacum  D. 1,5-dcqa in Don has obvious α - glucosidase inhibitory activity. Zhanghuating et al[46]It was found that 3-caffeoylquinic acid, 3,4-dcqa, 5-caffeoylquinic acid and arctigenin could significantly improve glucose tolerance in STZ induced diabetic mice（P< 0.05). Lu Tao et al[47] established an in vitro activity detection model of trace α - amylase inhibitors,It was found that 3,5-dcqa, 4,5-dcqa and chlorogenic acid in the hairy roots of Stevia rebaudiana had a good inhibitory effect on α - amylase in vitro. Zhuxiaolin et al[48] established two protein glycosylation reaction models of bovine serum albumin methylglyoxal and bovine serum albumin glyoxal,It was found that 3,4-dcqa in Malan had strong activity of inhibiting protein glycosylation induced by bovine serum albumin methylglyoxal and bovine serum albumin glyoxal.

3.4 regulating blood lipids

Atherosclerosis is the pathological basis of cardiovascular and cerebrovascular diseases. The fundamental cause of atherosclerosis is high blood lipids, which can lead to coronary heart disease, myocardial infarction, cerebral thrombosis, etc. Wuchongming et al[49] established a model of oleic acid-induced lipid accumulation in human hepatoma HepG2 cells,It was found that 3,5-dcqa in Acanthus ilicifolius could increase the expression of lipid oxidation related genes peroxisome proliferator activated receptor - α, carnitine palmitoyl transferase-1 and acyl CoA oxidase-1, promote fatty acid beta oxidation, significantly inhibit lipid synthesis related genes sterol regulatory element binding protein (SREBP) -1c, SREBP-2, acetyl CoA carboxylase, 3-hydroxy-3-methylglutarate Monoacyl CoA reductase and apoptosis related factors, reduce lipid accumulation and intracellular total cholesterol and triacylglycerol levels, and there was no significant cellular toxicity.

Raineri et al[50] induced pre adipose 3T3-L1 cell differentiation model by hormone containing fat formula,It was found that the cells treated with 3,5-dcqa showed no lipid droplet aggregation, no lipid deposition at the end of the differentiation process, maintained the pre adipocyte morphology, and activated AMP dependent protein kinase (AMPK) to inhibit fatty acid anabolism.

3.5 inhibition of platelet aggregation

In the early stage of atherosclerosis, platelets aggregate on the damaged arterial intima, further mediated by cytokines, and gradually form thrombus. Studies have shown that dcqas can inhibit platelet aggregation. Dengzhanxixin injection (containing dcqas) is often combined with aspirin in the treatment of cardiovascular and cerebrovascular diseases, and the curative effect is significant[51]. Chang et al[52] studyFound that caffeic acid methyl ester, 3,4-dcqa, and methyl-3,4-dcqa could strongly inhibit thromboxane A, which has vasoconstrictive effects2. Satake et al[53] study.

3.6 antimicrobial

Integration is a necessary process for human immunodeficiency virus (HIV) -1 to infect host cells, so integrase is the target of AIDS treatment. Dqcas are HIV-1 integrase inhibitors that irreversibly inactivate amino acids in the catalytically active site of the central region of the integrase. King et al[54]The structure-activity relationship study on the anti HIV activity of dqcas and their analogues found that caffeic acid, quinic acid and chlorogenic acid had no anti HIV activity. The simultaneous presence of two catechol structures was necessary for anti HIV, and the free carboxyl group in the structure was also essential. [55]Through molecular modeling technology, it was found that 3,4-dcqa could selectively bind to HIV integrase and inhibit its activity. Although many integrase inhibitors have been reported, most of them are cytotoxic, and natural dcqas are expected to become new anti HIV drugs due to their low toxicity[2]。

Chlorogenic acids can inhibit hepatitis B virus (HBV) virus infection by enhancing DNA self-protection, which has a good barrier effect on HBV replication in vivo. 1,5-dcqa, an effective component in Inula, has anti HBV effect [56]. Yang Anqi et al[57]Studies have shown that chlorogenic acids 4,5-dcqa and 3,5-dcqa have anti HBV effects. Hao et al[58] byD-,It was found that 3,5-dcqa could significantly improve the viability of HL-7702 cells, and the inhibition rates of HBsAg and HBeAg expression were 86.9% and 72.9%, respectively. In addition, 3,5-dcqa could significantly reduce the content of HBV covalently closed circular DNA and significantly induce the expression of heme oxygenase-1 in HepG2.2.15 cells. Ma et al[59] by measuringHepatitis C virusLuciferase activity in the replication system,.

. Shah et al[60]Through molecular docking, it was found that 3,5-dcqa and the novel coronavirus 3CL hydrolase (main protease, Mpro）The receptor has high affinity and is expected to inhibit MproProtein cleavage mRNA and virus assembly and other related functions. [61]Through molecular docking, molecular dynamics simulation and end state thermodynamics, it was found that dcqas interacted significantly with lysine 417, glutamine Gln 493, tyrosine Tyr 489, phenylalanine Phe 456, tyrosine Tyr 473, glutamate Glu 484, which are important amino acid residues of the spike protein receptor binding domain, and inhibited the virus from entering the host cell. Bharadwaj et al[62]Molecular dynamics simulation revealed that 1,3-dcqa and MproThe conserved amino acid residues in the catalytic pocket form strong intermolecular interactions and have potential anti covid-19 activity.

Tao Xin et al[63] through in vitro bacteriostatic experiments,It was found that 1,3-dcqa and 1,4-dcqa in Xanthium sibiricum had certain inhibitory effects on Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Shigella dysentery. Zhuwenqing et al[64]Network pharmacology was used to explore the antibacterial targets, mechanisms and related pathways of caffeoylquinic acid compounds. The results showed that there were 75 antibacterial targets of caffeoylquinic acid compounds, which were verified by molecular docking, providing a theoretical basis for the later research of antibacterial drugs. Huo Jinshuang et al[65] through Oxford cup method and minimum inhibitory concentration method.

Han et al[66] comparatively studied the antibacterial activity of three dcqas in Lonicera japonica flower against the growth of Bacillus Shigella by microcalorimetry,The sequence of its antibacterial activity was found to be 3,5-dcqa > 4,5-dcqa > 3,4-dcqa, and the caffeic ester group on C-5 may be the main group with high affinity for bacterial cells. Ligensen et al[67]Through the early 24 h static Pseudomonas aeruginosa Aspergillus fumigatus mixed biofilm model, it was found that the combined application of 3,5-dcqa (250 μ g/ml), 3,4-dcqa (500 μ g/ml), 4,5-dcqa (1000 μ g/ml) and amphotericin-B, meropenem significantly improved the killing effect of Aspergillus fumigatus and Pseudomonas aeruginosa in the mixed biofilm, and the two had synergistic effect on the killing of fungi and bacteria, and there was a dose correlation.

3.7 anti tumor

Zhouyuhang[68]It was found that 1,3-dcqa could bind to 14-3-3 τ protein, downregulate the expression of Janus kinase (JAK), Akt, proto oncogene serine / threonine protein kinase Raf-1, and rapamycin target of rapamycin (mTOR) in breast cancer cells, inhibit the protein synthesis and cell proliferation of breast cancer cells, upregulate the B-cell lymphoma (BCL) - 2 gene associated death (bad) promoter, and induce apoptosis based on caspase pathway in breast cancer cells. 1,3-dcqa inhibits breast cancer proliferation and metastasis through jak/pi3k/akt and raf/erk pathways, activates cyclic adenosine monophosphate response element binding protein (CREB), thereby upregulating the expression of IL-6 and colony stimulating factor, and induces breast cancer apoptosis through bad/ Bcl-2 associated X protein (Bax) /caspase-9signaling pathway[69]。

Wangmingyan[70]It was found that 3,4-dcqa could induce apoptosis of human breast cancer MCF-7 cells in a time dose dependent manner and significantly upregulate the expression ofP53Genes, downregulatedC-mycGenes. Lodise et al[71]It was found that 4,5-dcqa exerted a powerful anti prostate cancer effect in vivo by arresting the replication cycle of prostate cancer cells in S phase rather than inducing programmed cell death. Shiqiyuan et al[72]It was found that 3,5-dcqa in Artemisia annua flower could inhibit the proliferation and morphological damage of human cervical cancer HeLa cells in vitro in a dose-dependent manner. Wangmingyan[70]It was found that 3,5-dcqa induced apoptosis in human gastric cancer MGC-803 cells in a time dose correlation, and the inhibitory rate of 3,5-dcqa (400 μ g / ml) on MGC-803 cells reached 59.41% after 24 h. In addition,P53、Bax.

3.8 liver protection

Sunyanrong et al[73]It was found that 1,5-dcqa (7.8-250 mg / L) had no obvious toxicity on primary liver cells, and could promote the proliferation of normal and carbon tetrachloride injured hepatocytes, reduce the level of alanine aminotransferase (ALT) in the supernatant, inhibit liver apoptosis caused by carbon tetrachloride, and change the damaged cell cycle. Liu Xin et al[74]It was found that 3,4-dcqa had a protective effect on atorvastatin induced liver injury in mice, which was manifested by inhibiting the increase of serum glutamate aminotransferase (AST) and alt, and improving liver histopathological injury. Han Mengdi[75]The spectrum effect relationship of the hepatoprotective activity of blue potted flower was analyzed by serum fingerprint and gray correlation method. After ig administration in rats, the correlation degree of the active ingredient 3,5-dcqa was greater than 0.8, suggesting that it has high hepatoprotective activity.

Liver fibroblasts can synthesize collagen and other extracellular matrix, and excessive synthesis will lead to liver fibrosis, which is the necessary stage of liver cirrhosis. Sunyanrong et al[76-77] used in vitro cultureMouse embryonic fibroblast nih/3t3 cells..the study of the mechanism of the proliferation of NIH / 3T3 cells in vitro and in vivo of NIH / 3T3 cells in vitro and in vivo of NIH / 3T3 cells in vitro and in vivo of NIH / 3TAs a fibroblast replacement model,It was found that 1,5-dcqa could significantly inhibit the proliferation of nih/3t3 cells, and only affect the intracellular collagen synthesis, suggesting that 1,5-dcqa inhibition of intracellular collagen synthesis is one of the ways to prevent liver fibrosis. In addition, 1,5-dcqa could significantly reduce the levels of serum ast, ALT and liver fibrosis indicators, increase the protein synthesis rate, reduce the contents of serum laminin, hyaluronic acid, malondialdehyde, and nitric oxide, significantly improve the pathological damage, reduce tissue fibrosis, and improve the ultrastructure. The mechanism is to promote the proliferation of primary liver cells, change the proliferation cycle of damaged cells, inhibit liver apoptosis, significantly inhibit fibroblast proliferation, reduce fibroblast hyaluronic acid level, and protect the liver[78]。

Liu et al[79] induced a mouse model of nonalcoholic steatohepatitis by methionine and choline deficient diet,It was confirmed that 3,4-dcqa in Rabdosia auricula inhibited oxidative stress by regulating the transcription factor nuclear factor E2 related factor 2 (Nrf2), and inhibited a variety of profibrotic factors by microrna-122/ hypoxia inducible factor-1 α signaling pathway, which had a significant protective effect on the fibrosis of nonalcoholic steatohepatitis.

3.9 neuroprotection

N-Methyl-D-Aspartic acid（N-methyl-D-Excessive activation of aspartic acid (NMDA) receptors will lead to a large amount of calcium ion influx, thus triggering the downstream apoptotic pathway and causing neuronal damage, which plays an important role in the occurrence and development of neurodegenerative diseases. Tian Xing et al[25]Through NMDA induced excitotoxic injury model of SH-SY5Y cells, it was found that dcqas could inhibit NMDA receptor hyperactivation mediated calcium influx and mitochondrial apoptosis pathway related protein expression by antagonizing NMDA receptor subunits, and at the same time act on MAPKs, akt/gsk-3 β and crebsignaling pathway to exert anti NMDA excitotoxic effects. Chu Xiaofan et al[80] byTo study the effects of dcqas on neurobehavior and hippocampal neural apoptosis in rats with cerebral ischemia, it was found that dcqas can play a neuroprotective role by inhibiting caspase-3 protein expression, reducing neural apoptosis.

Xiao et al[81] through amyloid β 1-42-induced primary neuronal cell injury model,It was found that 1,5-dcqa could protect primary neurons from β - amyloid a β 42 damage through tropomyosin receptor kinase A, pi3k/akt, bcl-2/bax and GSK-3 β signaling pathway. Sheng Yanmei et al[82]Using the in vitro blood-brain barrier model combined with high-performance liquid chromatography technology, it was found that 3,5-dcqa could penetrate the blood-brain barrier, reduce the rate of cerebral infarction in rats, increase the activities of glutathione peroxidase and iNOS in serum of rats with cerebral ischemia-reperfusion injury, reduce the content of malondialdehyde in serum, improve its neurological behavior, and play a protective role against cerebral ischemia. [17]It was found that dcqas could reduce the expression of pormin index in astrocytes after cerebral ischemia induced by middle cerebral artery occlusion model, and play a protective role in astrocytes. Zhang Jing et al[83]It was found that 1,5-dcqa and 3,4-dcqa could promote the survival of rat cerebral cortical neurons in vitro.

Stress is a major risk factor for depression. Studies have found that dcqas have a protective effect on neuronal atrophy in mice and can alleviate the depressive behavior caused by stress hormones. Menopause is another risk factor for depression. Lim et al [84] used the estrogen deficiency induced ovariectomized (OVX) depression model in mice and found that 1,3-dcqa restored the nitric oxide deficiency caused by estrogen deficiency by upregulating the expression of iNOS in hippocampal neurons of OVX mice, thereby preventing the depression like behavior induced by estrogen deficiency. 1,3-dcqa can prevent estrogen deficiency induced depression like behavior by directly regulating neuronal nitric oxide synthase expression and ERK cyclic adenosine monophosphate (cAMP) response element binding protein brain-derived neurotrophic factor (BDNF) signaling pathway, increasing nitric oxide formation in hippocampus.

3.10 others

El askary et al[16]According to the in vitro scratch healing model of human skin fibroblast HSF cells, 10 µ g/ml of 4,5-dcqa and 3,4-dcqa can promote wound healing. After 24 h of treatment with 4,5-dcqa, the cell migration rate was enhanced, the scratch wound healed, and the wound was completely healed after 48 h, while 3,4-dcqa only increased the cell migration at 48 h, and the wound width was reduced from 37% of the control group to 23%. Excessive alcohol consumption can damage the gastric mucosa, carlotto et al[85] induced a rat gastric ulcer model by ethanol,It was found that 0.057 mg/kg 1,3-dcqa could protect 75% of gastric mucosa from damage (compared with 95% of omeprazole as a positive control). Wu et al[86] by. Among them, 3,5-dcqa had the best expectorant effect, and 4,5-dcqa significantly reduced the level of white blood cells. Dos Santos et al[87].

Xieminhao et al[88]By simulating the anaerobic environment of human intestinal tract in vitro, the microbiota in fecal samples were mixed cultured, and the structure of the microbiota was studied by fluorescence in situ hybridization. It was found that the number of beneficial bacteria such as Bifidobacterium increased within 36 h in the medium supplemented with 3,5-dcqa, and the growth of Fusobacterium histolyticum and Prevotella was inhibited, indicating that 3,5-dcqa has a certain role in improving human intestinal microecology and regulating intestinal balance.

. Li et al[89]Through molecular docking, it was found that six caffeoylquinic acids can be well embedded in the IGFR active pocket, and 3,5-dcqa has the strongest affinity with IGFR. Caffeoylquinic acid can significantly prolong the life span of wild-type Caenorhabditis elegans, and 3,5-dcqa has the strongest effect. 3,5-dcqa can increase the body bending and pharyngeal pump speed, reduce the intestinal lipofuscin level, and improve the healthy life span. Further studies showed that 3,5-dcqa downregulated the insulin / igfrsignaling pathway by inhibiting the activity of IGFR, activated the life span regulating transcription factor DAF-16, and thus induced the expression of stress response genes to play an anti-aging role. Collagenase is mainly synthesized and secreted by fibroblasts, which can degrade collagen and elastin in the skin, leading to skin aging[90]3,4-dcqa, 3,5-dcqa, and 4,5-dcqa from Paeonia grossedentata have significant collagenase inhibitory activity in vitro (the half inhibitory concentration is 5.8 ～ 37.2 μ g/ml), which is expected to be developed as an aging drug[91]。

4 conclusion and Prospect

As a widely existing natural product, dcqas exhibit antioxidant, anti-inflammatory, hypoglycemic, lipid regulating, platelet inhibition, antimicrobial, antitumor and other biological activities[92], and the specific mechanism of action is shown in Table 3It has good utilization value and development prospects in both medical and food fields. The new anti AIDS drug 1,5-dcqa developed by Jiangxi Jiangzhong pharmaceutical and the Chinese Academy of Military Medical Sciences has entered clinical trials after rigorous animal pharmacodynamics and safety tests.

 

 

Dcqas have a variety of biological activities. It is of far-reaching significance to explore the mechanism of action of these compounds combined with clinical trials. . Although new encapsulation technologies such as nanoparticles, milk preparations, liposome preparations, cyclodextrin inclusion complexes, phospholipid complexes and so on are expected to improve their bioavailability, how to improve the utilization efficiency of dcqas still needs further exploration.

The pharmacokinetic, pharmacodynamic and toxicological evaluation of dcqas is still insufficient, and the targets and molecular mechanisms of the compounds are still unclear. It is of great significance to further improve the added value of dcqas products and expand their application fields by systematically mining the functional characteristics of dcqas and applying them to the development of innovative drugs. In the future, we can find more bioactive lead compounds from six kinds of dcqas, and then modify their structures to improve their biological activities or improve their physicochemical properties to improve their drug likeness, while obtaining beneficial structure-activity relationships, so as to carry out more reasonable modification and transformation of dcqas. In addition, the biological activity screening types of dcqas and their derivatives need to be expanded, and their mechanisms and targets need to be further studied. In this paper, the plant sources, pharmacokinetics and biological activities of dcqas were summarized, in order to provide references for the research and development of new drugs related to dcqas.

Conflict of interest  All authors declare no conflict of interest

References (omitted)

Source: hanyaru, maguoli, hanyalong, Gao Jiamin, zhe Zhanfei, fengyubao, Xiaobin. Research progress on plant sources, pharmacokinetics and biological activities of dicaffeoylquinic acids [j]. Chinese herbal medicine, 2023, 54 (4): 1285-1298