CN109602744A - Piperlongumine is preparing the application in antibacterial-anti-inflammatory drug - Google Patents
Piperlongumine is preparing the application in antibacterial-anti-inflammatory drug Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The invention discloses piperlongumines to prepare the application in antibacterial-anti-inflammatory drug.RNA-seq transcriptome analysis is carried out by the cell of the people to bacterium infection, analysis method is enriched with based on coexpression access and drug gene collection, obtain the drug candidate list with antibacterial and anti-inflammation functions, it was found that including several marketed drugs with antibacterial and anti-inflammation functions, the before undiscovered piperlongumine for having antibacterial and anti-inflammation functions is among them, therefore, piperlongumine can be applied to prepare antibacterial-anti-inflammatory drug.
Description
Technical field
The present invention relates to new medicine use, the in particular to new application of piperlongumine, specially piperlongumine is anti-in preparation
Application in bacterium anti-inflammation drugs, belongs to biomedicine field.
Background technique
Piperlongumine (Piperlongumine) is to be present in one of Piperaceae plant fructus piperis longi natural biological bases
Object is closed, there is anti-malignant tumor, anti-platelet aggregation, adjusting blood lipid metabolism, anti-Parkinson's disease, promotion melanocyte to be proliferated,
The effects of anti-inflammatory, antimycotic, and to normal cell, tissue, organ without apparent toxic side effect (referring to Li Lianjian, Chen Chunlei
Piperlongumine pharmacotoxicological effect mechanism and the Hainan progress [J] medicine, 2015 (14): 2113-2115.).
It is horizontal that piperlongumine can increase intracellular reactive oxygen species (ROS), and selectively kills cancer
Cell., by inhibiting TrxR1 to inhibit gastric cancer, a kind of novel CRM1 inhibitor can press down in mankind mastopathy cell for it
PI3K/Akt/mTOR processed can induce the cell death of pancreatic cancer cell (referring to Iwashita, Masaya, et al. "
Piperlongumine,a constituent of Piper longum L.,inhibits rabbit platelet
aggregation as a thromboxane A2receptor antagonist."European journal of
pharmacology 570.1-3(2007):38-42.).Piperlongumine, can be with as a kind of thromboxane A (2) receptor antagonist
Inhibit platelet aggregation (referring to Iwashita, Masaya, et al. " Piperlongumine, a constituent of
Piper longum L.,inhibits rabbit platelet aggregation as a thromboxane
A2receptor antagonist."European journal of pharmacology 570.1-3(2007):38-
42.).Piperlongumine also can be by inhibiting Akt/mTOR signal path to promote cell autophagy, and the dead (ginseng of mediate tumor cell
See Ryu, Jahee, et al. " Piperlongumine as a potential activator of AMP-activated
protein kinase in HepG2cells."Natural product research 28.22(2014):2040-
2043.).Piperlongumine causes the growth inhibition of interior tumor cell, without changing biochemistry, hematology and histopathology
Parameter.(referring to Bezerra, Daniel P., et al. " In vivo growth inhibition of sarcoma 180by
piperlonguminine,an alkaloid amide from the Piper species."Journal of Applied
toxicology 28.5(2008):599-607.).Therefore, the medical usage of piperlongumine can be developed further.
Patent document piperlongumine analog, preparation method and applications (CN104910174A) disclose piperlongumine class
The drug for treating or preventing thrombotic disease is used to prepare like object;Patent document piperlongumine is preparing medicine for treating tumor metastasis
Utilization (CN104415035A) in object discloses piperlongumine and its pharmaceutical salts and is preparing the utilization in medicine for anti transfer of tumor.
It will lead to cell after bacteria-infected cells and generate inflammatory reaction, further result in Apoptosis, seriously affect the mankind
Health.Therefore, researching and developing a variety of antibacterial-anti-inflammatory drugs is the key method for solving bacterium infection.Fusobacterium nucleatum
(Fusobacterium nucleatum, Fn) belongs to Gram-negative without gemma fusiform bacilarmature, and obligate anaerobe is periodontitis
One of main pathogenic bacteria.Fusobacterium nucleatum is a kind of with periodontosis and body other each site disorders have the cause of disease of close ties
Bacterium.
Currently, piperlongumine is mainly used for the medicines such as antitumor, treatment or prevention thrombotic disease according to the prior art
The preparation of object, there is not yet in relation to piperlongumine in the report for preparing the application in antibacterial-anti-inflammatory drug.
Summary of the invention
The object of the present invention is to provide the new opplications of piperlongumine, and specially piperlongumine is in preparing antibacterial-anti-inflammatory drug
Application.
Term explanation:
The structural formula of piperlongumine of the present invention is as follows, and market is commercially available or presses prior art chemical synthesis system
?.
Technical scheme is as follows:
Piperlongumine is preparing the application in antibacterial-anti-inflammatory drug.
Preferred according to the present invention, in the application, the antibacterial refers to that Fusobacterium nucleatum Fn, i.e. piperlongumine are making
Application in standby anti-Fusobacterium nucleatum Fn drug.
Above-mentioned piperlongumine includes piperlongumine and piperlongumine clinically acceptable salt, contains piperlongumine
Compound medicament composition and clinically acceptable preparation.The preparation formulation can be injection, solution, emulsion, mouth
Take liquid, suspension, paste, creme, spray, drops, freeze drying powder injection, powder, granule, pill, tablet, patch etc..
In application of the present invention, piperlongumine be used alone or with other antibacterial-anti-inflammatory drug use in conjunction.It is excellent
Choosing, the antibacterial-anti-inflammatory drug includes metronidazole, gentamicin, azithromycin, Imipenem, Meropenem, promise fluorine sand
One or more of star.
Beneficial effect
The present invention is based on the transcript profile data that Fusobacterium nucleatum Fn bacterium infection HGF cell generates, and are relocated based on drug
Analysis software cogena finds drug candidate piperlongumine, related to a large amount of inflammation logical in conjunction with differential gene in path analysis result
Road is highly relevant, it was initially believed that piperlongumine has antibacterial and anti-inflammation functions.It only used Fusobacterium nucleatum Fn in the present invention, still
The drug can be generalized in other bacteriums.Therefore, the present invention extends the pharmaceutical applications of piperlongumine, discloses piperlongumine
The application in antibacterial-anti-inflammatory drug is being prepared, is providing a kind of new therapeutic choice for clinical treatment inflammation disease.
Detailed description of the invention
Fig. 1 is Fusobacterium nucleatum morphological feature figure.
Fig. 2 is people's Gingival Fibroblasts morphological feature figure (P4, HGF, X100).
Fig. 3 is the co-expression gene cluster thermal map analysis chart of Fn bacterium infection HGF.Based on cogena software, kmeans is used
Clustering method, choosing cluster numbers is that 3, C_xh and F_xh respectively represents control group and Fn processing group at x hours.The figure can be compared with
To see the changes in gene expression feature after bacteria-infected cells on a macro scale.
Fig. 4 is the KEGG signal path enrichment analysis chart of Fn infection HGF.Y-axis shows KEGG signal path, and X-axis is shown
Three clustering clusters and all differences expressing gene, score represent access and are enriched with score in the cogena of the gene cluster, and discovery is big
Measure immune, bacterium infection and the relevant signal path of metabolism.
Fig. 5 is the drug reorientation analysis chart of Fn bacterium infection HGF cell.Y-axis shows drug candidate, and X-axis is shown
Three clustering clusters and all differences expressing gene, score represent drug candidate and are enriched with score in the cogena of the gene cluster.Verifying
For treating drug Rimexolone (Rimexolone, the 5th) and the antibacterial agent benzethonium chloride of Inflammatory eye conditions
The antibacterial action of (methylbenzethonium chloride, the 7th) finds the position piperlongumine (Piperlongumine)
Column enrichment analysis result the 8th.In conjunction with inflammatory reactions enrichments a large amount of in coexpression path analysis as a result, piperlongumine has
Antibacterial and anti-inflammation functions.
Specific embodiment
Following embodiments are for further illustrating but being not limited to the present invention.
1. materials and methods:
1.1 bacteriums and cell
Fusobacterium nucleatum (F.nucleatum, Fn, ATCC 25586) is frozen from oral tissue regeneration key lab, Shandong Province
Deposit strain library acquisition.
Gingival Fibroblasts (HGF): isolated from 6 18-30 years old extraction of impacted third molar volunteer patients.
1.2 reagent
It defibrinates sheep blood (Hai Bo biotech firm, Qingdao, Shandong, China), PBS (Suo Laibao, Beijing, China), chlorine
Change ferroheme-vitamin K1 (Hai Bo biotech firm, Qingdao, Shandong, China), brain heart infusion blood meida (Suo Laibao, Beijing,
China), BHI fluid nutrient medium (Suo Laibao, Beijing, China), collagenase type I (Suo Laibao, Beijing, China), DispaseII points
Dissipate enzyme (Invitrogen, Carlsbad, CA, USA), reactive oxygen species detection kit (Bei Bo, Shanghai), piperlongumine
(MedChemExpress, Shanghai).
1.3 instrument
(Austria contains public for anaerobic culture box (Britain's DWS DG250- compact anaerobism work station, Britain), ultraviolet specrophotometer
Department, Hangzhou, Zhejiang, China), qPCR instrument (Roche, Basel, Switzerland), T25 culture bottle (Corning company, beauty
State).
1.4 experimental design
People's Gingival Fibroblasts cell is infected by building Fusobacterium nucleatum Fn, bacteria-infected cells model is established, presses
According to 0,
2,6,12,24,48 hours acquisition cells extract RNA and carry out the transcriptome analysis based on two generation sequence rna-Seq,
The gene expression spectrum signature of bacteria-infected cells is obtained, based on coexpression KEGG access and the joint enrichment point of CMap drug gene collection
Analysis, is found to have the drug candidate list of antibacterial and anti-inflammation functions.
1.5 experimentation
1.5.1 Fusobacterium nucleatum Fn separation, culture, identification
Defrosting Fusobacterium nucleatum (F.nucleatum, ATCC 25586) strain is inoculated in and defibrinates sheep containing 10%
Blood, 0.5% hemin-vitamin K1 brain heart infusion blood meida on, be placed in 37 DEG C of anaerobic culture boxes be incubated for 48h extremely
Grow bacterium colony, picking single colonie is placed in 100mL BHI fluid nutrient medium proliferation to logarithmic growth phase, 6000rpm × 5min from
The fresh bacterium solution of the heart, sterile PBS washing thalline 2 times are resuspended in BHI broth, and ultraviolet specrophotometer measures OD600nm absorbance
Value is completed to convert between OD value and number of bacteria, be identified using special primer row qPCR, it is standby to obtain Fusobacterium nucleatum (see Fig. 1)
With.The DNA of bacteria is extracted, by PCR amplification, amplified production send Hua Da gene Co., Ltd to carry out 16S sequencing, sequencing result
It is compared in HOMD database, is identified as 25586 bacterial strain of FN.
1.5.2 people's Gingival Fibroblasts HGF is separately cultured
Recruit 18-30 year old extraction of impacted third molar volunteer patient 6, informed consent, acquisition gingiva tissue.In vitro gum group
It knits and is dipped in sterile PBS, rapidly from clinical metastasis to laboratory, rinsed in sterile super-clean bench expert PBS, it is big to shred into 1-3mm2
Fractionlet collects fragment in sterile EP tube, and collagenase type I and DispaseII dispase digestion 2h hang postdigestive cell
Liquid is placed in T25 culture bottle, and 37 DEG C, 5%CO2Incubator is incubated for about 7-10 days, and cell growth, proliferation is reached to cell confluency
80%-90% is passed on 1:3 dilution ratio, expands culture.Cell grew into for the 4th generation, saved, spare (see Fig. 2).
1.5.3. Fusobacterium nucleatum Fn handles people's Gingival Fibroblasts HGF, carries out transcript profile sequencing analysis
The P4 of 5 patients is cultivated simultaneously for HGF, and pancreatin digests, and blood counting chamber counts, and is inoculated in 6 orifice plates respectively
(2X105The hole cell/), after cell adherent growth, HGF (Fn:HGF=100:1) is infected with Fn, is uninfected by a group conduct control,
Infection time is respectively 2,6,12,24,48 hours, after infection, and with Trizol lytic cell, cell pyrolysis liquid is received respectively
Combine in no enzyme EP pipe, number (cell origin number is B, C, D, E, F, control group C, experimental group F, the time with it is digital come
It indicates, such as: B2C represents cell derived from B patient, and 2 represent 2h, and C represents untreated fish group), send Hua Da gene Co., Ltd to carry out
Sequencing based on RNA-Seq obtains the transcript profile feature of the time series of bacteria-infected cells.
1.5.4 based on coexpression access and drug gene collection Conjoint Analysis discovery bacteria-infected cells related pathways and
Drug candidate
The co-expression gene collection enrichment analysis R software package cogena that coexpression enrichment analysis is developed before using applicant,
Select K-means clustering method, clustering cluster 3.Pathway gene collection selects KEGG signal path, and drug gene collection selects CMap medicine
Object collection, statistical test method are hypergeometric distribution hypothesis testing method.It is presented and is tied based on thermal map, access or drug-rich figure
Fruit.
2. experimental result
The changes in gene expression feature of 2.1Fn bacterium infection people's Gingival Fibroblasts HGF
For different time points (2,6,12,24,48 hours), it is based respectively on limma software package and analyzes to obtain differential expression
Gene takes the intersection of differential gene to obtain 971 genes and thermal map (see Fig. 3) is presented using cogena, can more see on a macro scale
Changes in gene expression feature after to bacteria-infected cells, horizontal axis is the sample changed according to natural time, longitudinal axis generation in the figure
Table gene expression profile is broadly divided into three coexpression clustering clusters (cluster), and wherein clustering cluster 1 and 2 is after bacteria-infected cells
Up-regulation gene cluster, 3 are down-regulated gene cluster.
2.2 coexpression path analysis are several immune and are metabolized relevant access
It is analyzed based on above-mentioned thermal map as a result, carrying out co-expression gene KEGG signal path analysis (Fig. 4), discovery is largely exempted from
Epidemic disease, bacterium infection and the relevant signal path of metabolism, such as cell factor and cytokine receptor interaction access (cytokine
Cytokine-receptor interaction pathway), Helicobacter pylori infection epithelial cell signal path
(epithelial cell signaling in helicobacter pylori infection pathway), Li Shiman are former
Insect infection signal path (leishmania infection pathway), glutathione metabolism access (glutathion
Metabolism pathway) etc..
2.3 coexpression drug reorientation analyses
By thermal map and access enrichment figure, finds the gene expression spectrum signature of Fn bacterium infection HGF cell, use cogena
Software carries out calculating drug reorientation analysis, (other candidate medicines of part as a result as shown in Figure 5 for co-expression gene clustering cluster 2
Object has blocked), demonstrate drug Rimexolone (Rimexolone, the 5th) and the antibacterial agent chlorine for treating Inflammatory eye conditions
Change the antibacterial action of benzyl ethoxy ammonium (methylbenzethonium chloride, the 7th), finds piperlongumine
(Piperlongumine) enrichment analysis result the 8th is ranked.It is enriched in conjunction with a large amount of inflammatory reactions in coexpression path analysis
As a result, piperlongumine has antibacterial and anti-inflammation functions, it is expected to develop into the drug with antibacterial and anti-inflammation functions.Therefore, piperlongumine
It can be applied to prepare in antibacterial-anti-inflammatory drug.
Claims (6)
1. piperlongumine is preparing the application in antibacterial-anti-inflammatory drug, the structural formula of the piperlongumine is as follows:
2. application as described in claim 1, it is characterised in that be piperlongumine in preparing anti-Fusobacterium nucleatum Fn drug
Using.
3. application as claimed in claim 1 or 2, it is characterised in that above-mentioned piperlongumine includes piperlongumine and fructus piperis longi acyl
Amine clinically acceptable salt, the compound medicament composition containing piperlongumine and clinically acceptable preparation.
4. application as claimed in claim 3, it is characterised in that clinically acceptable preparation formulation be injection, solution,
Emulsion, oral solution, suspension, paste, creme, spray, drops, freeze drying powder injection, powder, granule, pill, tablet, patch
Agent.
5. application as claimed in claim 1 or 2, it is characterised in that piperlongumine be used alone or with other antibiosis anti-inflammatory drugs
Object use in conjunction.
6. application as claimed in claim 5, it is characterised in that the antibacterial-anti-inflammatory drug include metronidazole, gentamicin,
One or more of azithromycin, Imipenem, Meropenem, Norfloxacin.
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Cited By (6)
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CN112266352A (en) * | 2020-11-20 | 2021-01-26 | 绍兴文理学院 | Piperlongumine derivative and preparation method and application thereof |
CN113796379A (en) * | 2021-10-25 | 2021-12-17 | 中国热带农业科学院环境与植物保护研究所 | Application of piperlongumine in preventing and treating plant bacterial diseases |
CN113812412A (en) * | 2021-10-25 | 2021-12-21 | 中国热带农业科学院环境与植物保护研究所 | Application of piperlongumine in herbicide for preventing and controlling agricultural weeds |
CN113975275A (en) * | 2021-11-29 | 2022-01-28 | 宜昌市第一人民医院(三峡大学人民医院) | New use of piperlongumine for inhibiting programmed necrosis |
CN114073693A (en) * | 2020-08-10 | 2022-02-22 | 华南理工大学 | Application of piperlongumine in inhibiting activation of NLRP3 inflammatory corpuscle |
WO2022153306A1 (en) * | 2021-01-14 | 2022-07-21 | B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University | Anti-quorum sensing, anti-biofilm, and inflammation attenuating compounds, compositions, and methods of using same |
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Cited By (9)
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CN114073693A (en) * | 2020-08-10 | 2022-02-22 | 华南理工大学 | Application of piperlongumine in inhibiting activation of NLRP3 inflammatory corpuscle |
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WO2022153306A1 (en) * | 2021-01-14 | 2022-07-21 | B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University | Anti-quorum sensing, anti-biofilm, and inflammation attenuating compounds, compositions, and methods of using same |
CN113796379A (en) * | 2021-10-25 | 2021-12-17 | 中国热带农业科学院环境与植物保护研究所 | Application of piperlongumine in preventing and treating plant bacterial diseases |
CN113812412A (en) * | 2021-10-25 | 2021-12-21 | 中国热带农业科学院环境与植物保护研究所 | Application of piperlongumine in herbicide for preventing and controlling agricultural weeds |
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CN113812412B (en) * | 2021-10-25 | 2023-01-03 | 中国热带农业科学院环境与植物保护研究所 | Application of piperlongumine in herbicide for preventing and controlling agricultural weeds |
CN113975275A (en) * | 2021-11-29 | 2022-01-28 | 宜昌市第一人民医院(三峡大学人民医院) | New use of piperlongumine for inhibiting programmed necrosis |
CN113975275B (en) * | 2021-11-29 | 2023-03-03 | 宜昌市第一人民医院(三峡大学人民医院) | New use of piperlongumine for inhibiting programmed necrosis |
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Application publication date: 20190412 |
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