CN113694054A - Application of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine - Google Patents
Application of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine Download PDFInfo
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses an application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine, wherein the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (molecular formula: C)27H28O12) Is applied to preparing medicines with anti-inflammatory and antioxidant activities. The invention relates to an application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicines, and provides the influence of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the phosphorylation level and nuclear shift of key proteins of MAPK signal pathway; also provided is the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester capable of inhibiting ROS levels induced by LPS and IFN- γ through the NRF2/HO-1 pathway; the compound 4-O-feruloyl-5-O-caffeoyl is provedThe quinic acid methyl ester regulates MAPK signal channels through targeting TAK1, and regulates macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators; the transcription level of HO-1 is also enhanced by the nuclear translocation of NRF2, thereby inhibiting the cell damage caused by oxidative stress and laying the foundation for the application of anti-inflammatory and antioxidant active ingredients in medicaments.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicines.
Background
Inflammation is a chain reaction of the immune system caused by the body induced by an irritant, and belongs to the physiological reaction of self-protection in immune reaction. Among the stimulators that cause inflammation, Lipopolysaccharide (LPS) is a component of the outer membrane of the cell wall of gram-negative bacilli, and it acts as a natural immune-inducing factor that activates the immune response and induces infectious inflammation. When LPS and a pattern recognition receptor Toll-like receptor 4 on a cell membrane are combined to form a compound, a connector protein medullary differentiation protein (MyD88) is activated, and stimulation is transmitted to a series of downstream proteins and related kinases, so that secretion of inflammatory factors is regulated, and finally inflammation is caused. Among the signal pathways for regulating and controlling various enzymes and inflammatory mediators in the inflammation process, the dominant pathway is the signal transduction transcription activator pathway (JAK-STAT pathway) of tyrosine kinase, the nuclear factor-kB signal pathway (NF-kB pathway) and the mitogen-activated protein kinase signal pathway (MAPK pathway).
The nuclear factor E2 related factor 2(nuclear factor-associated 2-related factor 2, NRF2) is an important transcription regulatory factor in a cell body, can regulate the expression of various anti-inflammatory and antioxidant genes, and has a very important position in the injury response of the body; heme Oxygenase (HO) -1 is a rate-limiting enzyme in heme catabolism, can degrade heme into carbon monoxide, biliverdin and iron ions, and is an important medium for NRF2 to play anti-inflammatory and antioxidant roles. The signal path formed by Nrf2 and HO-1 is involved in various inflammation-related processes.
The caffeoylquinic acid compounds are common natural organic acid compounds and exist in various traditional Chinese medicinal materials. Has remarkable effects in resisting bacteria and inflammation, and also has antioxidant, antiviral, antitussive, and hepatoprotective effects. The compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is a caffeoylquinic acid compound separated and purified from honeysuckle, and the caffeoylquinic acid is the main and characteristic active ingredient of the compound. In the prior art, the research on the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is few, only relevant activity is used for preliminary research on neuroprotection, and the application of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester anti-inflammatory active ingredient in medicines is unavailable so far.
Disclosure of Invention
The invention mainly aims to provide application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicines, which can effectively solve the problems in the background technology.
In order to achieve the purpose, the invention adopts the technical scheme that:
an application of 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine is provided, which has the following chemical structural formula of 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (molecular formula: C)27H28O12)：
Is applied to preparing medicines with anti-inflammatory and antioxidant activities.
Preferably, the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can eliminate the increase of NO level caused by LPS and IFN-gamma induction, inhibit the gene expression level of inflammatory factors and effectively inhibit M1 type polarization of macrophages; the influence of the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the phosphorylation level and nuclear translocation of MAPK signal pathway conduction related protein is determined; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is proved to regulate and control MAPK signal channel by targeting TAK1, and regulate macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators.
Preferably, the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is capable of inhibiting ROS levels induced by LPS and IFN- γ through the NRF2/HO-1 pathway; it was confirmed that the transcriptional level of HO-1/NQO1 by enhancing nuclear translocation of NRF2, thereby inhibiting cell damage caused by oxidative stress.
Preferably, the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can effectively eliminate the level of NO in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma, thereby reducing the protein level of iNOS and COX 2; can inhibit phosphorylation level of TAK1, thereby affecting phosphorylation levels of JNK and C-JUN downstream proteins of MAPK signal pathway, further inhibiting nuclear entry of JNK, thereby weakening combination with AP-1 site of transcription promoter region, and finally inhibiting secretion of cytokines IL-1 beta and IL-6.
Preferably, the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can increase the transcription and protein level of HO-1/NQO1 in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma; in a single-dosing experiment, the nuclear entry of NRF2 can be increased, and the transcription and protein level of HO-1/NQO1 can be further improved, so that cell damage caused by oxidative stress can be inhibited.
Preferably, the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of anti-inflammatory drugs.
Preferably, the antioxidant component of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of antioxidant drugs.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides the influence of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the phosphorylation level and nuclear translocation of MAPK signal pathway key protein; also provided is the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester capable of inhibiting ROS levels induced by LPS and IFN- γ through the NRF2/HO-1 pathway; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is proved to regulate and control MAPK signal channel by targeting TAK1, and regulate macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators; the transcription level of HO-1 is also enhanced by the nuclear translocation of NRF2, thereby inhibiting the cell damage caused by oxidative stress and laying the foundation for the application of anti-inflammatory and antioxidant active ingredients in medicaments.
Drawings
FIG. 1(A) is a schematic diagram of CCK8 experiment for detecting the effect of different concentrations of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on macrophage RAW264.7 cell viability; (B) a schematic diagram of the effect of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester detected by the NO kit on the NO release of macrophage RAW264.7 under the LPS and IFN-gamma treatment; (C-E) is a schematic diagram of the effect of detecting the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the iNOS and COX2 protein levels by Western blot under the treatment of LPS and IFN-gamma for 6h, 12h and 24h respectively; (F-H) is a graph showing the influence of qPCR detection of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the release of inflammatory factors of macrophage RAW264.7 under LPS and IFN-gamma treatment;
FIG. 2 (A) is a schematic diagram of Western blot for detecting the influence of 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester compound on MAKP-related pathway proteins; (B) a schematic diagram for detecting the nuclear entry condition of JNK for an immunofluorescence experiment;
FIG. 3 (A) is a schematic diagram showing the effect of Western blot on the levels of protein and phosphorylation of TAK1 by detecting the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester; (B) schematic diagram of detection of changes in TAK1 knockdown protein levels of TAK1 in cell lines for Western blot; (C) schematic representation of the change in TAK1 transcript levels in TAK1 knockdown cell lines for qPCR; (D) a schematic diagram for detecting the influence of the TAK1 added with or without the drug under the treatment of LPS and IFN-gamma on the reduction of the inflammatory key protein level in a cell line by Western blot; (E-G) is a graph illustrating the effect of qPCR on the reduction of inflammatory factor release in cell lines by dosed and non-dosed TAK1 under LPS and IFN-gamma treatment; (H) is a molecular docking schematic diagram of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester and TAK1 protein.
FIG. 4 (A) is a schematic diagram showing the detection of reactive oxygen species ROS in a cell; (B) the effect of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the protein levels of HO-1 and NQO1 under the treatment of LPS and IFN-gamma is detected by Western blot; (C) a schematic diagram of the effect of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on HO-1 and NQO1 transcription levels under LPS and IFN-gamma treatment for qPCR detection; (D) the effect of different concentrations of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester stimulation on HO-1 and NQO1 protein levels is detected by Western blot; (E) a schematic diagram of the effect of different concentrations of compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester stimulation on HO-1 and NQO1 transcription levels for qPCR detection; (F) schematic illustration of nuclear entry effect of NRF2 for immunofluorescence detection.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
In the description of the present invention, it should be noted that the terms "upper", "lower", "inner", "outer", "front", "rear", "both ends", "one end", "the other end", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplicity of description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention. Furthermore, the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
In the description of the present invention, it is to be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "disposed," "connected," and the like are to be construed broadly, such as "connected," which may be fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
Examples
An application of 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine is provided, which has the following chemical structural formula of 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (molecular formula: C)27H28O12)：
Is applied to preparing medicines with anti-inflammatory and antioxidant activities.
The compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can eliminate the increase of NO level caused by LPS and IFN-gamma induction, inhibit the gene expression level of inflammatory factors and effectively inhibit M1 type polarization of macrophages; the influence of the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the phosphorylation level and nuclear translocation of MAPK signal pathway conduction related protein is determined; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is proved to regulate and control MAPK signal channel by targeting TAK1, and regulate macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can effectively eliminate the level of NO in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma, thereby reducing the protein level of INOS and COX 2; can inhibit phosphorylation level of TAK1, thereby affecting phosphorylation levels of JNK and C-JUN downstream proteins of MAPK signal pathway, further inhibiting nuclear entry of JNK, thereby weakening combination with AP-1 site of transcription promoter region, and finally inhibiting secretion of cytokines IL-1 beta and IL-6; the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of anti-inflammatory drugs.
The compound methyl 4-O-feruloyl-5-O-caffeoylquiniate is able to inhibit ROS levels induced by LPS and IFN- γ through the NRF2/HO-1 pathway; it was confirmed that the transcription level of HO-1/NQO1 by enhancing nuclear translocation of NRF2, thereby inhibiting cell damage caused by oxidative stress; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can increase the transcription and protein level of HO-1/NQO1 in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma; in a single-dosing experiment, the nuclear entry of NRF2 can be increased, so that the transcription and protein level of HO-1/NQO1 are improved, and the cell damage caused by oxidative stress is inhibited; the antioxidant component of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of antioxidant drugs.
The invention relates to an application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicaments:
1. purpose of the experiment:
the influence of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on macrophage M1 type differentiation, inflammatory factor expression level and intracellular ROS is researched, and the activity of the compound is explored.
2. Experimental methods
2.1 cell viability assay
RAW264.7 cells were seeded in 96-well plates (5X 10 cells per well)3Individual cells) and treated with different concentrations of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (6.25 μ g/ml, 12.5 μ g/ml, 25 μ g/ml). Cells treated with DMSO (0.5%, v/v) served as vehicle controls. After 24h incubation, 10. mu.L of CCK-8 reagent was added to each well, incubated at 37 ℃ in an incubator for 3h, and the absorbance was measured at 450nm by a microplate reader.
2.2Griess method for detecting NO release amount of mouse mononuclear macrophage
RAW264.7 cells were seeded in 96-well plates (5X 10 cells per well)3Individual cells) and treated with different concentrations of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (6.25 μ g/ml, 12.5 μ g/ml, 25 μ g/ml). Cells treated with DMSO (0.5%, v/v) as a vehicle control to induce M1 type macrophage polarization, 10ng/ml LPS and 20ng/ml IFN-. gamma.as stimuli were added to each well, 5 duplicate wells were set for each group, and after 24h of incubation, 50. mu.l of culture supernatant was taken to a new 96-well plate, and then NO release was measured by an microplate reader at 540nm according to the protocol.
2.3Western blot detection of protein levels
Collecting cell samples of each group, using lysis solution containing protease inhibitor and phosphatase inhibitor to lyse cells, boiling at 95 ℃ for 10-15min, separating proteins by SDS-PAGE, transferring proteins on protein gel to PVDF membrane, sealing with 5% skimmed milk for 1h, incubating corresponding primary antibody and secondary antibody, and finally developing by ECL luminescence solution and scanning for archiving.
2.4qPCR detection of Gene expression levels
Samples of each group of cells were collected, total RNA was extracted using an RNA kit, and then the total RNA was inverted into cDNA using a reverse transcription kit. Specific primers are designed aiming at different genes, and at last, Forget-Me-Not is used for the specific primersTMEvaGreen qPCR master mix was subjected to real-time quantitative PCR, and the fold change in gene expression was calculated by relative quantitation (2-. DELTA.Ct), with the expression of the Gapdh gene as an internal control.
2.5 immunofluorescence detection of the entry of genes
RAW264.7 cells were seeded in a glass-plated 24-well plate (5X 104 cells per well) and incubated with LPS at a concentration of 10ng/ml and IFN-. gamma.at 20ng/ml as a stimulator for 24h with the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester at a concentration of 25. mu.g/ml, and cells treated with DMSO (0.5%, v/v) as a vehicle control. Samples were fixed in 4% paraformaldehyde for 10 minutes and then incubated with PBS containing 0.25% Triton X-100 for 10 minutes for membrane penetration. The cells were then blocked with 5% bovine serum albumin for 1h at room temperature and then incubated with the corresponding antibody overnight at 4 ℃. The cells were then plated with Alexa FluorTM594 conjugate secondary antibody for 1h, then for 5min at room temperature with Hoechst 33,258. Images were captured using a fluorescence microscope (Olympus, Tokyo, Japan).
2.6TAK1 knockdown cell line construction
TAK1 protein knock-down was performed on macrophage RAW264.7 by lentivirus transfection technique to construct the corresponding sh-RNA plasmid, the plasmid mixture was co-transfected with packaging plasmid into HEK293T cells, cell supernatants were collected for 24h and 48h for virus packaging, cell debris was filtered off with 0.5 μ M filter, mixed with 8 μ g/ml polybrene, and added to RAW264.7 cells. 48h after infection, resistant cells were selected using 4. mu.g/m puromycin. Cells transfected with pLKO.1-U6-EF1a-copGFP-T2A-puro (empty) served as controls. The effect of intracellular TAK1 knockdown was confirmed using Western blot.
2.7 molecular docking
The structure of the mouse TAK1 protein is predicted by carrying out homologous modeling by using the structure of the human TAK1 protein and a Swiss-Model Server. The structure of the compound methyl 4-O-feruloyl-5-O-caffeoylquiniate is plotted in ChembioDraw14.0 and converted to 3D structure by Chembio 3D Ultra 14.0 software. The molecular docking of the two was performed using AutoDock Vina software with default parameters. And finally, carrying out interaction image display by using PyMOL according to the form with the highest docking score.
2.8 detection of active oxygen
DCFH-DA was used as a fluorescent probe to detect intracellular ROS. Briefly, after incubation, cells were stained with 10 μ M DCFH-DA for 30 minutes at 37 ℃ and then washed 3 times with PBS. Photographs were taken by fluorescence microscopy (Thermo scientific, Waltham, MA, USA).
3. Results of the experiment
3.1 the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester attenuates the production of pro-inflammatory mediators in Raw264.7 cells stimulated by LPS plus IFN gamma;
raw264.7 cells were treated with different concentrations of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (6.25, 12.5, 25. mu.g/ml) to observe cytotoxicity. As shown in fig. 1(a), raw264.7 cell viability was not changed compared to the untreated group. The compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibited LPS plus IFN γ -induced NO production in raw264.7 cells in a dose-dependent manner as determined by Griess analysis (fig. 1B). The compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can inhibit the protein level expression of iNOS and COX2 in Raw264.7 cells induced by LPS plus IFN gamma at different time points (figure 1C-E). The compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibited LPS plus IFN gamma induced transcription levels of proinflammatory cytokines (IL-1 beta, IL-6) and COX2 by qPCR (FIG. 1F-H). The above results indicate that the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester attenuates pro-inflammatory mediator production in Raw264.7 cells stimulated by LPS and IFN gamma.
3.2 the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibits inflammation by regulating MAPK signal pathway protein;
the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can inhibit phosphorylation levels of JNK and c-JUN proteins of macrophage RAW264.7 after LPS and IFN- γ treatment, phosphorylation levels of other MAPK key proteins are not changed much (fig. 2A) and the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can inhibit nuclear invasion of JNK of macrophage RAW264.7 after LPS and IFN- γ treatment (fig. 2B). The results show that the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can inhibit inflammation by regulating MAPK signal pathway protein.
3.3 the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibits inflammation by targeting TAK 1;
the compound methyl 4-O-feruloyl-5-O-caffeoylquinite inhibits the level of phosphorylation of TAK1 in raw264.7 cells induced by LPS plus IFN γ (fig. 3A). A cell line stably knockdown in TAK1 was constructed by lentiviral transfection, as shown in FIG. 3B, with the most significant reduction in sh-TAK1.3 protein levels and also significant reduction in mRNA levels in the three constructed TAK1 knockdown cell lines (FIG. 3C). In TAK1 knockdown cell lines and NC cell lines, LPS and IFN-gamma stimulation were compared with no administration, and levels of proteins such as INOS, COX2 and the like and transcription levels of proinflammatory factors were examined by Western blot and qPCR. Western blot results showed that INOS and COX2 protein levels were not decreased in the dosing group compared to the model group in the TAK1 knockdown cell line (fig. 3D). The dosing group of the NC cell line is significantly reduced compared to the model group. The qPCR results concluded that there was no decrease in transcription levels of both pro-inflammatory cytokines (IL-1 β, IL-6) and COX2 in the administered group in the TAK1 knockdown cell line compared to the model group (fig. 3E-G). Through molecular docking experiments carried out by Autodock Vina software, we found that the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester has better affinity with TAK1 protein, and the binding energy is-9.3 kcal/mol. And interacts with amino acids Glu-105, Ala-107, Lys-158, Lys-190 of the TAK1 protein in a hydrogen bonding manner (FIG. 3H). The above results indicate that the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibits inflammation by targeting TAK1.
4.4 the compound methyl 4-O-feruloyl-5-O-caffeoylquiniate inhibits the level of ROS through the NRF2/HO-1 signaling pathway;
the literature reports that there is a complex interaction between inflammatory and oxidative stress pathways, NRF2 is an important transcription regulator and regulates the expression of various anti-inflammatory and antioxidant genes, and the downstream gene HO-1 is also an important medium for NRF2 to play an anti-inflammatory and antioxidant role, so that the balance mechanism between inflammation and oxidative stress can be taken as an exploration form. In the LPS-induced model, which is responsible for intracellular ROS production, 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester was also able to suppress intracellular ROS in our experimental study, in contrast to model group LPS plus IFN γ -induced Raw264.7 cells (FIG. 4A). To explore the role of the drug in the oxidative stress pathway, protein and transcript levels of HO-1/NQO1 were examined by Western blot and qPCR, and it was found that 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester could enhance the protein (FIG. 4B) and transcript levels (FIG. 4C) of HO-1/NQO1 in Raw264.7 cells induced by LPS plus IFN γ, compared to the model group. The same results were also obtained in the single-dose experiments, with increasing drug concentration, increasing protein levels (FIG. 4D) and transcript levels (FIG. 4E) of HO-1/NQO 1. Meanwhile, an immunofluorescence experiment is used for detecting the nuclear entry condition of the transcription factor NRF2, and the 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is found to be capable of increasing the nuclear entry rate of NRF 2. The above results indicate that the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester inhibits the level of ROS through NRF2/HO-1 signaling pathway, thereby regulating the balance between intracellular inflammation and oxidative stress.
In conclusion, the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester regulates MAPK signal pathway by targeting TAK1, and regulates macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators; the transcription level of HO-1 is also enhanced by the nuclear translocation of NRF2, thereby inhibiting the cell damage caused by oxidative stress and laying the foundation for the application of anti-inflammatory and antioxidant active ingredients in medicaments.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. The application of a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicaments is characterized in that: a compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester (molecular formula: C) with the following chemical structural formula27H28O12)：
Is applied to preparing medicines with anti-inflammatory and antioxidant activities.
2. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 1, wherein: the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can eliminate the increase of NO level caused by LPS and IFN-gamma induction, inhibit the gene expression level of inflammatory factors and effectively inhibit M1 type polarization of macrophages; the influence of the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester on the phosphorylation level and nuclear translocation of MAPK signal pathway conduction related protein is determined; the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is proved to regulate and control MAPK signal channel by targeting TAK1, and regulate macrophage M1 type differentiation, thereby inhibiting the secretion of inflammatory mediators.
3. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 1, wherein: the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can inhibit ROS levels induced by LPS and IFN-gamma through NRF2/HO-1 pathway; it was confirmed that the transcriptional level of HO-1/NQO1 by enhancing nuclear translocation of NRF2, thereby inhibiting cell damage caused by oxidative stress.
4. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 2, characterized in that: the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can effectively eliminate the level of NO in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma, thereby reducing the protein levels of iNOS and COX 2; can inhibit phosphorylation level of TAK1, thereby affecting phosphorylation levels of JNK and C-JUN downstream proteins of MAPK signal pathway, further inhibiting nuclear entry of JNK, thereby weakening combination with AP-1 site of transcription promoter region, and finally inhibiting secretion of cytokines IL-1 beta and IL-6.
5. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 3, wherein: the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester can increase the transcription and protein level of HO-1/NQO1 in a mouse macrophage RAW264.7 inflammation model induced by LPS and IFN-gamma; in a single-dosing experiment, the nuclear entry of NRF2 can be increased, and the transcription and protein level of HO-1/NQO1 can be further improved, so that cell damage caused by oxidative stress can be inhibited.
6. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 2, characterized in that: the anti-inflammatory active ingredient of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of anti-inflammatory drugs.
7. The use of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester in medicine according to claim 3, wherein: the antioxidant component of the compound 4-O-feruloyl-5-O-caffeoylquinic acid methyl ester is applied to the preparation of antioxidant drugs.
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