CN110123822A - Newborn source oligosaccharide is in preparation for by alleviating the purposes in the drug or food that enteron aisle anoxia-induced apoptosis treats or prevents NEC - Google Patents
Newborn source oligosaccharide is in preparation for by alleviating the purposes in the drug or food that enteron aisle anoxia-induced apoptosis treats or prevents NEC Download PDFInfo
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- CN110123822A CN110123822A CN201910501437.6A CN201910501437A CN110123822A CN 110123822 A CN110123822 A CN 110123822A CN 201910501437 A CN201910501437 A CN 201910501437A CN 110123822 A CN110123822 A CN 110123822A
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- Prior art keywords
- oligosaccharide
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- nec
- sialic acid
- food
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Classifications
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Abstract
The invention discloses newborn source oligosaccharide in preparation for by alleviating the purposes in the drug or food that enteron aisle anoxia-induced apoptosis treats or prevents NEC, the cream source oligosaccharide includes four kinds of newborn source oligosaccharide: carbon chain backbone is lactose, carry 3 '-sialyl lactoses (3 '-SL), the 6 '-sialyl lactoses (6 '-SL) of single sialic acid residues, carbon chain backbone is LNT or LNnT, carries sialic acid-lactoyl-N- tetrose b (LSTb), the sialic acid-lactoyl-N- tetrose c (LSTc) of single sialic acid residues.The invention demonstrates that 3 '-SL, 6 '-SL, LSTb and LSTc can significantly restore the proliferative capacity of Caco-2 cell under anoxic treatment；3 '-SL and 6 '-SL can significantly inhibit the up-regulation of HIF-1 α, p-P65 and IL-8mRNA in Caco-2 cell under anoxic treatment.
Description
Technical field
The invention belongs to technical field of food biotechnology, in particular to newborn source oligosaccharide is in preparation for being lacked by alleviating enteron aisle
Oxygen injury and treat or prevent the purposes in the drug or food of NEC.
Background technique
Necrotizing enterocolitis (Necrotizing enterocolitis, NEC) is a kind of height for being common in premature
Lethality disease, lethality is between 10%~50%.Extremely limited for the treatment means of NEC at present, usual earlier is taken
Antibiotherapy is alleviated, advanced stage can only be treated by operation, but postoperative nervous system and the digestive system of being often accompanied by
Complication seriously affects the growth and development of baby.Therefore, it is more satisfactory for carrying out prevention for the risk that NEC may cause
Means of prevention.
Research thinks that NEC has two big pathogenesis at present.One is body injury caused by excessive inflammatory reaction.Intestines
Microbial flora dystopy field planting in road is one of source of inflammatory reaction, and some pathogenic entero becterias are colonized meeting in terminal ileum and colon
The Gut barrie r for stimulating infant causes Gut barrie r damage and permeability to rise.Its endotoxin discharged, which can also enter blood, to stimulate
Other organs of body cause systemic immune to react.In addition to this, newborn is due to respiratory system depauperation or other reasons
Caused by intestines blood supply insufficiency so that caused by anoxic, it is impaired to also result in enterocyte, and then lead to the generation of inflammatory reaction.
Second, being that infant itself depauperation causes immunity of organism regulation and injury repair dysfunction that phylactic power defensive power is caused to decline.It removes
Except this, the difference of feeding patterns also results in the variation of disease incidence.Numerous studies have demonstrated that the preemie of breast-feeding
The baby for suffering from the Hazard ratio non-breastfeeding of NEC is 6-10 times low.Current baby formula milk powder does not prove can also be effective
Reduce the illness rate of NEC.Accordingly, it is determined that can prevent the component of NEC in breast milk has important researching value and economic value.
It is specifically which kind of or which ingredient is protecting breast-fed babies' enteron aisle in breast milk, reduces it and suffer from NEC's
Risk is not fully understood at present.But one of laboratory milk and breast milk is most important distinguish the type for being that its oligosaccharide and
Content, in the laboratory milk usually based on cow's milk, concentration of oligosaccharide will be well below breast milk, and type is very single.But according to
According to existing research, alleviation of the HMOs for NEC and the protective effect to baby intestinal may have the reason of from many aspects, packet
Include the growth for promoting probiotics, the adherency for resisting pathogen, to the adjusting of epithelial cell surface receptor, reduce neutrophil leucocyte
Infiltration and activation etc..
Since human milk oligosaccharides are the combinations for the oligosaccharide that one group of structure has great diversity, researchers couple
Further query is proposed in human milk oligosaccharides protection baby intestinal and the mechanism of action for alleviating NEC, which type of structure
Oligosaccharide to alleviate NEC or intestinal tract injury be it is maximally efficient, what the mechanism of effect is, between structure and effect
Does is what kind of relationship again?
Summary of the invention
Based on above-mentioned problem, hypoxia model is established using cell and zoopery, is selected according to design feature
Take different newborn source oligosaccharide, the purpose of the present invention is to newborn source oligosaccharide in vivo and in vitro to the relaxation effect of anoxia-induced apoptosis and right
The relaxation effect of NEC is studied, and explores its mechanism of action, provides reason for addition of the newborn source oligosaccharide in drug and food
By support.
The purpose of the present invention is what is be achieved through the following technical solutions:
Newborn source oligosaccharide is in preparation for by alleviating in the drug or food that enteron aisle anoxia-induced apoptosis treats or prevents NEC
Purposes, it is described cream source oligosaccharide include 3 '-sialyl lactoses (3 '-SL), 6 '-sialyl lactoses (6 '-SL), sialic acid-cream
The mixture of one or more of acyl-N- tetrose b (LSTb) or sialic acid-lactoyl-N- tetrose c (LSTc).
Another aspect of the present invention:
A kind of pharmaceutical composition for treating NEC, wherein the cream source oligosaccharide includes 3 '-salivas containing newborn source oligosaccharide
Yogurt sugar (3 '-SL), 6 '-sialyl lactoses (6 '-SL), sialic acid-lactoyl-N- tetrose b (LSTb) or sialic acid-lactoyl-N-
The mixture of one or more of tetrose c (LSTc).
Further, the concentration of newborn source oligosaccharide is 1mg/mL~1000mg/mL in described pharmaceutical composition.
Another aspect of the present invention:
A kind of food preventing NEC, wherein the cream source oligosaccharide includes 3 '-sialyl lactoses containing newborn source oligosaccharide
(3 '-SL), 6 '-sialyl lactoses (6 '-SL), sialic acid-lactoyl-N- tetrose b (LSTb) or sialic acid-lactoyl-N- tetrose c
One or more of (LSTc) mixture.
Further, the concentration of newborn source oligosaccharide is 2mg/mL~100ml/mL in the food.
Further, the food includes fermented fruits and vegetables juice, pickles, acidified milk, cheese, milk-contained drink and milk powder.
The present invention having the beneficial effect that compared with prior art
1, the present invention chooses rat small intestine Crypt Cells IEC-6 and people Colon and rectum gland cancer cell Caco-2 first, leads to
The expression for crossing measurement ability of cell proliferation and anoxia-induced apoptosis relevant gene and albumen, determine chemical hypoxia and physics anoxic this
Two different hypoxia in vitro handle the influence to cell.The result shows that chemical hypoxia processing can cause IEC-6 cell Proliferation
Activity drops to 38% ± 1.02%, Caco-2 cell-proliferation activity and drops to 70% ± 2.09%；But it is intracellular for two plants
The expression of HIF-1 α, p-P65, cleaved Caspase-3 and IL-8mRNA are raised without remarkable effect；Physics anoxic makes
IEC-6 and Caco-2 cell-proliferation activity drops to 83% ± 1.25% and 65% ± 2.37% respectively, while making Caco-2
Intracellular HIF-1 α, p-P65, cleaved Caspase-3 and IL-8mRNA relative expression rise 2-8 times respectively, it is right
IEC-6 cell then has no same effect.Therefore in vitro, it is more appropriate for handling Caco-2 cell with the mode of physics anoxic
Hypoxia model；
2, the difference with sialic acid residues number according to carbon chain backbone and institute has chosen eight kinds of cream source oligosaccharide, it was demonstrated that 3 '-
SL, 6 '-SL, LSTb and LSTc can significantly restore the proliferative capacity of Caco-2 cell under anoxic treatment；And 3 '-SL and 6 '-SL
The up-regulation of HIF-1 α, p-P65 and IL-8mRNA in Caco-2 cell under anoxic treatment can be significantly inhibited, zoopery confirms
3 '-SL+6 '-SL can significantly alleviate mouse intestinal tissue necrosis phenomena caused by NEC modeling and improve its pathological score.Also, 3 '-
SL+6 '-SL can make in mouse intestinal tissue IL-8 concentration drop to 9.2 ± 0.70pg/mL from 13.3 ± 1.24pg/mL, and make to make
HIF-1 α, p-I κ B α, p-P65, cleaved Caspase-3 being molded as express up-regulation and are significantly inhibited, while also inhibiting
The nuclear translocation of HIF-1 α and p-P65.Therefore, illustrate that newborn source oligosaccharide 3 '-SL and 6 '-SL can be effectively relieved in vivo and in vitro
The anoxia-induced apoptosis of enteron aisle.
Detailed description of the invention
Fig. 1 is influence schematic diagram of the different Hypoxic types to different intestinal cell systems proliferation activity；Wherein, Fig. 1 (A) shows
IEC-6 cell；Fig. 1 (B) shows that Caco-2 cell (is compared, label symbol * under same time different disposal, indicates at anoxic
Reason group has significant difference, p < 0.05 with normal group)；
Fig. 2 is influence schematic diagram of the different Hypoxic types to intestinal cell HIF-1 alpha expression；
Fig. 3 is the influence schematic diagram that different Hypoxic types express intestinal cell p-P65；
Fig. 4 is the influence schematic diagram that different Hypoxic types express intestinal cell IL-8mRNA；
Fig. 5 is the influence schematic diagram that different Hypoxic types express IEC-6 and Caco-2 cell death related protein；
In Fig. 2-Fig. 5, (mark different letter a, b, c, indicate there is conspicuousness to (A) IEC-6 cell (B) Caco-2 cell
Difference, p < 0.05)；
Fig. 6 is the structural schematic diagram of newborn source oligosaccharide；Wherein, 3 '-sialyl lactose of (A) lactoyl-N- tetrose (LNT) (B)
(3 '-SL) (C) 6 '-sialyl lactose (6 '-SL) (D) sialic acid-lactoyl-N- tetrose a (LSTa) (E) sialic acid-lactoyl-N-
Tetrose b (LSTb) (F) sialic acid-two sialic acid lactoyl-N- tetrose (DSLNT) (H) of lactoyl-N- tetrose c (LSTc) (G), 2 '-rock
Algae sugar lactose (2 '-FL)；
Fig. 7 is the influence schematic diagram to intestinal cell proliferation activity such as 2 '-FL of newborn source oligosaccharide；Wherein, (A) 2 '-FL
(B) 3 '-SL (C) 6 '-SL (are compared under different concentration of oligosaccharide processing, label symbol * indicates oligomeric under the conditions of anoxic treatment
Sugared processing group and anoxic group have significant difference, p < 0.05)；
Fig. 8 is the influence schematic diagram to intestinal cell proliferation activity such as cream source oligosaccharide LNT；Wherein, (A) LNT (B)
LSTa (C) LSTb (D) LSTc (E) DSLNT (is compared under different concentration of oligosaccharide processing, mark symbol under the conditions of anoxic treatment
Number * indicates that oligosaccharide processing group and anoxic group have significant difference, p < 0.05)；
Fig. 9 is 2 '-FL, the influence of 3 '-SL and 6 '-SL to HIF-1 alpha expression in Caco-2 cell under physics anoxia condition is shown
It is intended to；Wherein, (A) 2 '-FL (B) 3 '-SL (C) 6 '-SL；
Figure 10 is 2 '-FL, 3 '-SL and 6 '-SL show the influence expressed of p-P65 in Caco-2 cell under physics anoxia condition
It is intended to；Wherein, (A) 2 '-FL (B) 3 '-SL (C) 6 '-SL；
The shadow that Figure 11 is 2 '-FL, 3 '-SL and 6 '-SL express IL-8 mRNA in Caco-2 cell under physics anoxia condition
Ring schematic diagram；Wherein, (A) 2 '-FL (B) 3 '-SL (C) 6 '-SL；
Figure 12 is 2 '-FL, 3 '-SL and 6 '-SL are to cleaved Caspase-3 in Caco-2 cell under physics anoxia condition
The influence schematic diagram of expression；Wherein, (A) 2 '-FL (B) 3 '-SL (C) 6 '-SL；
Figure 13 is mouse modeling third day mouse weight difference schematic diagram；
Figure 14 is that mouse intestinal configuration changes schematic diagram；
Figure 15 is pathological change and histopathological scores under mouse intestinal tissue mirror: where (A) HE dyes (B) pathology
Scoring；
Figure 16 is the influence schematic diagram that newborn source oligosaccharide expresses HIF-1 α mRNA in NEC mouse intestinal tissue；
Figure 17 is influence schematic diagram of the newborn source oligosaccharide to HIF-1 α protein expression in NEC mouse intestinal tissue: where
(A) HIF-1 α in HIF-1 α (B) nucleus in cytoplasm；
Figure 18 is the influence schematic diagram that newborn source oligosaccharide expresses IL-1 β and IL-8 in NEC mouse intestinal tissue；Wherein,
(A)IL-1βmRNA(B)IL-8mRNA(C)IL-8；
Figure 19 is influence schematic diagram of the newborn source oligosaccharide to NF- κ B Pathway Activation in NEC mouse intestinal tissue；Wherein, (A)
The p-P65 in I κ B α (B) nucleus in cytoplasm；
Figure 20 is p-P65 immunofluorescence dyeing schematic diagram；
Figure 21 is that newborn source oligosaccharide influences signal to TLR-4mRNA expression in necrotizing enterocolitis mouse intestinal tissue
Figure；
Figure 22 is that newborn source oligosaccharide influences signal to TLR-4 protein expression in necrotizing enterocolitis mouse intestinal tissue
Figure；
Figure 23 is TLR-4 immunofluorescence dyeing schematic diagram；
Figure 24 is that newborn source oligosaccharide influences schematic diagram to cleaved Caspase-3 expression in NEC mouse intestinal tissue.
Specific embodiment
Embodiment 1 --- the foundation of intestinal cell hypoxia model
Cell strain:
Caco-2, people's Colon and rectum gland cancer cell；IEC-6, rat small intestine Crypt Cells, it is thin to be purchased from the Chinese Academy of Sciences
Born of the same parents library.Cell be all made of the sugared complete medium of DMEM high in 37 DEG C, containing 5%CO2Cell incubator in cultivated.
Cell processing:
Cell is with 2 × 104The concentration of a/mL is inoculated in 96 orifice plates, and culture is for 24 hours.Then replacement contains 200 μM of CoCl2's
Culture medium, every 100 μ L of hole, separately sets a control group and (CoCl is not added in a physics anoxic treatment group in culture medium2Solution is added same
Volume PBS), each processing group sets 6 in parallel.Control group and chemical hypoxia processing group are put in the incubator, by physics anoxic
Processing group is handled according to the above method, is placed in incubator, and different time is cultivated.
The influence that different Hypoxic types are proliferated intestinal cell:
In order to probe into influence of the different anoxic treatment modes to different ability of cell proliferation, the present embodiment is lacked using chemistry
Two kinds of distinct methods of oxygen and physics anoxic handle respectively IEC-6 and Caco-2 cell for 24 hours, 36 h, 48h, utilize CCK-8 kit
Method measures the proliferation activity of its cell.
Influence of the different Hypoxic types to different intestinal cell systems proliferation activity is as shown in Figure 1.
For IEC-6 cell, the different active inhibiting effect of anoxic treatment mode cell proliferation are with the processing time
Extend and aggravate, and physics Hypoxic types will be weaker than chemical hypoxia mode to the inhibitory effect of its proliferation activity.When IEC-6 cell
When chemical hypoxia condition is handled for 24 hours, proliferation activity drops to 58% ± 1.34%, after the processing time is increased to 36h, increases
It grows activity and drops to 38% ± 1.02%.When IEC-6 cell is handled for 24 hours under physics anoxia condition, proliferation activity only declines
To 86% ± 4.99%, the anoxic treatment time is improved to 36h, proliferation activity drops to 83% ± 1.25%.
For Caco-2 cell, different Hypoxic types processing, to the inhibiting effect of its proliferation activity equally also with processing
The extension of time and aggravate, and the mode of two kinds of different anoxic treatments to the inhibitory effect difference of its proliferation activity and not as good as
It is significant in IEC-6 cell.When Caco-2 cell chemical hypoxia condition processing for 24 hours, 36h, 48h after, proliferation activity respectively under
95% ± 1.53%, 85% ± 0.36%, 70% ± 2.09% is dropped to, and when Caco-2 cell is in the processing of physics anoxia condition
For 24 hours, after 36h, 48h, proliferation activity falls to 86% ± 2.08%, 75% ± 0.84%, 65% ± 2.37% respectively.
It follows that the intestinal cell of different differentiation degrees, for different anoxic treatment modes, the degree of response
It is different.Chemical hypoxia is more significant than the effect of physics anoxic for the inhibition of IEC-6 ability of cell proliferation；It is thin for Caco-2
Born of the same parents, though the function and effect difference of the mode of two kinds of anoxic treatments and having no so significant, the processing of physics anoxic is for its increasing
The inhibitory effect for growing ability is still better than chemical hypoxia.
Influence of the different Hypoxic types to intestinal cell anoxia-induced apoptosis:
Handle influence to intestinal cell anoxia-induced apoptosis to probe into different anoxia condition, respectively using chemical hypoxia and
Two methods of physics anoxic handle IEC-6 and Caco-2 cell 6h, 12h, 18h, measurement and anoxia-induced apoptosis related gene and albumen
Expression.
Influence of the different Hypoxic types to intestinal cell HIF-1 alpha expression:
Fig. 2 is different after intestinal cell handles 6h under different anoxia conditions, the change of intracellular HIF-1 α protein expression
Change situation.It is found that IEC-6 cell is in the case where two kinds of anoxia conditions are handled, HIF-1 alpha expression therein has up-regulation, relative expression
Amount rises to 0.38 ± 0.04 and 0.49 ± 0.04 by 0.23 ± 0.05 respectively, rises 1.7 and 2.1 times respectively, it is known that physics
Anoxia functions will significantly (p < 0.05) to the up-regulation effect of its HIF-1 alpha expression.For Caco-2 cell, the table of HIF-1 α
(0.67 ± 0.05vs.1.36 ± 0.15) significantly is increased up to only having after physics anoxic treatment 6h, and the processing of chemical hypoxia
Mode then expresses it does not make significant difference (0.67 ± 0.05vs.0.64 ± 0.01).
The influence that different Hypoxic types express intestinal cell p-P65:
In turn, after handling the longer time we have studied different Hypoxic types, the inflammation as caused by anoxic in intestinal cell
The case where expression of disease damage related gene and albumen.
After anoxic treatment 12h, the expression of IEC-6 and the intracellular p-P65 of Caco-2 is as shown in figure 3, different anoxic
Under the conditions of handle 12h, can cause the expression of the intracellular p-P65 of IEC-6 to increase, and the similar (0.35 ± 0.06vs.0.85 of effect
±0.07vs.0.91±0.11).For Caco-2 cell, its intracellular p-P65 is expressed without significant shadow in the processing of chemical hypoxia
It rings (0.16 ± 0.02vs.0.21 ± 0.02), only under the conditions of physics anoxic treatment, the expression of the p-P65 in Caco-2 cell
It shows significant changes (0.16 ± 0.02vs.0.43 ± 0.06, p < 0.05), has raised about 2.7 times.
The influence that different Hypoxic types express intestinal cell IL-8mRNA:
After we have detected different anoxia condition processing 12h, IEC-6 and the intracellular inflammatory factor IL-8 of Caco-2 exist
The variation of mRNA level in-site expression, as a result as shown in figure 4, for IEC-6 cell, only physics anoxic can make its IL-
The relative expression of 8mRNA significantly rises, and has raised 1.25 ± 0.05 times.And for Caco-2 cell, in two kinds of anoxic items
Under part, the relative expression of IL-8mRNA has raised 2.2 ± 0.54 and 8.6 ± 0.75 times respectively.It is found that different anoxic treatments
The relative expression of its IL-8mRNA can be raised, and function and effect are more more significant than its function and effect in IEC-6 cell.Together
When it can be found that the effect of physics anoxic is more significant than chemical hypoxia method.
Influence of the different Hypoxic types to intestinal apoptosis index:
We determine the expression variation of the intracellular cleaved Caspase-9 of IEC-6 and Caco-2 after anoxic treatment 12h
And the expression of cleaved Caspase-3 changes after anoxic treatment 18h, as a result as shown in Figure 5.Different anoxic treatments for
There is different degrees of the activation of Caspase-9 in IEC-6 cell, wherein the processing mode of physics anoxic is more significant, can
So that the relative expression of cleaved Caspase-9 is risen to 2.13 ± 0.34 by 0.80 ± 0.07, raises 2.6 times；And it is chemical
The effect of the processing activation Caspase-9 of anoxic will be weaker than physics anoxic (1.51 ± 0.10vs.2.13 ± 0.34).But two kinds
Under anoxia condition processing, fail the activation for leading to Caspase-3, therefore cleaved Caspase-3 expression is not detected
Up-regulation.And for Caco-2 cell, two kinds of Hypoxic types can activate Caspase-9, and physics anoxia functions in various degree
It is more significant (± 0.05vs.1.39 ± 0.14 1.05 ± 0.02vs.1.10) than chemical hypoxia.And it is put as signal downstream cascades
Greatly, physics anoxic activation Caspase-3 shearing activation than chemical hypoxia processing more significantly (0.98 ±
0.13vs.0.58±0.04vs.2.01±0.17)。
In conclusion passing through the proliferation activity and intracellular HIF-1 α, p-P65, cleaved of measurement cell
The expression of Caspase-9/3 and IL-8mRNA, evaluation obtain optimal cell hypoxia model, and Main Conclusions is as follows:
(1) two kind of Hypoxic types can cause intestinal cell proliferative capacity to be significantly inhibited.
(2) mode of physics anoxic, which is handled, can be such that anoxia-induced apoptosis related gene and protein expression in Caco-2 cell occurs
Significant changes, therefore be proper hypoxia model.
Embodiment 2 --- relaxation effect of the newborn source oligosaccharide to intestinal cell anoxia-induced apoptosis
Using acid newborn source oligosaccharide as research object, eight kinds of newborn source oligosaccharide is selected (see Fig. 6, to be respectively: neutral low
Glycan lactoyl-N- tetrose (LNT)；Carbon chain backbone is lactose, carry single sialic acid residues 3 '-sialyl lactoses (3 '-SL),
6 '-sialyl lactoses (6 '-SL)；Carbon chain backbone is LNT or LNnT, carries sialic acid-lactoyl-N- of single sialic acid residues
Tetrose a (LSTa), sialic acid-lactoyl-N- tetrose b (LSTb), sialic acid-lactoyl-N- tetrose c (LSTc)；Carbon chain backbone is
LNT carries the two sialic acid lactoyl-N- tetroses (DSLNT) of two sialic acid residues；And as control, carbon chain backbone is cream
Sugar carries the 2 '-fucose lactose (2 '-FL) an of fucosido.It is intended to study and there is different carbon chain backbone and entrained
Sialic acid residues number newborn source oligosaccharide to the difference of intestinal cell anoxia-induced apoptosis relaxation effect.
The present embodiment is thin as the external enteron aisle of the present embodiment using the selected physics anoxic treatment Caco-2 of embodiment 1
Born of the same parents' anoxia-induced apoptosis mould.Caco-2 cell 36h is handled under physics anoxia condition, while the newborn source oligosaccharide for giving its various concentration is dry
In advance, by measuring the variation of its proliferation activity, the newborn source oligosaccharide of acidity of different structure is probed into intestinal cell in anaerobic environment
Under proliferative capacity restitution.
Two kinds are compared first using lactose as the effect of the oligosaccharide 3 '-SL and 6 '-SL of the mono-sialylated of carbon chain backbone
Effect, and be control with single 2 '-FL of fucosyllactose, as a result as shown in Figure 7.It is found that two kinds of 3 '-SL of single sialic acid lactose and
6 '-SL have certain relaxation effect for the reduction of intestinal cell proliferative capacity as caused by anoxic, and not with dose-dependant
Mode work.Wherein the 3 '-SL of 1,100,1000 μ g/mL can make the proliferation activity of Caco-2 cell by anoxic control group
66% ± 1.33% be restored to 82% ± 2.54%, 72% ± 0.74%, 79% ± 1.95% respectively, and 1,10,100,
The 6 '-SL of 1000 μ g/mL can be such that the proliferation activity of Caco-2 cell is restored respectively by the 59% ± 2.50% of anoxic control group
To 73% ± 1.22%, 78% ± 0.84%, 77% ± 3.34%, 72% ± 0.80%.And the fucosylation as control
2 '-FL of lactose does not have significant relaxation effect (59% ± 2.50% for the proliferation activity of Caco-2 cell under anaerobic condition
Vs..58 ± 1.12vs.63% ± 2.23%vs.64% ± 1.36%vs. 62% ± 1.41%).
Then we compare the sialylated newborn source oligosaccharide of newborn source oligosaccharide LSTa/b/c and two of mono-sialylated
DSLNT is to the restitution of Caco-2 ability of cell proliferation, and using neutral oligosaccharide LNT as control.LSTa/b/c and DSLNT
Its carbon chain backbone is the LNT of tetrose composition, passes through α -2,3 or α -2 respectively, and different location of 6 glycosidic bonds in LNT links
One or two sialic acid and formed.
As a result as shown in Figure 8.In LNT and its sialylated derivative oligosaccharide LSTa/b/c and DSLNT, only
The LSTb/c decline tool of the Caco-2 cell-proliferation activity caused by alleviating anoxic has certain effect.Such as 1,10,100 μ g/mL
LSTb can make its proliferation activity be restored to 50% ± 0.40%, 51% respectively by the 32% ± 3.29% of anoxic control group ±
1.38%, 53% ± 1.21%；1, the LSTc of 10,100 μ g/mL can make its proliferation activity by anoxic control group 47% ±
3.82% is restored to 59% ± 1.98%, 72% ± 1.09%, 73% ± 0.73 respectively.And neutral oligosaccharide LNT and secondly saliva
Liquid acidification derived carbohydrate DSLNT, then to restore anaerobic condition under Caco-2 cell proliferative capacity, without remarkable effect (LNT:
69% ± 0.60%vs.65% ± 0.13%vs.66% ± 3.25%vs.71% ± 1.25%；DSLNT:67% ± 3.40%
Vs.65% ± 0.13vs.66% ± 3.25%vs.71% ± 1.25%).
In conclusion the intestinal cell for caused by anoxic increases in the acid human milk oligosaccharides that the present embodiment is compared
Grow ability decline have relaxation effect be all mono-sialylated oligosaccharide, be single sialic acid lactose respectively: 3 '-SL, 6 '-SL
With LNT:LSTb, LSTc of mono-sialylated.
The relaxation effect that newborn source oligosaccharide damages Caco-2 cell hypoxia:
In order to further probe into relaxation effect of the above-mentioned acid oligosaccharides to intestinal cell anoxia-induced apoptosis, we are right
Caco-2 cell carry out physics anoxic treatment while, give the acid oligosaccharides intervention of its various concentration, detect its HIF-1 α,
The variation of p-P65, cleaved Caspase-3 and IL-8mRNA expression.In conjunction with above-mentioned newborn source oligosaccharide to intestines under anaerobic condition
The content distribution situation of the result of the influence of road cell-proliferation activity and 3 '-SL, 6 '-SL, LSTb/c in human milk, we are only
It has chosen single sialic acid lactose 3 '-SL and 6 '-SL and continues following experiments, and be pair with single 2 '-FL of fucosyllactose
According to.
Influence of the newborn source oligosaccharide to Caco-2 cell HIF-1 alpha expression:
We have detected first when giving various concentration 3 '-SL and 6 '-SL and intervening, under anaerobic condition in Caco-2 cell
The case where HIF-1 alpha expression, as a result as shown in Figure 9.Know that 3 '-SL and 6 '-SL can effectively be lowered in the Caco-2 cell of anoxic
The rising of HIF-1 alpha expression.As 3 '-SL of various concentration can make HIF-1 α relative expression at most decline about 2 times (0.61 ±
0.08vs.0.27 ± 0.06), it is restored to the expression of Normal group (0.23 ± 0.05)；And the function and effect of 6 '-SL are then
It is significant and stable not as good as 3 '-SL.As 2 '-FL of control, then do not make significant difference to HIF-1 alpha expression.
The influence that newborn source oligosaccharide expresses Caco-2 cell p-P65:
In turn, we have detected when giving the processing of various concentration acid oligosaccharides, p- in Caco-2 cell under anaerobic condition
The situation of change of P65 expression, the results are shown in Figure 10.It is found that p-P65 expression in the Caco-2 cell for caused by anoxic
Significant up-regulation, be still 3 '-SL to it with remarkable effect, so that its relative expression is declined 1.8 times of left sides (when 10 μ g/mL)
Right (0.45 ± 0.11vs.0.74 ± 0.13).And the variation that 6 '-SL and 2 '-FL express p-P65, then it has no very significant
It influences.
The influence that newborn source oligosaccharide expresses Caco-2 cell IL-8mRNA:
Meanwhile we also measured were when giving the intervention of various concentration acid oligosaccharides, the transcription of IL-8 in Caco-2 cell
Level variation, as a result as shown in figure 11.It is found that the 3 '-SL and 6 '-SL of either mono-sialylated are still as the rock compareed
The glycosylated 2 '-FL of algae, IL-8 is ramping up what mRNA level in-site was expressed in the Caco-2 cell for caused by anoxic, is had
The inhibiting effect of highly significant.Wherein, the 3 '-SL of 10 μ g/mL can be such that IL-8mRNA relative expression declines compared with anoxic control group
3.7 times (1.58 ± 0.40vs. 7.46 ± 0.71), the 6 '-SL of 1000 μ g/mL can make IL-8mRNA relative expression compared with anoxic
Control group declines 3.2 times (1.78 ± 0.39vs.7.60 ± 0.50), and 2 '-FL of various concentration can make IL-8mRNA opposite
Expression declines 1 times or so compared with anoxic control group (7.79 ± 1.07).
The influence that newborn source oligosaccharide expresses Caco-2 cell cleaved Caspase-3:
Finally, we determine when giving the intervention of various concentration acid oligosaccharides, Caco-2 cell inner feelings is withered under anaerobic condition
The activation situation of PROTEIN C aspase-3 is died, as a result as shown in figure 12.Anoxic causes apoptosis cascade reaction to activate, Caspase-3 quilt
Shearing forms cleaved Caspase-3 after activation, it is known that, cleaved Caspase-3 in Caco-2 cell is expressed,
The 3 '-SL of 1000 μ g/mL can significantly inhibit its expression and rise, its relative expression is made to decline 1.1 times (0.43 compared with anoxic control group
±0.03vs.0.92±0.18).And 6 '-SL and the 2 '-FL as control are then without remarkable effect.
In conclusion measuring it to cell under anaerobic condition by the newborn source oligosaccharide intervention for giving cell various concentration
The influence of energization power and influence to anoxia-induced apoptosis related gene and protein expression in cell, the acidity for having probed into different structure are low
Relaxation effect of the glycan to intestinal cell anoxia-induced apoptosis, Main Conclusions are as follows:
(1) newborn 3 '-FL of source oligosaccharide, 6 '-SL, LSTb and LSTc with single sialic acid residues can be effectively relieved scarce
Inhibition of the oxygen to intestinal cell proliferation activity.
(2) 3 '-SL of single sialic acid lactose can significantly reduce under anaerobic condition HIF-1 α in Caco-2 cell, p-P65,
The expression of cleaved Caspase-3 and the transcription of IL-8, so that intestinal cell anoxia-induced apoptosis be effectively relieved.
Embodiment 3 --- relaxation effect of the newborn source oligosaccharide to mouse necrotizing enterocolitis
The experimental animal that the present embodiment uses: seven age in days C57BL/6 mouse 60 (not distinguishing male and female) of SPF grade is purchased from Beijing
Tie up experimental animal Co., Ltd, tonneau China.The mouse generation cream formula design for feeding mouse is shown in Table 1.
Table 1 mouse generation cream formula design
100mL mouse generation cream: long-chain fat yogurt+2.6g in 10g nest prescription emulsifiable powder+7g protein powder+47.5mL20%
Lactose is settled to 100mL, after tepidarium dissolution, 4 DEG C of preservations.
The mouse generation cream of the 2 '-FL containing 4mg/mL: 2 '-FL of 120mg is dissolved in 30mL mouse generation cream, 4 DEG C of preservations after mixing, often
It is secondary to take preceding warm water heating.
The mouse generation cream of 3 '-the SL+6 '-SL containing 2mg/mL: 3 '-the SL+6 '-SL of 100mg/mL is added in 29.4mL mouse generation cream
600 μ L of mixed solution, 4 DEG C of preservations after mixing, warm water heating before taking every time.
The foundation of mouse NEC model and the collection and processing of sample:
Grouping: the mouse of seven ages in days is randomly divided into four groups according to weight, every group 15, respectively Normal group is (female
Mouse is fed), modeling group, 2 '-FL nursing groups and 3 '-SL+6 '-SL nursing group；It weighs and records daily.
Modeling: by the dosage of 50 μ L/g BW to modeling group, 2 '-FL nursing groups and 3 '-SL+6 '-SL nursing group intragastric administration on mice
Mouse generation cream, then places it in 90%N2+5%CO2+5%O2,10min in 4 DEG C of environment, then takes out.Three times a day stomach-filling+
Modeling, every minor tick 8h.
The collection and processing of mouse intestinal tissue: the 4th day, by all modeling groups, 2 '-FL nursing groups and 3 '-SL+6 '-
SL nursing group and the disconnected neck of control group mice are put to death, and are taken the intestinal segment embedding of 1cm above colon, are immersed in tissue fixative solution；Again
2cm intestinal segment is up taken, is divided into two parts, freezes in -80 DEG C respectively, RNA and albumen to be extracted.
Pathology morphologic observation, immunofluorescence dyeing are carried out to mouse intestinal tissue, and ELSIA survey is carried out to albumen therein
It is fixed, nucleoprotein and plasmosin in the tissue of field are extracted respectively, carry out protein immunoblot.
The modeling process of newborn mice Model of Necrotizing Enterocolitis continues three days altogether, before putting to death to third day, respectively
The body weights of group mouse are as shown in figure 13.Normal ten day-old Mices weight is 5.07 ± 0.18 g, and passes through the small of modeling
Mouse, whether by newborn source oligosaccharide stomach-filling, weight significantly decreases, and modeling group is 3.23 ± 0.17g, 3 '-SL+
6 '-SL stomach-filling groups are 3.02 ± 0.16g；The mouse weight outline of 2 '-FL stomach-filling groups is higher than first two groups, reach 3.49 ±
0.19g.Before execution, the general physiological status of each group mouse also has apparent difference, and normal group mouse physique is good, and fur is smooth
It is suitable bright, and the mouse Jing Guo modeling, there is phenomena such as different degrees of difficulty with feeding, abdomen swelling, withered hair, but pass through
The case where mouse that 3 '-SL+6 '-SL is fed, will be substantially better than remaining two groups.
It is taken after mouse is put to death to study the change of modeling processing and oligosaccharide nursing to mouse intestinal configuration
Its duodenum to the complete intestinal segment of rectum is taken pictures, and is visually observed, and enteron aisle configuration is as shown in figure 14.The mouse normally organized,
Faint yellow, no hydrops pneumatosis phenomenon of health is presented in its enteron aisle；The mouse of modeling group, intestinal tissue color burn is dimmed, occurs
Apparent pneumatosis, expansion phenomenon, intestinal wall is thinning, is highly vulnerable to breakage fracture；The mouse of 3 '-SL+6 '-SL nursing group, Intestinal Morphology with
It normally organizes similar, presents faint yellow and without pneumatosis；The mouse of 2 '-FL nursing groups, though enteron aisle is without obvious pneumatosis situation, color phase
It shows slightly to deepen dimmed situation than normal group.
In order to further study the change of modeling processing and the nursing of different oligosaccharide to mouse intestinal tissue microstructure, we
Take each group mouse intestinal tissue HE stained slice in microscopically observation, as a result as shown in figure 15.The enteron aisle group for the mouse normally organized
Knit clear in structure, crypts and the continuous whole arrangement of villus, mucous layer, submucosa and lamina propria are intact；Modeling group mouse
Intestinal tissue structure destroys obvious, oedema occurs in villus, fracture even falls off the case where disappearing, the thinning fracture of lamina propria；3'-SL
+ 6 ' although-SL nursing group villus also has oedema phenomenon, grown form is complete, and lamina propria has no thinning oedema；2 '-FL are fed
It supports a group intestinal morphology and is substantially similar to 3 '-SL+6 '-SL nursing group, the slight oedema of villus but substantially complete, lamina propria is relatively right
It is slightly thinning according to organizing, but without obvious fracture.
In order to study relaxation effect of the different oligosaccharide nursings to anoxia-induced apoptosis in NEC modeling mouse intestinal tissue, I
Determine the situation of change of its HIF-1 α protein level in mRNA level in-site, cytoplasm and nucleus respectively, as a result as Figure 16,
Shown in Figure 17.NEC modeling processing does not make significant difference for HIF-1 α in the expression of mRNA level, this is because anoxic signal
Transmitting is usually to be completed by HIF-1 α in the directly accumulation of protein level, and anoxia-induced apoptosis can't cause HIF-1 α in mRNA
The variation of horizontal expression, thus, oligosaccharide nursing does not make significant difference for the expression of its mRNA yet.And on protein level,
NEC modeling handles the content (1.38 ± 0.61vs.0.08 ± 0.05) for not only increasing HIF-1 α in cytoplasm, and nucleus
In HIF-1 alpha expression also significantly raise (1.27 ± 0.06vs.0.08 ± 0.02), illustrate that NEC modeling can cause HIF-1 α a large amount of
Migrated into nucleus, and pass through oligosaccharide feed mouse, whether 3 '-SL+6 '-SL (0.13 ± 0.06&0.06 ±
0.03) or 2 '-FL (0.16 ± 0.07& 0.16 ± 0.13), HIF-1 α can be reduced to some extent in cytoplasm and cell
Accumulation in core.
It feeds to further study different newborn source oligosaccharide to the inflammation damnification as caused by anoxic in NEC mouse intestinal
Relaxation effect, we determine IL-1 β in its intestinal tissue, the expression of IL-8mRNA, concentration and the inflammation correlation of IL-8 again
The expression and nuclear translocation situation of p-I κ B α and p-P65 in access NF- κ B, as a result as shown in Figure 18, Figure 19 and Figure 20.It is found that NEC
Modeling handles the relative expression that can significantly improve IL-1 β (1.99 times) and IL-8mRNA (1.59 times) to some extent, simultaneously
The concentration of IL-8 also significantly rises in tissue, it is made to be increased to modeling group from 2.6 ± 0.15pg/mL of Normal group
13.3 ± 1.24pg/mL improves 5 times or so.And 3 '-SL+6 '-SL feed and 2 '-FL nursing can be significantly reduced IL-1 β and
IL-8 mRNA level in-site expression, and in intestinal tissue the concentration of IL-8 also drop to respectively 9.2 ± 0.7pg/mL and 10.2 ±
1.06pg/mL.Further, for the expression of intracellular NF- κ B pathway associated protein, 3 '-SL+6 '-SL and 2 '-FL
In various degree reduce the cytoplasm as caused by NEC modeling in p-I κ B alpha expression up-regulation (0.01 ± 0.003vs.0.48 ±
± 0.03 vs.0.02 ± 0.01 0.08vs.0.10) and nucleus in p-P65 accumulation (0.32 ± 0.07vs.1.07 ±
0.18vs.0.21± 0.06vs.0.31±0.07)。
Meanwhile we also measured were TLR-4 in each group mouse intestinal tissue and as a result such as scheme in the expression of each level
21, shown in Figure 22 and Figure 23.NEC modeling can significantly make TLR-4 mRNA expression in mouse intestinal cell rise 1.79 times, albumen
It is opposite to rise to 3.61 ± 0.18 by 0.15 ± 0.04, but in two groups of oligosaccharide nursing groups, TLR-4mRNA relative expression difference
It is 2.39 and 2.1 times of Normal group；The relative expression of TLR-4 albumen is respectively 2.29 ± 0.10 and 1.97 ± 0.31.It can
Know, although-SL and 2 '-FL can not significantly inhibit the transcription of TLR-4, the expression for its albumen still has 3 '-SL+6 '
Certain inhibitory effect.
In order to study influence of the different oligosaccharide nursings to Apoptosis in NEC mouse intestinal tissue, it is thin to determine its enteron aisle
The expression of cleaved Caspase-3 albumen in plasmosin, as a result as shown in figure 24.In NEC modeling mouse intestinal tissue
Caspase-3 is activated, activated form cleaved Caspase-3 after generating a large amount of shearings (0.97 ± 0.19vs.0.08 ±
0.01) Apoptosis, is caused to enter the irreversible stage, and different oligosaccharide is fed, and can inhibit the activation of Caspase-3,
So that the relative expression of cleaved Caspase-3 is dropped to 0.26 ± 0.05 and 0.15 ± 0.03 respectively, have dropped 2.7 times and
5.4 times, to play the role of the protection to intestinal cell.To sum up, 3 '-SL+6 '-SL of single sialic acid lactose can improve by
The general physiological status of mouse caused by NEC modeling is deteriorated, and can configuration to its enteron aisle and microstructure all play one
Fixed protective effect.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (6)
1. newborn source oligosaccharide is in preparation for by alleviating in the drug or food that enteron aisle anoxia-induced apoptosis treats or prevents NEC
Purposes, which is characterized in that it is described cream source oligosaccharide include 3 '-sialyl lactoses (3 '-SL), 6 '-sialyl lactoses (6 '-SL),
The mixture of one or more of sialic acid-lactoyl-N- tetrose b (LSTb) or sialic acid-lactoyl-N- tetrose c (LSTc).
2. a kind of pharmaceutical composition for treating NEC, which is characterized in that described containing newborn source oligosaccharide in described pharmaceutical composition
Newborn source oligosaccharide includes 3 '-sialyl lactoses (3 '-SL), 6 '-sialyl lactoses (6 '-SL), sialic acid-lactoyl-N- tetrose b
(LSTb) or the mixture of one or more of sialic acid-lactoyl-N- tetrose c (LSTc).
3. the pharmaceutical composition for the treatment of NEC according to claim 2, which is characterized in that newborn source in described pharmaceutical composition
The concentration of oligosaccharide is 1mg/mL~1000mg/mL.
4. a kind of food for preventing NEC, which is characterized in that contain newborn source oligosaccharide, cream source oligosaccharide packet in the food
Include 3 '-sialyl lactoses (3 '-SL), 6 '-sialyl lactoses (6 '-SL), sialic acid-lactoyl-N- tetrose b (LSTb) or saliva
The mixture of one or more of acid-lactoyl-N- tetrose c (LSTc).
5. the food of prevention NEC according to claim 4, which is characterized in that the concentration of newborn source oligosaccharide in the food
For 2mg/mL~100ml/mL.
6. the food of prevention NEC according to claim 4, which is characterized in that the food includes fermented fruits and vegetables juice, bubble
Dish, acidified milk, cheese, milk-contained drink and milk powder.
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