CN105147684A - Application of piperine to preparation of drugs for preventing and treating septicemia - Google Patents
Application of piperine to preparation of drugs for preventing and treating septicemia Download PDFInfo
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Abstract
The invention discloses application of piperine to the preparation of drugs for preventing and treating septicemia. Piperine can strongly enhance the leucine-induced activation of mTORC1. Piperine can prevent bacterial abdominal infection and further prevent septicemia, and can also enhance the functions of macrophages, including bacterial phagocytosis and TNF-alpha and IL-6 secretion capability, to prevent bacterial infection induced macrophage apoptosis. Therefore, piperine or the combination of piperine, leucine and glutamine can enhance the mTORC1 activity of bodies and be used for treating bacterial infections and septicemia.
Description
Technical field
The invention belongs to drug world, be specifically related to piperine in the anti-application cured the septicaemia in medicine of preparation.
Background technology
Piperine (Piperine) is the native compound of Piperaceae plant extract, and its molecular formula is C
17h
19nO
3; Chemical name is (E, E)-1-[5-(1,3-benzodioxolane-5-base)-1-oxo-2,4-pentadienyl]-piperidines.White crystalline powder.Fusing point 130 ~ 133 DEG C.Be dissolved in acetic acid, benzene, ethanol and chloroform, be slightly soluble in ether.Its chemical constitution is as follows:
Theory of Chinese medical science and practice show, Fructus Piperis enters stomach large intestine channel, warming spleen and stomach for dispelling cold, the therapeutic method to keep the adverse QI flowing downwards, expectorant.Can be used for gastrofrigid vomiting, stomachache is had loose bowels, inappetence, epilepsy abundant expectoration.Briefly, Fructus Piperis can be used for treatment gastrointestinal upset and epilepsy.The purposes of piperine in treatment colitis, visible publication file (application publication number CN103690537A).
Septicemia is a class because of after pathogen enters body blood system, and breed and produce a large amount of toxin rapidly, excitating organism immune system produces the symptom of excessive inflammation reaction, and fatality rate is high.The anti-treatment cured the septicaemia mainly adopts the anti-infective therapy of injection of antibiotics and strengthens the supportive treatments such as nutrition clinically is at present main.But due to antibiotic abuse, a lot of antibacterial creates Drug resistance, weakens the effect of anti-infective therapy.In some cases, as intestinal ulcer, when intestinal is not yet repaired, noxious bacteria is sustainable enters body.MTORC1 (rapamycin target protein) plays very important effect in maintenance immunity of organism balance, it is responsible for integrating ambient signal and Intracellular signals, as nutrient substance (as aminoacid and glucose), cellular stress and somatomedin.When immunocompromised, metabolism and the absorbability of patient are weak, and mTORC1 activity is low, low to the immunity of bacteriological infection, easily develop into septicemia.
Develop effective medicine and illustrate the difficult point that its antisepsis mechanism is septicemia treatment.The research of antisepsis medicine has benefited from the foundation of several animal models, and wherein lumbar injection bacillus coli DH 5 alpha mouse model has good stability and repeatability, can be used for the mechanism of drugs antisepsis well.
Summary of the invention
The object of the present invention is to provide piperine in the anti-application cured the septicaemia in medicine of preparation, it is active that piperine can improve cell mTORC1, strengthens the function of tissue macrophages, prevents curing the septicaemia.
Object of the present invention is achieved through the following technical solutions:
Piperine can be used for preparing the anti-medicine cured the septicaemia, and during by piperine and glutamine, leucine coupling, prevention effect is better;
The described anti-medicine cured the septicaemia also comprises acceptable adjuvant and other play the synergistic effective ingredient of compatibility;
The described anti-medicine cured the septicaemia can be various dosage form, as tablet, granule, capsule, drop pill, slow releasing agent, oral liquid, injection etc.
Find after deliberation, piperine can raise the activity of mTORC1 in cell, can raise the distribution of amino acid carrier SLC7A5/SLC3A2 at cell surface.When malnutrition, amino acid levels low (as low-level glutamine and leucine), piperine is the reinforcing agent of mTORC1; When amino acid starvation, cell mTORC1 are totally constrained, piperine, by combining with glutamine, leucine, activates mTORC1 signal path.
In addition, piperine can raise resident macrophages that tissue settles down to the phagocytic function of bacterial infection, can raise the cytokines such as resident macrophages TNF secretion-α and IL-6, strengthen tissue injury's repair ability.Under inflammatory conditions, piperine can suppress macrophages secrete IFN-γ; Piperine can protect infected peritoneal macrophage to avoid apoptosis; Piperine also can prevent the important subgroup of peritoneal macrophage (as Gata6
+subgroup) loss.
The present invention has following advantage and effect relative to prior art:
Piperine can strengthen the activation of the mTORC1 of leucine induction strongly.Piperine also can prevent antibacterial abdominal cavity infection, prevents the generation of septicemia.Piperine also can strengthen the function of macrophage, comprises its bacterial phagocytosis function, the ability of TNF secretion-α and IL-6, prevents the macrophage apoptosis that bacteriological infection is induced.Therefore, piperine or piperine are combined with leucine, glutamine, can enhancing body mTORC1 active, be used for the treatment of bacteriological infection and septicemia.The above-mentioned new activity of piperine and purposes, there is not yet open source literature report.
Accompanying drawing explanation
Fig. 1 western blot figure that to be piperine activate prostate gland cancer cell LNCaP cell mTORC1 signal shaft and gray analysis figure.
Fig. 2 is western blot figure and the gray analysis figure of the activation of piperine antithetical phrase cervical cancer cell HeLa cell mTORC1 signal shaft.
Fig. 3 western blot figure that to be piperine activate mice RAW264.7 macrophage mTORC1 signal shaft and gray analysis figure.
Fig. 4 western blot figure that to be piperine activate the mTORC1 signal shaft of the HeLa cell of the EBSS solution hunger of serum-free and gray analysis figure.
Fig. 5 is that piperine combines the western blot figure and gray analysis figure that activate the HeLa cell mTORC1 signal shaft of KRBB solution hunger with glutamine and leucine.
Fig. 6 is the western blot figure and gray analysis figure that piperine combines that with leucine and the HeLa cell mTORC1 signal shaft of pre-loaded glutamine hungry to KRBB solution activate.
Fig. 7 is the western blot figure and gray analysis figure that piperine combines that with leucine and the mouse peritoneal resident macrophages mTORC1 signal shaft of pre-loaded glutamine hungry to KRBB solution activate.
Fig. 8 is the Fluorescence Intensity Assays figure that piperine distributes at HeLa cell surface to amino acid carrier SLC7A5/SLC3A2.
Fig. 9 is that metformin is on the flow cytometry figure of the abdominal cavity resident macrophages ratio impact of the piperine protection F4/80 positive and Variant statistical analysis figure.
Figure 10 is that metformin raises to piperine flow cytometry figure and the Variant statistical analysis figure that abdominal cavity resident macrophages engulfs antibacterial capacity.
Figure 11 is the analysis chart of piperine pretreatment LPS stimulation peritoneal macrophage expression TNF-α and IL-6 level after 1 hour.
Figure 12 is the analysis chart that the piperine pretreatment peritoneal macrophage that after 6 hours, LPS stimulates expresses TNF-α and IL-6 level.
Figure 13 is the analysis chart that the piperine pretreatment peritoneal macrophage that after 48 hours, LPS stimulates expresses TNF-α and IL-6 level.
Figure 14 is the quantitative analysis figure that Turnover of Mouse Peritoneal Macrophages that In vitro culture is taken out in pretreatment in piperine body (gavage) for 10 days afterwards expresses TNF-α and IL-6 level under LPS stimulates.
Figure 15 is the analysis chart of the struvite macrophages secrete IFN-γ level that after piperine process, LPS stimulates.
Figure 16 is that piperine is to the Flow cytometry figure of the peritoneal macrophage activation apoptotic proteins Cleavedcaspase-3 expression of the CD11b positive of bacteriological infection and statistical analysis figure.
Figure 17 is that piperine is to the Flow cytometry figure of the peritoneal macrophage activation apoptotic proteins Cleavedcaspase-3 expression of the F4/80 positive of bacteriological infection and statistical analysis figure.
Figure 18 is that the important subgroup of the peritoneal macrophage of piperine to bacteriological infection is (as Gata6
+subgroup) immunofluorescence and karyomorphism observe figure.
Figure 19 is the survival Analysis figure of the mice of piperine pretreatment pneumoretroperitoneum inoculated bacteria.
Figure 20 is the mouse survival rate analysis chart injecting piperine after intraperitoneal inoculation antibacterial again.
Figure 21 is the organ injury analysis chart of the mice of piperine pretreatment pneumoretroperitoneum inoculated bacteria.
Figure 22 is inflammatory Cytokines Expression quantitative analysis figure in the mouse peritoneal irrigating solution of piperine pretreatment pneumoretroperitoneum inoculated bacteria.
Figure 23 is bacterial loads (cultivation clump count) analysis chart in the mouse peritoneal irrigating solution of piperine pretreatment pneumoretroperitoneum inoculated bacteria.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
Piperine raises the activity of mTORC1 in cell
The piperine of variable concentrations (40,80,160 μm of ol/L) is added the cell line (prostate cancer cell line LNCaP, Human cervical cancer cell lines HeLa, mouse macrophage RAW264.7) being incubated at 6 orifice plates and hatch 2 hours, albumen after collecting cell cracking, detects the phosphorylation of mTORC1 stream substrates p70S6K and 4E-BP1 by Westernblot method.
Result shows, piperine respective pretreatment LNCaP (Fig. 1), HeLa (Fig. 2) and RAW264.7 cell (Fig. 3), raise the phosphorylation of p70S6K and 4E-BP1 albumen dose dependent (concentration is respectively 40,80,160 μm of ol/L), and do not affect p70S6K and 4E-BP1 expressing quantity in cell.Fig. 1-3 bar diagram to add up in three kinds of cells p-p70S6K/p70S6K respectively with the ratio of p-4E-BP1/4E-BP1, * P<0.05 (difference has statistical significance), * P<0.01 (significant difference), * * * P<0.001 (difference is extremely remarkable).P70S6K and 4E-BP1 albumen is the substrate specificity of mTORC1 kinase complex, and their phosphorylation level raises, and illustrates that piperine dose-dependently can raise the activity of mTORC1.
Embodiment 2
During malnutrition (in cell, mTORC1 activity is lower), piperine is as the reinforcing agent of mTORC1
40 μm of ol/L piperines are added in the HeLa cell culture medium (EBSS or the DMEM culture medium of serum-free) of serum starvation, detect the phosphorylation of mTORC1 stream substrates p70S6K by Westernblot method, the activity of assessment mTORC1.
Found that, HeLa cell is after the EBSS hunger of serum-free, the phosphorylation level (i.e. the activity of mTORC1) of p70S6K is lower, whether containing glucose (Glc) in EBSS culture medium, no matter also whether containing piperine, do not affect the phosphorylation level (Fig. 4) of p70S6K, the effect of piperine to mTORC1 is described, have nothing to do with glucose.But the DMEM culture medium of serum-free can activate the phosphorylation of p70S6K, and piperine extremely significantly can strengthen the p70S6K phosphorylation (* * * P<0.001) of DMEM induction.This result illustrates, piperine raises mTORC1 effect, may with to there is aminoacid in culture medium relevant.
Embodiment 3
When cell mTORC1 hypoactivity, piperine is combined with glutamine, leucine, activates mTORC1 signal path
By 40 μm of ol/L piperines, the left-handed leucine (L-Leucine of 0.8mmol/L, and the l-GLUTAMINE (L-Glutamine of 2mmol/L Leu), Gln) (lower with), in the HeLa cell (Fig. 5-6) adding serum starvation respectively and Turnover of Mouse Peritoneal Macrophages (Fig. 7) culture medium.
Result shows, the phosphorylation (activation of instruction mTORC1) of p70S6K depends on the existence of Gln and Leu in cell.As shown in Figure 5, HeLa cell under serum and amino acid starvation (50min) condition, the activity inhibited (the first swimming lane) of mTORC1.Gln itself can not activate mTORC1.After short time hunger, still there is a small amount of Gln, Leu in cell slightly can raise mTORC1.After adding piperine, significantly can raise the mTORC1 activity (* P<0.01) that Leu activates.
Fig. 6 shows further, and HeLa cell is under aminoacid (Gln+Leu, wherein Gln shifts to an earlier date loading in 1 hour) existent condition, and piperine significantly can raise the activity of mTORC1.Similarly, under aminoacid existent condition (wherein Gln shifts to an earlier date loading in 1 hour), piperine significantly can raise the activity of the mTORC1 of Leu induction in Turnover of Mouse Peritoneal Macrophages (Fig. 7).
These results illustrate, piperine significantly can raise the activity of the mTORC1 induced by Leu.
Embodiment 4
Piperine raises the distribution of amino acid carrier SLC7A5/SLC3A2 at cell surface
By piperine (40 μm of ol/L), Leu (0.8mmol/L), add in the HeLa cell culture medium (KRBB of serum-free) of serum starvation, by the amino acid transporter SLC3A2 of fluorescence microscope fluorescent antibody labelling.
Result shows, solvent itself can not affect the distribution of neutral amino acid receptor SLC7A5/SLC3A2 on cell membrane.But after adding piperine, the average fluorescent strength of this amino acid receptor significantly raises, whether the existence of Leu seems not affect the distribution of this receptor on cell membrane (Fig. 8).These results illustrate, piperine, by raising the distribution of neutral amino acid receptor SLC7A5/SLC3A2 on cell membrane, raises the activity of the mTORC1 of aminoacid induction.
Embodiment 5
Piperine raises organizes the macrophage of settling down to the phagocytic function of bacterial infection
With piperine (every mice 20mg/kg), metformin (every mice 250mg/kg), gavage is carried out to C57BL/6 mice, the E. coli effect of the deactivation of 4 hours pneumoretroperitoneum injection CFSE labellings 0.5 hour, macrophage is separated, fluorescent antibody F4/80 labelling macrophage from abdominal cavity.By flow cytomery F4/80 positive cell to the phagocytic activity of CFSE-E.coli.
Result shows, mice injects abdominal cavity after 0.5 hour through antibacterial E.coli, and in cell, the ratio of F4/80 macrophage drops to rapidly 23% (this ratio of normal mouse is about 80%).But in piperine gavage mice, the ratio of F4/80 macrophage drops to 32% after bacteriological infection, illustrate that piperine can alleviate the loss of the F4/80 macrophage because of bacteriological infection induction.If during piperine gavage, add metformin (this medicine can activate AMPK and suppress the activity of mTORC1), after bacteriological infection, the ratio of F4/80 macrophage is more down to 16% (Fig. 9).
E.coli, through CFSE labelling, thus can detect with Flow Cytometry methods.Result shows, CFSE positive cell (cell of load antibacterial) is also F4/80 positive cell (Figure 10) simultaneously.This result explanation; F4/80 be early stage (this example the is 0.5 hour) intraperitoneal of bacteriological infection main engulf bacterial cell; and piperine gavage can alleviate the loss of the positive peritoneal macrophage of F4/80 that mice is induced because of bacteriological infection, this protective effect is relevant with the activity that piperine raises mTORC1 in cell.
Embodiment 6
Piperine raises the cytokines such as macrophages secrete TNF-α and IL-6
Get the peritoneal macrophage of normal C57BL/6 mice, plant in 24 orifice plates uniformly.By piperine (40 μm of ol/L) pretreatment of mice peritoneal macrophage 1 hour (Figure 11), 6 hours (Figure 12) and 48 hours (Figure 13), bacteria lipopolysaccharide (LPS) (100ng/ml) irritation cell 24 hours.The continuous gavage C57BL/6 mice of another piperine (every mice 20mg/kg) 10 days, then the peritoneal macrophage of separating mouse is cultivated in 24 orifice plates, adds LPS (100ng/ml) irritation cell 24 hours (Figure 14).Collecting cell culture medium supernatant, by the CBA inflammatory factor detection kit of BD company, flow cytometer detects the expression of the cytokines such as TNF-α and IL-6.
Measurement result shows, piperine pretreatment short time (1 hour and 6 hours) or long-time (48 hours) all can raise secretion by peritoneal macrophages TNF-α and the IL-6 inflammatory factor of LPS stimulation afterwards, and the macrophage that the piperine gavage mouse peritoneal of 10 days is separated, LPS stimulates rear TNF-α and the IL-6 factor all higher than group of solvents in vitro, illustrates that piperine can strengthen the function (see also embodiment 10) of inherent immunity cell.
Embodiment 7
Piperine inflammation-inhibiting macrophages secrete IFN-γ
Piperine (40 μm of ol/L) is acted in vitro respectively peritoneal macrophage and the lumbar injection thioglycolate salt (Thioglycollate of the normal mice of cultivating in 24 orifice plates, the macrophage of TG) inducing 48 hours, then adds LPS (100ng/ml) irritation cell 24 hours.Collecting cell culture supernatant, uses CBA test kit, by the expression of the factors such as flow cytomery IFN-γ.
Result shows, piperine does not affect normal secretion by peritoneal macrophages IFN-γ, and the expression of macrophage IFN-γ under inflammatory conditions that can significantly suppress TG to induce, show that piperine has immunoregulation effect (Figure 15) to inflammatory cells.
Embodiment 8
Piperine protects infected peritoneal macrophage to avoid apoptosis
By piperine (20mg/kg), metformin (250mg/kg) gavage C57BL/6 mice, the E.coli (0.5 × 10 that pneumoretroperitoneum injection in 4 hours is lived
9cFU/mouse) act on 0.5 hour, from abdominal cavity, be separated macrophage, with fluorescent antibody CD11b, F4/80 (macrophage marker) and cleavedcaspase-3 (apoptotic proteins) dyeing.By the activation apoptotic proteins cleavedcaspase-3 fluorescence intensity in flow cytomery peritoneal macrophage.
Result show, peritoneal macrophage engulf antibacterial after 0.5 hour apoptotic proteins cleavedcaspase-3 at CD11b
+(Figure 16) and F4/80
+(Figure 17) have obvious expression in cell, and piperine can the expression of apoptosis inhibit albumen cleavedcaspase-3 in cell, the effect of piperine inhibited apoptosis can be reversed by metformin.This shows, the apoptosis that piperine is caused because of bacteriological infection by mTORC1 signal protection peritoneal macrophage.
Embodiment 9
Piperine prevents the important subgroup of peritoneal macrophage (as Gata6
+subgroup) loss
By piperine (20mg/kg), metformin (250mg/kg) gavage C57BL/6 mice, the E.coli (0.5 × 10 that pneumoretroperitoneum injection in 4 hours is lived
9cFU/mouse) act on 0.5 hour, from abdominal cavity, be separated macrophage then plant in culture vessel with glass bottom, after adherent 3 hours, wash away non-attached cell.By cellular immunofluorescence method labelling CD11b (mark of macrophage), Gata6 (transcription factor) and Hoechst33342 (core dyestuff).
Display is observed under fluorescence inverted microscope; after the Turnover of Mouse Peritoneal Macrophages of bacteriological infection solvent gavage; CD11b positive cell reduces, the Gata6 factor fades away, concentrated or cracked (in apoptosis morphology) appear in nucleus; and the macrophage nuclear phase of piperine gavage Mus is gathered in core to complete, Gata6; illustrate that piperine can protect peritoneal macrophage to avoid because of bacteriological infection dead, but this protective effect of piperine can suppress by metformin.In this embodiment, more intuitive result shows, the apoptosis that piperine can be protected peritoneal macrophage to avoid bacteriological infection to cause, and prevents critical function subgroup (this routine centre halfback Gata6
+cell) loss (Figure 18).
Embodiment 10
Piperine separately or with glutamine, leucine coupling, can infect by anti-bacteria, prevent and treat the generation of septicemia
By the piperine of various dose gavage C57BL/6 mice 3 days in advance, then lumbar injection fatal dose (2 × 10
9the E.coli (Figure 19) of work CFU), or first lumbar injection half lethal dose (1 × 10
9the E.coli of work CFU), again with piperine (20mg/kg) gavage (Figure 20) after 1 hour, every the survival condition of 6 hours observed and recorded mices, amount to 4 days, draw mouse survival tracing analysis survival rate, result display piperine can resist the dead mouse that bacteriological infection causes;
Another piperine (20mg/kg) gavage C57BL/6 mice 3 days in advance, then lumbar injection fatal dose (2 × 10
9the E.coli of work CFU) acts on 8 hours, and mice is put to death in the dislocation of strength vertebra, gets liver and colon, and after fixing, dehydration, paraffin embedding, section carries out H.E. dyeing (Figure 21), basis of microscopic observation.Result shows, and piperine reduces the inflammatory injury of the leukocytic infiltration of liver and colon;
Piperine (20mg/kg) gavage C57BL/6 mice 3 days in advance, then lumbar injection half lethal dose (1 × 10
9the E.coli effect different time (6 hours and 24 hours) of work CFU), collect mouse peritoneal irrigating solution, the expression (Figure 22) of inflammatory factor TNF-α and IL-6 etc. in CBA kits abdominal cavity, and the amount (Figure 23) of colony counting intraperitoneal antibacterial alive, result display piperine raises TNF-α in abdominal cavity in early days at bacteriological infection, the expression of the IL-6 factor, but lower this two kinds of cytokine-expressings in the later stage (24 hours), and the removing presentative time dependency of antibacterial, illustrate that piperine can strengthen the inherent immunity function of the peritoneal macrophage of mice, promote the reparation of the organ injury that antibacterial is removed and septicemia causes.
Above result shows, piperine can infect by anti-bacteria, effectively prevents and treat the generation of septicemia.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (4)
1. piperine is in the anti-application cured the septicaemia in medicine of preparation.
2. piperine according to claim 1 is in the anti-application cured the septicaemia in medicine of preparation, it is characterized in that: containing piperine, glutamine and leucine in the described anti-medicine that cures the septicaemia.
3. piperine according to claim 1 is in the anti-application cured the septicaemia in medicine of preparation, it is characterized in that: the described anti-medicine that cures the septicaemia also comprises acceptable adjuvant and other play the synergistic effective ingredient of compatibility.
4. piperine according to claim 1 is in the anti-application cured the septicaemia in medicine of preparation, it is characterized in that: the described anti-medicine that cures the septicaemia is tablet, granule, capsule, drop pill, slow releasing agent, oral liquid or injection.
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| JPH08143562A (en) * | 1994-11-04 | 1996-06-04 | Cadila Lab Ltd | Composition containing piperine |
| CN1850073A (en) * | 2006-02-20 | 2006-10-25 | 珠海联邦制药股份有限公司 | Medicinal composition containing ampicillin and its preparing method |
| CN101686919A (en) * | 2007-03-22 | 2010-03-31 | 笛卡尔巴黎大学 | Citrulline is used for the treatment of the purposes that increases relevant pathologic state with protein carbonylation |
| KR20100091495A (en) * | 2009-02-10 | 2010-08-19 | 주식회사한국전통의학연구소 | Composition for preventing and treating inflammatory disease comprising piperine or pharmaceutically acceptable salt thereof as an active ingredient |
| KR101247802B1 (en) * | 2012-05-02 | 2013-03-27 | 주식회사한국전통의학연구소 | Composition for preventing and treating inflammatory disease comprising piperine or pharmaceutically acceptable salt thereof as an active ingredient |
-
2015
- 2015-09-30 CN CN201510664801.2A patent/CN105147684B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08143562A (en) * | 1994-11-04 | 1996-06-04 | Cadila Lab Ltd | Composition containing piperine |
| CN1850073A (en) * | 2006-02-20 | 2006-10-25 | 珠海联邦制药股份有限公司 | Medicinal composition containing ampicillin and its preparing method |
| CN101686919A (en) * | 2007-03-22 | 2010-03-31 | 笛卡尔巴黎大学 | Citrulline is used for the treatment of the purposes that increases relevant pathologic state with protein carbonylation |
| KR20100091495A (en) * | 2009-02-10 | 2010-08-19 | 주식회사한국전통의학연구소 | Composition for preventing and treating inflammatory disease comprising piperine or pharmaceutically acceptable salt thereof as an active ingredient |
| KR101247802B1 (en) * | 2012-05-02 | 2013-03-27 | 주식회사한국전통의학연구소 | Composition for preventing and treating inflammatory disease comprising piperine or pharmaceutically acceptable salt thereof as an active ingredient |
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