CN105147684B - Application of the pipering in the anti-medicine that cures the septicaemia is prepared - Google Patents
Application of the pipering in the anti-medicine that cures the septicaemia is prepared Download PDFInfo
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Abstract
The invention discloses application of the pipering in the anti-medicine that cures the septicaemia is prepared.Pipering can strongly enhance the mTORC1 of leucine induction activation.Pipering can also prevent bacterium abdominal cavity infection, prevent the generation of septicemia.Pipering can also strengthen the function of macrophage, including its bacterial phagocytosis function, TNF secretion α and IL 6 ability, the macrophage apoptosis for preventing bacterium infection from inducing.Therefore, pipering or pipering are combined with leucine, glutamine, can strengthen body mTORC1 activity, for treating bacterium infection and septicemia.
Description
Technical field
The invention belongs to drug field, and in particular to application of the pipering in the anti-medicine that cures the septicaemia is prepared.
Background technology
Pipering (Piperine) is the native compound of Piperaceae plant extract, and its molecular formula is C17H19NO3；Chemical name
Referred to as (E, E) -1- [5- (1,3- benzodioxolane -5- bases) -1- oxo -2,4- pentadienyls]-piperidines.White crystal powder
End.130~133 DEG C of fusing point.Acetic acid, benzene, ethanol and chloroform are dissolved in, is slightly soluble in ether.Its chemical constitution is as follows：
Theory of traditional Chinese medical science and practice have shown that, pepper enters stomach large intestine channel, warming spleen and stomach for dispelling cold, lower gas, dissolving phlegm.Available for gastrofrigid vomiting,
Stomachache diarrhea, poor appetite, epilepsy abundant expectoration.Briefly, pepper can be used for treatment upset,gastro-intestinal and epilepsy.Pipering is being treated
Purposes in terms of colitis, it is seen that publication file (application publication number CN103690537A).
Septicemia is after one kind enters body blood system because of pathogen, to breed rapidly and produce a large amount of toxin, exactor
Body immune system produces the symptom of excessive inflammation reaction, and fatal rate is high.Clinically prevent that the treatment that cures the septicaemia is main at present
Based on the supportive treatments such as the anti-infective therapy of injection of antibiotics and reinforcement nutrition.However, due to the abuse of antibiotic, very
More bacteriums generate the resistance to the action of a drug, weaken the effect of anti-infective therapy.In some cases, such as enteron aisle ulcer, not yet repaiied in enteron aisle
In the case of multiple, harmful bacteria is sustainable to enter body.MTORC1 (rapamycin target protein) is in immunity of organism balance is maintained
Very important effect is played, it is responsible for integrating ambient signal and Intracellular signals, such as nutriment (such as amino acid and grape
Sugar), cellular stress and growth factor.In the case of immunocompromised, the metabolism of patient and absorbability are weak, and mTORC1 lives
Property is low, low to the immunity of bacterium infection, easily develops sepsis.
Develop effective medicine and illustrate the difficult point that its antisepsis mechanism is septicemia treatment.Antisepsis medicine is ground
The foundation for having benefited from several animal models is studied carefully, wherein intraperitoneal injection bacillus coli DH 5 alpha mouse model has good stability and can
Repeatability, it can be used for studying the mechanism of medicine antisepsis well.
The content of the invention
It is an object of the invention to provide application of the pipering in the anti-medicine that cures the septicaemia is prepared, pipering can improve carefully
Born of the same parents mTORC1 activity, strengthen the function of tissue macrophages, it is anti-to cure the septicaemia.
The purpose of the present invention is achieved through the following technical solutions：
Pipering can be used for preparing the anti-medicine to cure the septicaemia, when pipering and glutamine, leucine are combined, preventing and treating
Effect is more preferable；
The described anti-medicine to cure the septicaemia also comprising acceptable auxiliary material and other rise compatibility synergy it is effective into
Point；
The described anti-medicine to cure the septicaemia can be various formulations, as tablet, granule, capsule, dripping pill, sustained release agent,
Oral liquid, injection etc..
It has been investigated that pipering can raise intracellular mTORC1 activity, amino acid carrier SLC7A5/ can be raised
Distributions of the SLC3A2 in cell surface.It is low (such as low-level glutamine and leucine) in nutritional deficiency, amino acid levels
In the case of, pipering is mTORC1 reinforcing agent；In the case where amino acid starvation, cell mTORC1 are totally constrained, recklessly
Green pepper alkali can activate mTORC1 signal paths by combining with glutamine, leucine.
In addition, pipering can raise phagocytic function of the resident macrophages to bacterial infection of tissue colonization, can raise often
The cell factor such as TNF-α in macrophages secrete and IL-6, strengthen tissue damage repair ability.Under inflammatory conditions, pipering
Macrophages secrete IFN-γ can be suppressed；Pipering can protect infected peritoneal macrophage from apoptosis；Pipering may be used also
Prevent important subgroup (such as Gata6 of peritoneal macrophage+Subgroup) loss.
The present invention is had the following advantages relative to prior art and effect：
Pipering can strongly enhance the mTORC1 of leucine induction activation.Pipering can also prevent bacterium abdominal cavity infection,
Prevent the generation of septicemia.Pipering can also strengthen the function of macrophage, including its bacterial phagocytosis function, TNF secretion-α and
IL-6 ability, the macrophage apoptosis for preventing bacterium infection from inducing.Therefore, pipering or pipering and leucine, glutamy
Amine is combined, and can strengthen body mTORC1 activity, for treating bacterium infection and septicemia.The above-mentioned new activity of pipering is with using
On the way, there is not yet open source literature is reported.
Brief description of the drawings
Fig. 1 is western blot figure and gray scale of the pipering to prostate gland cancer cell LNCaP cell mTORC1 signal activation shafts
Analysis chart.
Fig. 2 is western blot figure and gray scale point of the pipering to sub- cervical cancer cell HeLa cell mTORC1 signal activation shafts
Analysis figure.
Fig. 3 is western blot figure and gray scale of the pipering to the macrophage mTORC1 signal activation shafts of mouse RAW 264.7
Analysis chart.
Fig. 4 is the Diagnosis of Sghistosomiasis of the mTORC1 signal activation shafts of the hungry HeLa cells of EBSS solution of the pipering to serum-free
Mark figure and gray analysis figure.
Fig. 5 is that pipering is combined with glutamine and leucine to the hungry HeLa cell mTORC1 signal shafts of KRBB solution
The western blot figure and gray analysis figure of activation.
Fig. 6 is the HeLa cells that pipering combines hungry to KRBB solution and pre-loaded glutamine with leucine
The western blot figure and gray analysis figure of mTORC1 signal activation shafts.
Fig. 7 is that pipering is combined the mouse peritoneal of hungry to KRBB solution and pre-loaded glutamine with leucine and resided
The western blot figure and gray analysis figure of macrophage mTORC1 signal activation shafts.
Fig. 8 is the fluorescence intensity that pipering is distributed to amino acid carrier SLC7A5/SLC3A2 in HeLa cell surfaces
Analysis chart.
Fig. 9 is that the streaming that the abdominal cavity resident macrophages ratio that melbine protects F4/80 positive pipering influences is thin
Born of the same parents' art analysis chart and Variant statistical analysis figure.
Figure 10 is fluidic cell of the melbine to pipering up-regulation abdominal cavity resident macrophages phagocytosis bacterium capacity
Art analysis chart and Variant statistical analysis figure.
Figure 11 is the analysis of pepper oxygenation pretreatment LPS stimulations peritoneal macrophage expression TNF-α and IL-6 levels after 1 hour
Figure.
Figure 12 is the pepper oxygenation pretreatment peritoneal macrophage that LPS is stimulated after 6 hours expression TNF-α and point of IL-6 levels
Analysis figure.
Figure 13 is that the pepper oxygenation pretreatment peritoneal macrophage that LPS is stimulated after 48 hours expression TNF-α and IL-6 are horizontal
Analysis chart.
Figure 14 is that pretreatment (gavage) takes out the Turnover of Mouse Peritoneal Macrophages of in vitro culture in LPS in pipering body after 10 days
Stimulate the horizontal quantitative analysis figure of lower expression TNF-α and IL-6.
Figure 15 is the horizontal analysis chart of LPS is stimulated after pepper alkali process inflammatory macrophages secrete IFN-γ.
Figure 16 is that the positive peritoneal macrophages of CD11b of the pipering to bacterium infection activate apoptotic proteins Cleaved
The Flow cytometry figure and statistical analysis figure of caspase-3 expression quantity.
Figure 17 is that the positive peritoneal macrophages of F4/80 of the pipering to bacterium infection activate apoptotic proteins Cleaved
The Flow cytometry figure and statistical analysis figure of caspase-3 expression quantity.
Figure 18 is peritoneal macrophage important subgroup (such as Gata6 of the pipering to bacterium infection+Subgroup) immunofluorescence
Observe and scheme with karyomorphism.
Figure 19 is the survival Analysis figure of the mouse of pepper oxygenation pretreatment pneumoretroperitoneum inoculated bacteria.
Figure 20 is the mouse survival rate analysis chart for injecting pipering after intraperitoneal inoculation bacterium again.
Figure 21 is the organ damage analysis chart of the mouse of pepper oxygenation pretreatment pneumoretroperitoneum inoculated bacteria.
Figure 22 be pepper oxygenation pretreatment pneumoretroperitoneum inoculated bacteria mouse peritoneal irrigating solution in inflammatory Cytokines Expression amount point
Analysis figure.
Figure 23 be pepper oxygenation pretreatment pneumoretroperitoneum inoculated bacteria mouse peritoneal irrigating solution in bacterial loads (culture bacterium colony
Number) analysis chart.
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are unlimited
In this.
Embodiment 1
Pipering raises intracellular mTORC1 activity
The piperings of various concentrations (40,80,160 μm of ol/L) is added and is incubated at the cell line of 6 orifice plates (prostate cancer is thin
Born of the same parents system LNCaP, Human cervical cancer cell lines HeLa, mouse macrophage RAW 264.7) it is incubated 2 hours, after collecting cell cracking
Albumen, mTORC1 stream substrates p70S6K and 4E-BP1 phosphorylation is detected with Western blot methods.
As a result show, pipering respective pretreatment LNCaP (Fig. 1), HeLa (Fig. 2) and the cells of RAW 264.7 (Fig. 3),
The phosphorylation of p70S6K and 4E-BP1 albumen is raised, without shadow dose dependent (concentration is respectively 40,80,160 μm of ol/L)
Ring intracellular p70S6K and 4E-BP1 expressing quantities.Fig. 1-3 column diagrams count three kinds of intracellular p-p70S6K/p70S6K respectively
With p-4E-BP1/4E-BP1 ratio, * P<0.05 (difference is statistically significant), * * P<0.01 (significant difference), * * * P<
0.001 (difference is extremely notable).P70S6K and 4E-BP1 albumen is the substrate specificity of mTORC1 kinase complex, their phosphorylation
Level up-regulation, illustrates that pipering can dose-dependently raise mTORC1 activity.
Embodiment 2
(intracellular mTORC1 activity is relatively low), reinforcing agent of the pipering as mTORC1 during nutritional deficiency
40 μm of ol/L piperings are added to HeLa cell culture mediums (EBSS or the DMEM culture of serum-free of serum starvation
Base) in, mTORC1 stream substrates p70S6K phosphorylation is detected with Western blot methods, assesses mTORC1 activity.
As a result find, HeLa cells are after the EBSS starvation of serum-free, and p70S6K phosphorylation level be (i.e. mTORC1's
Activity) it is relatively low, whether contain glucose (Glc) in EBSS culture mediums, also whether contain pipering, do not affect p70S6K
Phosphorylation level (Fig. 4), illustrate effect of the pipering to mTORC1, it is unrelated with glucose.But the DMEM of serum-free is cultivated
Base can activate p70S6K phosphorylation, and pipering can pole significantly increase p70S6K phosphorylations (the * * * P of DMEM inductions<
0.001).The result illustrates that pipering up-regulation mTORC1 effects may be relevant with amino acid in culture medium be present.
Embodiment 3
In cell mTORC1 hypoactivities, pipering is combined with glutamine, leucine, activates mTORC1 signal paths
By the left-handed paddy of 40 μm of ol/L piperings, the left-handed leucines of 0.8mmol/L (L-Leucine, Leu) and 2mmol/L
Glutamine (L-Glutamine, Gln) (similarly hereinafter), it is separately added into the HeLa cells (Fig. 5-6) and mouse peritoneal macrophage of serum starvation
In cell (Fig. 7) culture medium.
As a result show, p70S6K phosphorylation (instruction mTORC1 activation) depends on intracellular Gln and Leu presence.
As shown in figure 5, HeLa cells, under the conditions of serum and amino acid starvation (50min), (first swims mTORC1 activity inhibited
Road).Gln can not activate mTORC1 in itself.After short time starvation, a small amount of Gln is still suffered from into the cell, and Leu can be raised slightly
mTORC1.Add after pipering, can significantly raise mTORC1 activity (the * P of Leu activation<0.01).
Fig. 6 further demonstrates that HeLa cells are in bar existing for amino acid (Gln+Leu, wherein Gln shift to an earlier date 1 hour and loaded)
Under part, pipering can significantly raise mTORC1 activity.Similarly, (wherein it is small to shift to an earlier date 1 by Gln under the conditions of existing for amino acid
When load), pipering can significantly raise the activity for the mTORC1 that Leu in Turnover of Mouse Peritoneal Macrophages (Fig. 7) is induced.
These results illustrate that pipering can significantly raise the activity of the mTORC1 by Leu inductions.
Embodiment 4
Pipering raises distributions of the amino acid carrier SLC7A5/SLC3A2 in cell surface
By pipering (40 μm of ol/L), Leu (0.8mmol/L), the HeLa cell culture medium (serum-frees of serum starvation are added
KRBB) in, the amino acid transporter SLC3A2 that is marked by fluorescence microscope fluorescence antibody.
As a result show, solvent can not influence distributions of the neutral amino acid acceptor SLC7A5/SLC3A2 on cell membrane in itself.
But after adding pipering, the average fluorescent strength of the amino acid receptor significantly raises, Leu presence or absence seem not influence this by
Distribution (Fig. 8) of the body on cell membrane.These results illustrate that pipering can be by raising neutral amino acid acceptor SLC7A5/
Distributions of the SLC3A2 on cell membrane, the mTORC1 of up-regulation amino acid induction activity.
Embodiment 5
Phagocytic function of the macrophage that pipering up-regulation tissue is settled down to bacterial infection
C57BL/6 mouse are carried out with pipering (every mouse 20mg/kg), melbine (every mouse 250mg/kg)
Gavage, the E. coli of the inactivation of 4 hours pneumoretroperitoneum injection CFSE marks are acted on 0.5 hour, separated from abdominal cavity huge
Phagocyte, fluorescence antibody F4/80 mark macrophages.By flow cytomery F4/80 positive cells to CFSE-E.coli
Phagocytic activity.
As a result show, mouse is after bacterium E.coli injects abdominal cavity 0.5 hour, the ratio of intracellular F4/80 macrophages
It is rapid to drop to 23% (this ratio of normal mouse is 80% or so).But in pipering gavage mouse, F4/80 after bacterium infection
The ratio of macrophage drops to 32%, illustrates that pipering can alleviate the loss of the F4/80 macrophages because of bacterium infection induction.
If during pipering gavage, melbine (medicine can activate AMPK and suppress mTORC1 activity) is added, F4/ after bacterium infection
The ratio of 80 macrophages is more down to 16% (Fig. 9).
E.coli marks through CFSE, thus available Flow Cytometry methods detection.As a result show, CFSE positive cells are (negative
Carry the cell of bacterium) while be also F4/80 positive cells (Figure 10).The result illustrates that F4/80 is bacterium infection early stage (this example
For 0.5 hour) intraperitoneal main phagocytosis bacterial cell, and pipering gavage can alleviate the F4/ that mouse induces by bacterium infection
The loss of 80 positive peritoneal macrophages, the activity that the protective effect raises intracellular mTORC1 with pipering are relevant.
Embodiment 6
Pipering raises the cell factor such as macrophages secrete TNF-α and IL-6
The peritoneal macrophage of normal C57BL/6 mouse is taken, in uniform plantation to 24 orifice plates.By pipering (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) stimulates cell 24 hours.Another pipering (every mouse 20mg/kg) continuous gavage C57BL/6 mouse 10 days, so
The peritoneal macrophage of separating mouse is cultivated in 24 orifice plates afterwards, adds LPS (100ng/ml) to stimulate cell 24 hours (Figure 14).Receive
Collect cell culture medium supernatant, by the CBA inflammatory factor detection kits of BD companies, detected on flow cytometer TNF-α and
The expression quantity of the cell factors such as IL-6.
Measurement result shows, pepper oxygenation pretreatment short time (1 hour and 6 hours) or for a long time (48 hours) equal energy afterwards
Raise secretion by peritoneal macrophages TNF-α and the IL-6 inflammatory factors that LPS is stimulated, and the pipering gavage mouse peritoneal of 10 days
The macrophage of separation, TNF-α and the IL-6 factors are above solvent group after LPS is stimulated in vitro, and it is solid to illustrate that pipering can strengthen
There is the function (see also embodiment 10) of immunocyte.
Embodiment 7
Pipering can suppress inflammatory macrophages secrete IFN-γ
The abdominal cavity macrophage that pipering (40 μm of ol/L) is respectively acting on to normal mice of the culture in 24 orifice plates in vitro is thin
Born of the same parents and the macrophage 48 hours of intraperitoneal injection thioglycolate salt (Thioglycollate, TG) induction, then plus LPS
(100ng/ml) stimulates cell 24 hours.Cells and supernatant is collected, using CBA kits, passes through flow cytomery
The expression of the factors such as IFN-γ.
As a result show, pipering does not influence on normal secretion by peritoneal macrophages IFN-γ, and can significantly inhibit
The expression of macrophage IFN-γ under inflammatory conditions of TG inductions, shows that pipering has immunoregulation effect to inflammatory cells
(Figure 15).
Embodiment 8
Pipering protects infected peritoneal macrophage from apoptosis
By pipering (20mg/kg), melbine (250mg/kg) gavage C57BL/6 mouse, pneumoretroperitoneum injection in 4 hours is lived
E.coli (0.5 × 109CFU/mouse) act on 0.5 hour, macrophage is separated from abdominal cavity, with fluorescence antibody CD11b,
F4/80 (macrophage marker) and cleaved caspase-3 (apoptotic proteins) dyeing.Pass through flow cytomery abdominal cavity
Activation apoptotic proteins cleaved caspase-3 fluorescence intensities in macrophage.
As a result show, peritoneal macrophage apoptotic proteins cleaved caspase-3 after phagocytosis bacterium 0.5 hour exist
CD11b+(Figure 16) and F4/80+There is obvious expression in (Figure 17) cell, and pipering can suppress apoptotic proteins cleaved
Expression of the caspase-3 in cell, the effect that pipering suppresses Apoptosis can be reversed by melbine.This shows, pepper
Alkali passes through mTORC1 signal protection peritoneal macrophages apoptosis caused by bacterium infection.
Embodiment 9
Pipering prevents important subgroup (such as Gata6 of peritoneal macrophage+Subgroup) loss
By pipering (20mg/kg), melbine (250mg/kg) gavage C57BL/6 mouse, pneumoretroperitoneum injection in 4 hours is lived
E.coli (0.5 × 109CFU/mouse) act on 0.5 hour, macrophage is separated from abdominal cavity and then is planted to glass bottom culture
In ware, non-attached cell is washed away after adherent 3 hours.By cellular immunofluorescence method mark CD11b (mark of macrophage),
Gata6 (transcription factor) and Hoechst 33342 (core dyestuff).
Observe and show under fluorescence inverted microscope, after the Turnover of Mouse Peritoneal Macrophages of bacterium infection solvent gavage, CD11b
Positive cell is reduced, the Gata6 factors fade away, nucleus occurs concentrating or fragmentation (being in apoptosis morphology), and pipering
The macrophage nuclear phase of gavage mouse is gathered in core to complete, Gata6, illustrate pipering can protect peritoneal macrophage from because
Bacterium infection and it is dead, but this protective effect of pipering can be suppressed by melbine.In the embodiment more intuitively
As a result show, pipering can protect peritoneal macrophage from apoptosis caused by bacterium infection, prevent critical function subgroup (this example
Centre halfback Gata6+Cell) loss (Figure 18).
Embodiment 10
Pipering individually or with glutamine, leucine is combined, and can be suppressed bacterium infection, be prevented and treat the hair of septicemia
It is raw
By advance gavage C57BL/6 mouse of the pipering of various dose 3 days, be then injected intraperitoneally lethal dose (2 ×
109CFU the E.coli (Figure 19) of work), or half lethal dose (1 × 10 is first injected intraperitoneally9CFU the E.coli of work), 1 is small
Shi Houzai every the survival condition that 6 hours observe and record mouse, 4 days altogether, is painted with pipering (20mg/kg) gavage (Figure 20)
Mouse survival tracing analysis survival rate processed, as a result show that pipering can resist dead mouse caused by bacterium infection；
Another pipering (20mg/kg) gavage C57BL/6 mouse 3 days in advance, be then injected intraperitoneally lethal dose (2 ×
109CFU the E.coli of work) is acted on 8 hours, and mouse is put to death in the dislocation of strength vertebra, takes liver and colon, fixed, dehydration, FFPE
Section carries out H.E. dyeing (Figure 21), micro- Microscopic observation afterwards.As a result show, pipering reduce liver leucocyte infiltration and
The inflammatory injury of colon；
Pipering (20mg/kg) gavage C57BL/6 mouse 3 days in advance, be then injected intraperitoneally half lethal dose (1 ×
109CFU the E.coli effect different times (6 hours and 24 hours) of work), collect mouse peritoneal irrigating solution, and CBA kits are surveyed
The expression (Figure 22) of inflammatory factor TNF-α and IL-6 etc. in abdominal cavity are measured, and bacterium colony counts the amount (figure of intraperitoneal bacterium living
23) expression of pipering TNF-α, the IL-6 factors in bacterium infection early stage up-regulation abdominal cavity, is as a result shown, but (24 is small in the later stage
When) both cytokine-expressings are lowered, and time dependence is presented in the removing of bacterium, illustrates that pipering can strengthen the abdomen of mouse
The inherent immunity function of chamber macrophage, promote the reparation of organ damage caused by bacterium removing and septicemia.
Result above shows that pipering can suppress bacterium infection, effectively prevents and treat the generation of septicemia.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (3)
1. application of the pipering in the anti-medicine that cures the septicaemia is prepared, it is characterised in that：Contain in the described anti-medicine that cures the septicaemia
There are pipering, glutamine and leucine.
2. application of the pipering according to claim 1 in the anti-medicine that cures the septicaemia is prepared, it is characterised in that：Described
The anti-medicine that cures the septicaemia also includes acceptable auxiliary material.
3. application of the pipering according to claim 1 in the anti-medicine that cures the septicaemia is prepared, it is characterised in that：Described
The anti-medicine that cures the septicaemia is tablet, granule, capsule, dripping pill, sustained release agent, oral liquid or injection.
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| JP2946452B2 (en) * | 1994-11-04 | 1999-09-06 | カディラ ラボラトリーズ リミテッド | 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 |
| FR2913885B1 (en) * | 2007-03-22 | 2012-07-20 | Univ Paris Descartes | USE OF CITRULLINE FOR THE TREATMENT OF PATHOLOGIES ASSOCIATED WITH INCREASED CARBONYLATION OF PROTEINS |
| KR101184343B1 (en) * | 2009-02-10 | 2012-09-20 | 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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