CN117771225A - Application of caffeic acid and derivatives thereof in preparation of medicines for treating clostridium difficile infection - Google Patents
Application of caffeic acid and derivatives thereof in preparation of medicines for treating clostridium difficile infection Download PDFInfo
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- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 title claims abstract description 58
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 title claims abstract description 28
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 title claims abstract description 27
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- 238000002360 preparation method Methods 0.000 title description 3
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical class C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 claims abstract description 28
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 claims abstract description 28
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- YMGFTDKNIWPMGF-AGYDPFETSA-N 3-(3,4-dihydroxyphenyl)-2-[(e)-3-[2-[(e)-2-(3,4-dihydroxyphenyl)ethenyl]-3,4-dihydroxyphenyl]prop-2-enoyl]oxypropanoic acid Chemical compound C=1C=C(O)C(O)=C(\C=C\C=2C=C(O)C(O)=CC=2)C=1/C=C/C(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 YMGFTDKNIWPMGF-AGYDPFETSA-N 0.000 claims description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to application of caffeic acid and derivatives thereof in preparing medicines for resisting clostridium difficile infection, C57BL/6 mice are taken as infection carriers, cell rounding experiments and clostridium difficile infection treatment experiments of mice prove that caffeic acid and derivatives of caffeic acid phenethyl ester can inhibit cell rounding induced by clostridium difficile toxin TcdB, and caffeic acid phenethyl ester can reduce clostridium difficile virulence by inhibiting self-cleavage and glucosyltransferase activity of clostridium difficile toxin TcdB, and has a protective effect on clostridium difficile infection models. Compared with the traditional antibacterial drugs, the natural compound caffeic acid and the derivatives thereof give bacteria a smaller survival pressure, are not easy to induce the generation of drug resistance, have the characteristics of wide sources and low cost, and have important significance for developing new drugs for resisting clostridium difficile infection.
Description
Technical Field
The invention discloses a new application of caffeic acid and a derivative thereof, in particular relates to an application of caffeic acid and a derivative thereof in preparing medicines for treating clostridium difficile infection, and belongs to the technical field of medical pharmacy.
Background
Clostridium difficile is a gram-positive anaerobic bacillus that is widely distributed in the human, animal gut and environment. Clostridium difficile was originally identified as part of the healthy infant flora in 1935 and its relationship to human disease was not revealed until the 70 s of the 20 th century. The frequency and severity of clostridium difficile infection has increased worldwide over the last decade, becoming one of the most common hospital-acquired infections. Clostridium difficile has been reported as a major cause of neonatal enteritis in piglets since 2000. This pathogen is transmitted by the faecal route, and potential hosts include asymptomatic carriers, infected patients, environmental pollution and animal intestinal tracts (canine, feline, porcine, avian). Clinical manifestations vary from asymptomatic carrier status to life threatening colitis and cause death.
Clostridium difficile infection is mainly caused by the spread of spores, dormant cells that are highly resistant to environmental conditions. After bile acids reach the gut, which plays an important role in the induction of germination of clostridium difficile spores, primary bile acids generally stimulate germination of clostridium difficile spores, while secondary bile acids in the colon inhibit this process. When the intestinal microbial balance is disrupted, clostridium difficile begins to dominate and colonize the large intestine, and some patients develop symptoms of clostridium difficile infection. Clostridium difficile produces several toxins during disease onset, tcdA, tcdB, which is considered the most predominant causative agent, and binary toxins (CDT) produced in some strains. During clostridium difficile infection, once the toxin is secreted, tcdB binds to the receptor and will enter the colonic epithelial cells to cause inflammatory chemokine and cytokine production, neutrophil influx, tight junctions destruction and ultimately cell death. Currently, vancomycin or non-daptomycin is generally used for treating clostridium difficile infection (the main function of the non-daptomycin is to prevent recurrent infection), but drug-resistant strains are inevitably generated along with a large amount of long-term use of antibiotics. Thus, there is a great clinical need to find new anti-infective strategies and new drugs to treat clostridium difficile infection.
Caffeic acid, known as 3, 4-dihydroxycinnamic acid, is widely used in Chinese herbal plants such as eucommia ulmoides, honeysuckle, etc. Caffeic acid has antiinflammatory, antibacterial, and antiviral effects, and can be used for treating diseases related to oxidative stress, inflammation and viral infection. The caffeic acid derivative caffeic acid phenethyl ester has abundant resources, but the resource utilization rate is very low at present, and some natural plants rich in caffeic acid phenethyl ester are not fully developed and utilized. Therefore, the development of caffeic acid and derivatives thereof as a novel antitoxic drug has very important significance.
Disclosure of Invention
The invention provides medical application of caffeic acid and derivatives thereof in preparing medicines for treating clostridium difficile infection, and discloses the function of caffeic acid and derivatives thereof in inhibiting clostridium difficile toxins.
According to the invention, the caffeic acid and the derivatives thereof can inhibit the function of clostridium difficile toxin TcdB through a cell rounding test, a toxin self-cutting test, a glucosyltransferase activity test and an animal test, so that the protection effect on organisms is achieved.
The molecular structure of the caffeic acid and the derivative thereof is as follows:
caffeic acid: the molecular formula: c (C) 9 H 8 O 4 Molecular weight: 180.16
Caffeic acid phenethyl ester: the molecular formula: c (C) 17 H 16 O 4 Molecular weight: 284.31
Caffeic acid ethyl ester: the molecular formula: c (C) 11 H 12 O 4 Molecular weight: 208.21
Salvianolic acid A: the molecular formula: c (C) 26 H 22 O 10 Molecular weight: 494.45
Rosmarinic acid: the molecular formula: c (C) 18 H 16 O 8 Molecular weight: 360.31
Acteoside: the molecular formula: c (C) 29 H 36 O 15 Molecular weight: 624.59
The present invention has found that caffeic acid and its derivatives are capable of inhibiting the function of clostridium difficile toxin TcdB. Among the derivatives, caffeic acid phenethyl ester is taken as a main research object.
The invention discovers that caffeic acid and derivatives thereof inhibit cell rounding induced by clostridium difficile toxin TcdB.
The invention can prepare various dosage forms from caffeic acid and derivatives thereof and pharmaceutically acceptable auxiliary materials.
Drawings
Fig. 1: caffeic acid phenethyl ester significantly inhibits TcdB-mediated cell rounding
Fig. 2: phenethyl caffeate inhibits TcdB self-cleavage over a range of concentrations tested
Fig. 3: phenethyl caffeate inhibits glucosyl transferase activity over a range of concentrations tested
Fig. 4: body weight change of mice after treatment with phenethyl caffeate
Fig. 5: significantly reducing the colonial planting number of the faeces of infected mice after treatment by caffeic acid phenethyl ester
Detailed Description
The invention is further illustrated by the following examples, which are not in any way limiting, and any modifications or alterations of the invention, which are easily realized by a person skilled in the art, will fall within the scope of the claims of the present invention without departing from the technical solutions of the invention.
Example 1
Caffeic acid and its derivatives can be used as clostridium difficile toxin inhibitor and in preparation of medicine for treating clostridium difficile infection, and can be used for any pharmaceutically acceptable carrier.
Example 2
Caffeic acid and its derivatives are used as clostridium difficile toxin inhibitors for preparing medicines for treating infectious diseases.
Example 3
Caffeic acid and its derivatives are used as clostridium difficile toxin inhibitors for the treatment of infectious diseases caused by bacteria, in particular infections caused by clostridium difficile.
Test example 1
Effect of caffeic acid and its derivative phenethyl caffeate on TcdB-mediated cell rounding
Hela cells were seeded in 96-well plates and experiments were performed after overnight cell growth had occurred. Caffeic acid and its derivative caffeic acid phenethyl ester were pre-incubated with TcdB for 1h to post-treat cells, toxin alone treatment was used as a control group, and cell morphology changes were observed.
The results show that: compared with DMSO blank control group and single toxin treatment group, 16 μg/mL caffeic acid or 8 μg/mL caffeic acid phenethyl ester can inhibit TcdB-mediated cell rounding (see figure 1).
Test example 2
Effect of caffeic acid derivative caffeic acid phenethyl ester on TcdB self-cleavage
Toxin TcdB was diluted with 10mm Tris buffer ph7.5, the diluted toxin was pre-incubated with phenethyl caffeate for 1h, and instrp 6 was added to react at 37 ℃ for 6h. After the reaction, samples were collected and treated with SDS loading buffer to detect the occurrence of self-cleavage by the toxin.
The results show that: 4 μg/mL of phenethyl caffeate inhibited self-cleavage of TcdB (see FIG. 2).
Test example 3
Influence of caffeic acid derivative caffeic acid phenethyl ester on glucosyl transferase activity
The expression of the protein GTD with the activity of the glucosyl transferase in the purified full-length toxin TcdB, and the influence of different concentrations of caffeic acid phenethyl ester on the activity of the GTD according to the instruction of the glucosyl transferase activity detection kit.
The results show that: 2 μg/mL of phenethyl caffeate significantly inhibited the activity of GTD (see FIG. 3).
Test example 4
Protection of clostridium difficile infected mice by caffeic acid derivative phenethyl caffeate
4.1 establishment of a model of Clostridium difficile infected mice
Male C57BL/6 mice (18-22 g) of 6-8 weeks old are adaptively fed for 3 days, free feeding and drinking water are carried out during the period, then the drinking water is replaced by 0.5g/L cefoperazone sodium, the pretreatment is carried out for 5 days, after normal drinking water is given for 2 days, clostridium difficile infection diarrhea models of the mice are established by adopting an oral and gastric lavage mode.
4.2 changes in body weight of mice after treatment with phenethyl caffeate
The cefoperazone sodium pretreated mice were randomly divided into healthy control groups, clostridium difficile infection + in vivo solvent treatment groups, clostridium difficile infection + phenethyl caffeate treatment groups. The clostridium difficile infection + phenethyl caffeate treatment group is infused with 100mg/kg phenethyl caffeate after bacterial infection of mice for 2 times/day, wherein the clostridium difficile infection + in-vivo solvent treatment group is infused with the corresponding in-vivo solvent in the same time, the healthy control group does not perform any treatment, and the weight change condition of the mice in different treatment groups is counted after continuously observing for 5 days.
The results show that: healthy control mice continue to gain weight over 5 days; mice in the infected group continuously decrease in body weight 3 days before infection, and increase in body weight on days 4 and 5; the mice in the treatment group had a weight loss 2 days before, and a weight gain from day 3 and a magnitude of the gain was greater than that in the infection group, indicating that caffeic acid phenethyl ester had a protective effect on mice in clostridium difficile diarrhea model (see figure 4).
4.3 fecal colony colonization conditions
Mice were sacrificed on day 3 post infection, faeces from each group were weighed and ground to make tissue homogenates, which were diluted in sterile PBS and plated on CCFA agar bacteria culture plates, and colony counts were performed after incubation at 37 ℃.
The results show that: colony colonization in mouse feces was significantly reduced after treatment with phenethyl caffeate compared to the infected group (see figure 5).
In conclusion, the study successfully establishes a clostridium difficile infected mouse model in a mode of gastric lavage infection of clostridium difficile, discovers that caffeic acid phenethyl ester reduces diarrhea degree of clostridium difficile infected mice and inhibits colonial colonization in feces, and lays a foundation for developing new clostridium difficile infected medicines.
Claims (4)
1. Use of caffeic acid and its derivatives in preparing medicines for treating clostridium difficile infection is provided.
2. The use according to claim 1, wherein said caffeic acid and derivatives thereof are pharmaceutically acceptable carriers, such as injections, capsules, tablets or powder injections, and the caffeic acid derivatives mainly comprise: phenethyl caffeate, ethyl caffeate, salvianolic acid a, rosmarinic acid, acteoside, and the like.
3. Use of caffeic acid and derivatives thereof according to claim 1 in the manufacture of a medicament for the treatment of clostridium difficile infection, wherein said infection is an infection caused by clostridium difficile.
4. The use of claim 1, any readily realizable modification or variation of the invention shall fall within the scope of the claims.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311733526.6A CN117771225A (en) | 2023-12-18 | 2023-12-18 | Application of caffeic acid and derivatives thereof in preparation of medicines for treating clostridium difficile infection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311733526.6A CN117771225A (en) | 2023-12-18 | 2023-12-18 | Application of caffeic acid and derivatives thereof in preparation of medicines for treating clostridium difficile infection |
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| CN117771225A true CN117771225A (en) | 2024-03-29 |
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| CN202311733526.6A Pending CN117771225A (en) | 2023-12-18 | 2023-12-18 | Application of caffeic acid and derivatives thereof in preparation of medicines for treating clostridium difficile infection |
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| Country | Link |
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| CN (1) | CN117771225A (en) |
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