阅读说明：本技术 低聚木糖在制备抗深静脉血栓的药物中的应用 (Application of xylo-oligosaccharide in preparation of medicine for resisting deep venous thrombosis ) 是由 马衍青 张泽萍 胡箫 肖德胜 倪园 许祯 于 2020-06-17 设计创作，主要内容包括：本发明提供了低聚木糖在制备抗深静脉血栓的药物中的应用,属于生物医学技术领域。本发明提供了低聚木糖在制备抗深静脉血栓的药物中的应用。所述低聚木糖的原料包括以玉米芯、甘蔗渣或麦麸。实验证明,通过给深静脉血栓小鼠模型喂食三种不同来源的低聚木糖,结果表明,三种低聚木糖组均可以抑制深静脉血栓的形成,且与空白对照组相比,具有统计学差异(p<0.05)。因此,本发明提供的低聚木糖为潜在深静脉血栓药物活性成分,将低聚木糖或联合其他种类低聚糖制备一种可预防和治疗深静脉血栓形成的潜在药物。(The invention provides an application of xylo-oligosaccharide in preparing a deep vein thrombosis resistant medicine, belonging to the technical field of biomedicine. The invention provides an application of xylo-oligosaccharide in preparing a medicine for resisting deep venous thrombosis. The raw material of the xylo-oligosaccharide comprises corncob, bagasse or wheat bran. Experiments prove that three xylo-oligosaccharides from different sources are fed to a deep venous thrombosis mouse model, and the results show that the three xylo-oligosaccharides can inhibit the formation of deep venous thrombosis and have statistical difference (p is less than 0.05) compared with a blank control group. Therefore, the xylo-oligosaccharide provided by the invention is a potential deep vein thrombosis drug active component, and the xylo-oligosaccharide or the xylo-oligosaccharide combined with other oligosaccharides is used for preparing a potential drug capable of preventing and treating deep vein thrombosis.)

1. Application of xylooligosaccharide in preparing medicine for resisting deep venous thrombosis is provided.

2. Use according to claim 1, characterized in that the raw material of xylo-oligosaccharides comprises corncobs, bagasse or wheat bran.

3. Use according to claim 1 or 2, characterized in that the raw material of xylo-oligosaccharides is bagasse.

4. The use of claim 1, wherein the resistance to deep vein thrombosis comprises decreasing thrombus length and/or thrombus weight for thrombus formation.

5. The use of claim 1, wherein the feeding amount of the xylo-oligosaccharide is 0.33-0.34 mg/mouse/d.

6. The use of claim 1, wherein the medicament is in the form of an oral dosage form.

7. The use of claim 6, wherein the oral formulation comprises a decoction, an oral liquid, a syrup, a granule, a pill, a tablet or a capsule.

8. The use according to any one of claims 1 to 7, wherein the use of the xylo-oligosaccharide in combination with other oligosaccharides for the preparation of a medicament for the prevention and/or treatment of deep vein thrombosis;

the other kind of oligosaccharide comprises fructo-oligosaccharide and/or malto-oligosaccharide.

9. The deep venous thrombosis resistant medicine comprises an active ingredient and an auxiliary material, and is characterized in that the active ingredient comprises the following components in parts by weight: 1-10 parts of xylo-oligosaccharide, 1-10 parts of fructo-oligosaccharide and 1-10 parts of malto-oligosaccharide.

10. The medicament according to claim 9, characterized by comprising the following components in weight ratio: 3-7 parts of xylo-oligosaccharide, 3-7 parts of fructo-oligosaccharide and 3-7 parts of malto-oligosaccharide.

Technical Field

The invention belongs to the technical field of biomedicine, and particularly relates to application of xylooligosaccharide in preparation of a deep vein thrombosis resistant medicine.

Background

Deep Venous Thrombosis (DVT) refers to a disease in which blood clots in Deep venous vessels, resulting in complete or incomplete occlusion of the vessel [1 ]. Usually due to delayed coagulation of blood in the deep venous circulation [2], common in the lower extremities. Thrombus formed in the lower limb can flow to the lung through the blood, so that the Pulmonary artery is blocked, and Pulmonary Embolism (PE) is further caused. Pulmonary embolism refers to the flow of venous blood clots with the blood flow through the right side of the heart to the pulmonary circulation and lodge in one or more branches of the pulmonary arteries [3], with high morbidity and mortality, with thrombi from the deep veins of the legs or arms being the most common [4 ]. The most severe pulmonary artery embolisms usually originate in the deep veins of the lower limb and/or pelvis [5 ]. In addition, if the deep venous thrombosis is not treated in time or is not treated correctly, sequelae are easy to occur, the limbs can swell to cause inconvenient limb movement, early twilight and severe pain, and the limbs are also sour, heavy, sleepy and swollen, large-area pigmentation of the lower limbs can occur after a long time, or superficial secondary vein dilatation, pruritus of the skin, even ulceration and the like. Even after treatment, deep vein thrombosis and pulmonary embolism may cause post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension [3,4], respectively, and once so, the patient may require long-term additional medical care and treatment, seriously affecting the quality of life of the patient.

At present, the specific molecular mechanism of deep venous thrombosis still needs to be explored, and the corresponding indexes of clinical detection cannot cover all the indexes, so that a timely and effective method cannot be adopted to reduce the death risk of patients. Therefore, in order to realize accurate control and treatment aiming at deep vein thrombosis as early as possible, the regulation mechanism and the molecular mechanism of deep vein thrombosis are researched from various aspects, and the method has important clinical significance and social value.

Intestinal microorganisms are considered as symbionts of animal organisms, play an important role in aspects such as nutrient metabolism and immune regulation, and contribute to maintaining intestinal homeostasis. Thousands of microorganisms inhabit the human intestinal tract and produce a variety of metabolic bioactive signal molecules that affect the health of the body [6 ]. For a normal healthy subject, the intestinal microbiota is maintained in a steady state in vivo, controlling the growth of pathogenic microorganisms, and this dynamic balance between human and microorganisms is called microecological balance. Factors affecting the microecological balance include external environmental factors as well as factors of the host itself. If beneficial flora exists, the stability of the beneficial flora is maintained by producing bacteriocin, antibiotics and metabolites thereof, competing nutrition and space to prevent the invasion of the bypath flora. The ecological balance can maintain the normal physiological functions of the host, such as nutrition, immunity, digestion and the like. Once this dysbiosis is, it may induce a massive proliferation of pathogenic microorganisms leading to gut related diseases such as Inflammatory Bowel Disease (IBD), obesity, allergic diseases, diabetes, autism, colorectal and cardiovascular diseases etc. [7] [8] [9 ]. In animal models, sterile mice receiving fecal microflora transplantation have shown susceptibility to obesity and atherosclerosis, indicating a great potential for fecal microflora transplantation in the treatment of a range of complex diseases [10] [11 ].

In order to rationally regulate the ecological balance of intestinal microorganisms, the consumption of prebiotics has developed in recent years as an important dietary strategy by which the intestinal microbial composition can be improved, thereby contributing to the promotion of health. Prebiotics (probiotics), originally defined by Gibson and Roberfroid in 1995 as "a non-digestible food ingredient, beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, thereby improving host health [12 ]. Among them, oligosaccharides are increasingly gaining attention as prebiotic functional food ingredients. Oligosaccharide sugars can be extracted from a variety of biomass sources by enzymatic hydrolysis or can be synthesized by enzymatic transfer reactions using oligosaccharides [13 ]. Because it is not absorbed in small intestine, it can directly enter large intestine and become proliferation factor of some beneficial flora, so as to regulate ecological balance of intestinal canal microorganism, and enhance immunity and health balance.

With the recent intensive understanding of intestinal microorganisms, it has been found that intestinal flora and its metabolites can affect the occurrence of cardiovascular diseases in multiple ways, such as affecting lipid metabolism via bile acid pathway, promoting the formation of atherosclerotic plaque, and promoting the occurrence of heart failure due to intestinal flora shift. These studies indicate that gut microbes are closely related to a variety of diseases, but their relationship to deep vein thrombosis remains to be explored further.

Xylo-oligosaccharides (XOS), one of the commonly used prebiotics, are oligosaccharides of 2-7 xylose single molecules linked by β -1,4 [14], which are common dietary fiber hydrolysates in corn stover, wheat bran and rice bran [15 ]. XOS is used as intestinal motility source [16], has minimum effective dosage and strongest function compared with other oligosaccharides, and is utilized by microorganisms in host colon after reaching colon, thereby greatly improving gastrointestinal function, and promoting digestion and absorption of food and discharge of intestinal waste [17 ]. In addition, XOS shows strong antioxidant and antibacterial activity in vitro [18 ]. Although XOS is not digestible by humans, it is metabolized by intestinal microorganisms [19 ]. Furthermore, XOS promotes the growth of bifidobacteria and lactobacilli in the gut and increases the content of Short Chain Fatty Acids (SCFA) in these gut microorganisms, enhancing gut barrier function [20 ]. In particular, dietary supplementation with XOS may increase the relative abundance of lactobacilli and bifidobacteria, enhancing the expression of the tight junction protein occludin (ocln) in the intestinal tract in the caecum tissue [21 ]. Both XOS and bifidobacteria can enhance immune function in the host [22 ]. And there are studies finding associations of XOS in various diseases, such as: in pre-diabetic patients, XOS can enhance insulin sensitivity and reverse changes in microbial composition caused by insulin insensitivity [23 ]; XOS also regulates intestinal flora in obese rats, increases SCFA levels and reduces High Fat Diet (HFD) induced colonic inflammation, among others. However, no report about the therapeutic effect of xylooligosaccharide on deep venous thrombosis exists at present.

Reference to the literature

[1]Bevis P M,Smith F C T.Deep vein thrombosis[J].Surgery(UnitedKingdom),Elsevier Ltd,2016,34(4):159–164.

[2]Derek G.WallerBSc(HONS),DM,MBBS(HONS),FRCPAnthony P.SampsonMA,PhD,FHEA Fbp.Platelets and platelet aggregation Blood coagulation and thecoagulation cascade[J].Medical Pharmacology and Therapeutics(Fifth Edition),2018:175–190.

[3]Heinrich F.Pulmonary embolism[J].Deutsches medizinisches Journal,1970,21(7):430–444.

[4]Leroyer C.Pulmonary embolism[J].Revue du Praticien,1999,49(5):561–567.

[5]Gupta.K N B S R D L L N.Catheter Directed Thrombolysis OfPulmonary Embolism[J].StatPearls Publishing,2020.

[6]Wang Z,Zhao Y.Gut microbiota derived metabolites in cardiovascularhealth and disease[J].Protein and Cell,Higher Education Press,2018,9(5):416–431.

[7]Battson M L,Lee D M,Jarrell D K,et al.Suppression of gut dysbiosisreverses Western diet-induced vascular dysfunction[J].American journal ofphysiology.Endocrinology and metabolism,2018,314(5):E468–E477.

[8]Degruttola A K,Low D,Mizoguchi A,et al.Current understanding ofdysbiosis in disease in human and animal models[J].Inflammatory BowelDiseases,2016,22(5):1137–1150.

[9]Yang T,Santisteban M M,Rodriguez V,et al.Gut microbiota dysbiosisis linked to hypertension.[J].Hypertension.,2016,65(6):1331–1340.

[10]Turnbaugh P J,Ley R E,Mahowald M A,et al.An obesity-associatedgut microbiome with increased capacity for energy harvest[J].Nature,2006,444(7122):1027–1031.

[11]Gregory J C,Buffa J A,Org E,et al.Transmission of atherosclerosissusceptibility with gut microbial transplantation[J].Journal of BiologicalChemistry,2015,290(9):5647–5660.

[12]Ouwerkerk J P,Ark K C H Van Der,Davids M,et al.Adaptation ofAkkermansia muciniphila to the Oxic-Anoxic Interface of the Mucus Layer[J].APPLIED AND ENVIRONMENTAL MICROBIOLOGY,2016,82(23):6983–6993.

[13]Bosscher.D,Breynaert.A,Pieters.L,Hermans N.FOOD-BASED STRATEGIESTO MODULATE THE COMPOSITION OF THE INTESTINAL MICROBIOTA AND THEIR ASSOCIATEDHEALTH EFFECTS[J].JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY,2009,60(Suppl6):5–11.

[14]Jordan D B,Wagschal K.Properties and applications of microbial β-D-xylosidases featuring the catalytically efficient enzyme from Selenomonasruminantium[J].Applied Microbiology and Biotechnology,2010,86(6):1647–1658.

[15]Manrique Vergara D,González Sánchez M E.Grasos De CadenaCorta(Butírico)Y Patologías Intestinales[J].Nutricion hospitalaria,2017,34:58–61.

[16]Moens F,Verce M,De Vuyst L.Lactate-and acetate-based cross-feeding interactions between selected strains of lactobacilli,bifidobacteriaand colon bacteria in the presence of inulin-type fructans[J].InternationalJournal of Food Microbiology,Elsevier B.V.,2017,241:225–236.

[17]M S,Fredslund F,Majumder A,et al.Enzymology and structureof the GH13_31 glucan 1,6-α-glucosidase that confers isomaltooligosaccharideutilization in the probiotic lactobacillus acidophilus NCFM[J].Journal ofBacteriology,2012,194(16):4249–4259.

[18]Yonglin Gao,Shumin Zhang,Chunmei Li,Lin Xiao J S Y.Acute andsubchronic toxicity of xylo-oligosaccharide in mice and rats[J].ToxicologyMechanisms and Methods,2012,22(8):605–610.

[19]Gao Y,Wang Y,Li Y,et al.Repeated sub-chronic oral toxicity studyof xylooligosaccharides(XOS)in dogs[J].Regulatory Toxicology andPharmacology,Elsevier Ltd,2017,86:379–385.

[20]Li Z,Summanen P H,Komoriya T,et al.In vitro study of theprebiotic xylooligosaccharide(XOS)on the growth of Bifidobacterium spp andLactobacillus spp[J].International Journal of Food Sciences and Nutrition,2015,66(8):919–922.

[21]Christensen E G,Licht T R,Leser T D,et al.Dietary Xylo-oligosaccharide stimulates intestinal bifidobacteria and lactobacilli but haslimited effect on intestinal integrity in rats[J].BMC Research Notes,2014,7(1):1–14.

[22]Childs C E,H,Alhoniemi E,et al.Xylo-oligosaccharides aloneor in synbiotic combination with Bifidobacterium animalis subsp.lactis inducebifidogenesis and modulate markers of immune function in healthy adults:Adouble-blind,placebo-controlled,randomised,factorial cross-over study[J].British Journal of Nutrition,2014,111(11):1945–1956.

[23]Yang J,Summanen P H,Henning S M,et al.Xylooligosaccharidesupplementation alters gut bacteria in both healthy and prediabetic adults:Apilot study[J].Frontiers in Physiology,2015,6(Aug):1–11.

Disclosure of Invention

In view of the above, the present invention aims to provide a new use of xylooligosaccharide, namely, an application of xylooligosaccharide in preparing a deep vein thrombosis resistant drug, wherein the xylooligosaccharide can effectively inhibit the formation of deep vein thrombosis.

The invention provides an application of xylo-oligosaccharide in preparing a medicine for resisting deep venous thrombosis.

Preferably, the raw material of the xylo-oligosaccharide comprises corncob, bagasse or wheat bran.

Preferably, the raw material of the xylo-oligosaccharide is bagasse.

Preferably, the anti-deep vein thrombosis comprises decreasing thrombus length and/or thrombus weight for thrombus formation.

Preferably, the feeding amount of the xylo-oligosaccharide is 0.33-0.34 mg/mouse/d.

Preferably, the dosage form of the medicament is preferably an oral preparation.

Preferably, the oral preparation comprises decoction, oral liquid, syrup, granules, pills, tablets or capsules.

Preferably, the application of the xylo-oligosaccharide and other oligosaccharides in preparing the medicine for preventing and/or treating deep vein thrombosis is provided;

the other kind of oligosaccharide comprises fructo-oligosaccharide and/or malto-oligosaccharide.

The invention provides a deep vein thrombosis resistant medicine, which comprises active ingredients and auxiliary materials, wherein the active ingredients comprise the following components in parts by weight: 1-10 parts of xylo-oligosaccharide, 1-10 parts of fructo-oligosaccharide and 1-10 parts of malto-oligosaccharide.

Preferably, the active ingredients comprise the following components in parts by weight: 3-7 parts of xylo-oligosaccharide, 3-7 parts of fructo-oligosaccharide and 3-7 parts of malto-oligosaccharide.

The invention provides an application of xylo-oligosaccharide in preparing a medicine for resisting deep venous thrombosis. Experiments prove that three xylo-oligosaccharides from different sources are fed to a deep venous thrombosis mouse model, and the results show that the three xylo-oligosaccharides can inhibit the formation of deep venous thrombosis and have statistical difference (p is less than 0.05) compared with a blank control group. Therefore, the xylo-oligosaccharide provided by the invention is a potential drug for preventing and treating deep vein thrombosis.

Furthermore, the invention specifically limits the application of the xylo-oligosaccharide and other oligosaccharides in preparing the antithrombotic drug, greatly enriches the types of active ingredients of the drug and provides a novel antithrombotic drug.

Drawings

FIG. 1 is a graph showing that deep vein thrombosis can be significantly inhibited by mice fed with xylo-oligosaccharide from three different sources, wherein (A) the morphology of thrombosis formed by different treatment groups is shown; (B) a length statistical plot of four groups of thrombus tissues, wherein the p-value of the corn core group is 0.0225, the p-value of the bagasse group is 0.0002, and the p-value of the wheat bran group is 0.0235; (C) a weight statistical plot of four groups of thrombus tissues, wherein the p-value of the corn core group was 0.0475, the p-value of the bagasse group was 0.0037, and the p-value of the wheat bran group was 0.0468; in the figure,. p <0.01, indicating that the data were very significantly different in the statistical analysis; p <0.05, indicating that the data were significantly different in statistical analysis; if p >0.05, the data are not significantly different in the statistical analysis.

Detailed Description

The invention provides an application of xylo-oligosaccharide in preparing a medicine for resisting deep venous thrombosis.

The raw materials for preparing the xylo-oligosaccharide are not particularly limited in the invention, and the raw materials for preparing the xylo-oligosaccharide which are well known in the field can be adopted. To illustrate the anti-deep vein thrombosis effect of xylo-oligosaccharides from different sources, the invention is specifically illustrated by taking corn cob, bagasse or wheat bran as an example, but this should not be construed as limiting the scope of the invention. The method for preparing the xylo-oligosaccharide is not particularly limited, and the preparation of the xylo-oligosaccharide known in the field can be adopted. Sources of such xylo-oligosaccharides may also be obtained from common commercial sources. In the examples of the present invention, the xylo-oligosaccharide derived from corncob was obtained from zhoxin biotechnology limited, the xylo-oligosaccharide derived from bagasse was obtained from qianpin bioengineering limited, shandong, and the xylo-oligosaccharide derived from wheat bran was obtained from shanxi pannier biotechnology limited.

In the present invention, the deep vein thrombosis resistance preferably comprises decreasing the length and/or weight of the thrombosis plug. The medicine for resisting deep vein thrombosis comprises prevention and/or treatment of deep vein thrombosis.

In the invention, because the xylo-oligosaccharide is not digested and decomposed by the digestive tract, the dosage form of the medicament is preferably oral preparation; the oral preparation comprises decoction, oral liquid, syrup, granule, pill, tablet or capsule. The invention has no special limit on the auxiliary materials of the medicine, and the auxiliary materials are selected according to different oral preparation formulations in the field. The content of xylooligosaccharide in the medicament is not particularly limited, and the content of the medicinal active ingredients well known in the field can be adopted. The method for preparing the drug is not particularly limited, and the method for preparing the drug well known in the field can be adopted. The feeding amount of the xylo-oligosaccharide is preferably 0.33-0.34 mg/mouse/d, and the dosage of the xylo-oligosaccharide is converted into the dosage of a human body according to the dosage of an animal medicament.

The invention provides application of xylo-oligosaccharide and other oligosaccharides in preparation of a medicine for preventing and/or treating deep venous thrombosis. The other kind of oligosaccharide comprises fructo-oligosaccharide and/or malto-oligosaccharide. The mass ratio of the xylooligosaccharide to the fructooligosaccharide or maltooligosaccharide is preferably 1-10: 1-10, more preferably 3-7: 3-7, and most preferably 5: 2. The present invention is not particularly limited in kind and source of the fructo-oligosaccharide and/or malto-oligosaccharide, and those known in the art can be used.

The invention provides a deep vein thrombosis resistant medicine, which comprises active ingredients and auxiliary materials, and comprises the following components in parts by weight: 1-10 parts of xylo-oligosaccharide, 1-10 parts of fructo-oligosaccharide and 1-10 parts of malto-oligosaccharide, preferably: 3-7 parts of xylo-oligosaccharide, 3-7 parts of fructo-oligosaccharide and 3-7 parts of malto-oligosaccharide, and more preferably 5 parts of xylo-oligosaccharide, 2 parts of fructo-oligosaccharide and 3 parts of malto-oligosaccharide. The dosage form and preparation method of the medicine are the same as those of the medicine in the application, and the details are not repeated herein.

The application of xylo-oligosaccharide provided by the present invention in the preparation of drugs for resisting deep vein thrombosis is described in detail with reference to the following examples, but they should not be construed as limiting the scope of the present invention.