CN108653298B - Monosaccharide composition, pharmaceutical preparation and application thereof - Google Patents
Monosaccharide composition, pharmaceutical preparation and application thereof Download PDFInfo
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- CN108653298B CN108653298B CN201810607136.7A CN201810607136A CN108653298B CN 108653298 B CN108653298 B CN 108653298B CN 201810607136 A CN201810607136 A CN 201810607136A CN 108653298 B CN108653298 B CN 108653298B
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- China
- Prior art keywords
- monosaccharide composition
- monosaccharide
- arabinose
- group
- mannose
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Abstract
The invention discloses a monosaccharide composition, a pharmaceutical preparation and application thereof, wherein the monosaccharide composition comprises the following components: l-arabinose and rare sugars; the rare sugar is selected from any 2-4 of D-mannose, D-xylose, D-tagatose and D-psicose. The monosaccharide composition improves the effects of maintaining the muscle activity of a human body, resisting diabetes complications and reducing blood sugar by combining 2-4 kinds of rare sugars and L-arabinose, and is particularly suitable for improving the life quality of diabetics. In another aspect of the invention, pharmaceutical formulations of the monosaccharide compositions are provided. In another aspect of the invention, the use of monosaccharide compositions is also provided.
Description
Technical Field
The invention relates to a monosaccharide composition, a medicinal preparation and application thereof, and belongs to the field of functional foods.
Background
The increasing incidence of diabetes has become a global public health problem. Persistent hyperglycemia and long-term metabolic disorders can lead to damage to and dysfunction and failure of systemic tissues and organs, particularly the eye, kidney, cardiovascular and nervous systems. Serious patients can cause acute complications of ketoacidosis and hyperosmolar coma, such as dehydration, electrolyte disturbance and acid-base balance disturbance. Although various medicines for treating diabetes exist at present, due to the problems of diet and the like, the phenomena of hyperglycemia, abnormal glucose tolerance, insulin resistance and the like often occur in the lives of diabetes patients and normal people, and the health of people is seriously affected, so that the invention of the hypoglycemic medicine or the health-care product which is safe and healthy and is beneficial to the normal people is very significant.
Sugar is a necessity of human life and plays an indispensable role in human nutrition and health. The traditional sugar product can provide sweet taste and calorie, and is easy to cause health problems such as dental caries and obesity, and has great harm to patients with hyperglycemia. Along with the remarkable improvement of scientific technology and living standard in recent years, people pay more attention to health problems, and the health sugar which has low calorie, no fat and a health care function and is friendly to diabetics is favored. The health sugar is not easy to digest and absorb in vivo, has a glycemic index far lower than that of common sugar, has the characteristics of no decayed tooth, no burden on diabetes patients, stable property and the like, and has great attention in the fields of food, health care products and medicine research and development.
Monosaccharides can be broadly classified into aldoses having a polyhydroxyaldehyde structure, ketoses having a polyhydroxyketone structure, and sugar alcohols obtained by reducing these sugars. Monosaccharides which are abundantly present in nature include D-glucose, D-fructose, L-arabinose, D-mannose, D-xylose, D-galactose and D-ribose, and are rare sugars in addition to these sugars. Rare sugars can now be defined as a class of monosaccharides and their derivatives that occur in nature but in very small amounts, such as D-tagatose, D-psicose and D-psicose. Most of the monosaccharides have the characteristics of low calorie, difficult digestion and absorption and the like, and have various physiological functions.
Although a great deal of research is carried out on various performances of each rare sugar in the prior art, each rare sugar can only play a role independently, has a single effect, needs to be taken respectively when used, has too many times of taking, increases the taking complexity and reduces the user experience; meanwhile, when the rare sugar is taken alone, the effects of controlling the blood sugar and the sugar tolerance of the rare sugar cannot be well exerted, and the effects of immunoregulation and probiotic proliferation of the rare sugar cannot be fully exerted.
Disclosure of Invention
According to one aspect of the application, the monosaccharide composition is provided, and 2-4 rare sugars and L-arabinose are combined, so that the monosaccharide composition has the effects of maintaining the muscle activity of a human body, resisting diabetes complications and reducing blood sugar, and is particularly suitable for improving the life quality of diabetics. Meanwhile, the composition also has the effects of improving the immunity, improving the sugar resistance and regulating intestinal probiotics.
The monosaccharide composition, comprising: l-arabinose and 2-4 rare sugars.
The monosaccharide composition can be administered after mixing at an acceptable dosage. The 2 to 4 rare sugars here may be: d-mannose, D-xylose, D-tagatose or D-psicose.
Preferably, the rare sugar is selected from any 2-4 of D-mannose, D-xylose, D-tagatose and D-psicose.
The L-arabinose and the 4 rare sugars can also reduce the injury of the continuous hyperglycemia of the diabetes to the muscles of the human body and the motor nerve and muscle inflammation caused by the continuous hyperglycemia of the diabetes. Improving the life quality of the diabetic. As can be seen from specific animal experiments, the monosaccharide composition can reduce the degree of joint swelling caused by arthritis and accelerate the recovery thereof.
Optionally, the monosaccharide composition consists of L-arabinose, D-mannose, D-xylose, D-tagatose and D-psicose.
After the 4 kinds of rare sugar are preferably mixed with the L-arabinose, the metabolism of insulin in the body can be synergistically regulated, the sensitivity of insulin to other ingested sugar is improved, and the insulin antagonistic strength of diabetes mellitus is reduced.
Optionally, the monosaccharide composition comprises: 1-20g of L-arabinose, 1-10g of D-mannose, 1-10g of D-xylose, 1-10g of D-psicose and 1g of D-tagatose. Namely, the monosaccharide composition contains L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose;
wherein L-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is (1-20): (1-20): (1-20): (1-20): 1.
preferably, the monosaccharide composition contains L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose;
wherein L-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is (1-10): (1-10): (1-10): (1-10): 1. when the D-tagatose is mixed with other monosaccharides according to the proportion, the obtained monosaccharide composition can synergistically enhance the anti-inflammatory and muscle-increasing effects and simultaneously effectively protect motor nerves.
Optionally, the lower limit of L-arabinose in the monosaccharide composition (in g) may be 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5. The upper limit of L-arabinose (in g in each case) may be 20, 19.5, 19, 18, 18.5, 17.5, 17.
Alternatively, the lower limit of D-mannose (in g) may be: 1.2, 2.5, 3, 3.5, 4, 4.5, 5. The upper limit of D-mannose (in g) may be 10, 9, 8, 7, 7.5.
Alternatively, the lower limit of D-xylose (in g) may be: 1.2, 2.5, 3, 3.5, 4, 4.5, 5. The upper limit of D-xylose (in g) may be 10, 9, 8, 7, 7.5.
Alternatively, the lower limit of D-psicose (in g) may be: 2. 2.5, 3, 3.5 and 4. The upper limit of D-psicose (in g) may be: 10. 9.5, 9, 8.5, 8, 7.5.
Optionally, the monosaccharide composition is administered in an amount of 50mg/kg body weight of L-arabinose.
For example: the formula, namely the proportion, is determined according to the experiment of the embodiment by calculating 70 kg of the weight of an adult, and the minimum preparation unit composition of the monomer compound is determined as follows: l-arabinose (6g), D-mannose (1.3g), D-xylose (1.2g), D-psicose (1.2g) and D-tagatose (0.3g), the total mass of each monosaccharide in the preparation unit is 10 g.
Preferably, the monosaccharide composition contains L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose;
wherein L-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is 3-10: 1-10: 1-10: 1-10: 1.
in yet another aspect, the present invention provides a pharmaceutical formulation of a monosaccharide composition, comprising: when the monosaccharide composition is administered in the form of a medicament, the monosaccharide composition contains 1-15g of L-arabinose per unit preparation;
more preferably, the monosaccharide composition has an L-arabinose content of 1-5g per unit formulation.
Herein, the following: "per unit formulation" means a unit of formulation in minimal packaging or minimal administration form, e.g., as per bag of granules or powder, per oral solution, per capsule, per tablet or pill, per tube of ointment. The monosaccharide composition can be mixed with a pharmaceutically acceptable medicinal carrier or excipient to prepare any pharmaceutically acceptable medicinal preparation.
The medicinal preparation of the monosaccharide composition can be prepared into various preparations according to the existing method, for example, powder is prepared by crushing, sieving and uniformly mixing all the components in the monosaccharide composition. The taking method comprises the following steps: 1 bag (10g) of the powder is taken each time, 2 times a day, and taken with water at lunch, dinner and 2 hours after meal.
The invention also provides application of the monosaccharide composition in preparation of a medicament for preventing and/or treating diabetes. Diabetes herein includes, but is not limited to, gestational diabetes, type i diabetes, type ii diabetes, impaired glucose tolerance, insulin resistance.
Optionally, in the application of the monosaccharide composition in preparing a medicament for preventing and/or treating diabetes, the dosage of the L-arabinose is 30-120 mg/kg of body weight. More preferably 120 mg/kg.
The invention also provides the application of the monosaccharide composition in preparing a medicament for controlling postprandial blood sugar.
Optionally, in the application of the monosaccharide composition in preparing a medicine for controlling postprandial blood sugar, the dosage of L-arabinose is 30-120 mg/kg of body weight. More preferably 120 mg/kg.
The invention also provides the application of the monosaccharide composition in preparing immunomodulatory drugs. Immunomodulation herein includes, but is not limited to: as gastrointestinal prebiotics, intestinal probiotics, and immune regulation related to Treg cells.
Optionally, in the application of the monosaccharide composition in preparation of an immunomodulatory drug, the dosage of the L-arabinose is 30-120 mg/kg of body weight. More preferably 120 mg/kg.
The rare sugar herein means a monosaccharide other than D-glucose, D-fructose, L-arabinose, D-mannose, D-xylose, D-galactose and D-ribose.
As used herein, "L-arabinose" means a compound of the formula C5H10O5The organic compound of (1).
"D-mannose" refers to the molecular formula C6H12O6The organic compound of (1).
"D-xylose" means a compound of formula C5H10O5The organic compound of (1).
"D-tagatose" refers to the formula C6H12O6The organic compound of (1).
"D-psicose" means the formula C6H12O6The organic compound of (1).
The beneficial effects of the invention include but are not limited to:
(1) the monosaccharide composition provided by the invention can obviously reduce the sugar, resist the sugar and regulate the immunity by proportionally combining the L-arabinose, the D-mannose, the D-xylose, the D-psicose and the D-tagatose. Experiments such as streptozotocin induced type II diabetes rat models are carried out, and the monosaccharide composition is found to be capable of remarkably reducing the blood sugar of streptozotocin diabetes rat models, improving the sugar tolerance and effectively reducing the postprandial blood sugar; can also effectively regulate intestinal probiotics; the monosaccharide composition can effectively regulate the function of Treg cells and enhance the immunity; the monosaccharide composition can reduce blood sugar and inhibit blood sugar from being converted into fat, and has blood lipid regulating effect.
(2) After the monosaccharide composition provided by the invention is prepared by proportionally mixing the L-arabinose, the D-mannose, the D-xylose, the D-psicose and the D-tagatose, the monosaccharide composition is cooperated with the effect that the L-arabinose is not easily absorbed by a human body to inhibit lipogenesis and the effect that the D-tagatose inhibits glucose absorption enzyme in small intestine, so that the skeletal muscle degeneration of a diabetic patient is reduced, the skeletal muscle of the human body is repaired, and the resistance to various inflammations of the diabetic patient at the later stage of illness is further realized. The quality of life of the diabetic can be improved. The composition can remarkably exert the effects of reducing blood sugar, regulating immunity, promoting the propagation of intestinal probiotics and improving blood fat after being combined according to the composition.
(3) The monosaccharide composition provided by the invention can play a role in reducing blood sugar, resisting insulin resistance and regulating immunity. And can be prepared into corresponding dosage forms for use according to the required dosage forms. Convenient administration and remarkable effect.
Drawings
FIG. 1 is a schematic diagram of the blood glucose-dosing time curves resulting from the effect of treatment groups on glucose tolerance in diabetic model rats in a preferred embodiment of the present invention;
FIG. 2 is a schematic blood glucose-dosing time curve showing the effect of treatment groups on glucose tolerance in normal rats in a preferred embodiment of the present invention;
FIG. 3 is a graph showing the effect of each treatment group on the swelling of the joints of normal rats on the swelling degree score of the joints versus the administration time in the preferred embodiment of the present invention.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
Unless otherwise specified, the raw materials and catalysts in the examples of the present invention were all purchased from commercial sources.
Example 1 monosaccharide composition powder sample 1#Preparation of
According to the proportion of L-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is 1: 1: 1: 1: 1, weighing 0.3g of L-arabinose, 0.3g of D-mannose, 0.3g of D-xylose, 0.3g of D-psicose and 0.3g of D-tagatose respectively. The L-arabinose and the rare sugar are respectively crushed into 180 meshes (180 meshes in the embodiment) with the grain size of 100 at normal temperature, and then sieved, and the L-arabinose and the rare sugar are uniformly mixed to obtain monosaccharide composition powder.
Example 2 monosaccharide composition powder sample 2#Sample 7#Preparation of
The concrete procedure is the same as that of sample 1#Except that L-arabinose and a rare sugar were changed according to Table 1 (conditions not specified in Table 1 and sample 1 in example 1)#Preparation ofSame conditions), sample 2 was obtained, respectively#Sample 7#。
TABLE 1
EXAMPLE 3 pharmaceutical tablet of monosaccharide composition
The powder sample 1 obtained in example 1 was mixed#Tabletting to obtain the tablet. The content of L-arabinose in one tablet of monosaccharide composition is 15 g.
EXAMPLE 4 monosaccharide composition pharmaceutical capsules
The difference from example 3 is that: the content of L-arabinose in one tablet of monosaccharide composition is 1 g.
EXAMPLE 5 monosaccharide composition pharmaceutical capsules
The difference from example 3 is that: the content of L-arabinose in one tablet of monosaccharide composition is 5 g.
Example 6 Effect of monosaccharide compositions on blood glucose and glucose tolerance
This example examines the effect of monosaccharide compositions on blood glucose and glucose tolerance in normal rats and diabetic model rats.
(I) Experimental method
1. Rat model of Streptozotocin (STZ) induced type II diabetes
SD (Spraque-Dawley) male rats, about 10 weeks old, weighing 252 + -23 g, after 1 week of acclimation, were randomly assigned: normal control group and diabetes mellitus treatment group. After 1 week of adaptive feeding, model rats were fed with high-sugar, high-fat diet (containing 10.0% lard, 20.0% sucrose, 2.5% cholesterol, 1.0% cholate, 66.5% regular diet) for 4 weeks to induce development of insulin resistance. At 5 weeks, after rats in each experimental group were fasted for 12 hours without water deprivation, (STZ) was injected intraperitoneally with 30mg/kg, and normal control groups were injected intraperitoneally with an equal volume of citrate buffer. After 1 week of injection, the rats in each group were fasted for 12 hours without water deprivation, and then Blood was taken by tail-off to measure Fasting Blood Glucose (FBG). Fasting plasma glucose (FBG) > 15mmol/L is regarded as successful molding.
2. Blood glucose determination and glucose tolerance test
Fasting glucose was measured using an automated glucometer and expressed as mmol/L. Sugar tolerance test: the model intervention group is given monomer and compound treatment for 4 weeks, the model control group is given distilled water with the volume corresponding to the body mass, and the positive control drug is rosiglitazone (3mg/kg RGZ). On the day of the glucose tolerance test, animals in each group were fasted for 3 to 5 hours, and blood glucose levels before (i.e., at 0 hour) glucose administration were measured, and after 15 to 20 minutes, 2.0g/kg body weight of glucose was orally administered to each group, and blood glucose levels after administration of glucose were measured at 0.5 and 2.0 hours in each group.
3. Experiment grouping
Diabetes model animal experiments: rats, which had been identified as diabetic models, were grouped:
(1) a normal animal group;
(2) model group, given equal volume of saline;
(3) a low dose monosaccharide formulation;
(4) a medium-dose monosaccharide compound group;
(5) a high dose monosaccharide formulation;
(6) and (4) a positive drug group. All groups were fed with high-sugar and high-fat diet at the same time, and the gavage monosaccharide compound and the positive control drug were continuously administered for 4 weeks. The treatment group was gavaged 2 times daily at AM9:00 and PM5:00 for 1 time each, rosiglitazone (3mg/kg, RGZ) was selected for the positive control for 1 gavage/day, and equal volume of saline was given 2 times daily to the negative control group and the model group. The effect of monosaccharide compositions on blood glucose was examined.
Normal animal experiments: SD (Spraque-Dawley) male rats, about 14 weeks old, weighing 283 ± 19g, were assigned to groups after 1 week of acclimation: (1) normal animal group, given equal volume of normal saline; (2) model animal group, given equal volume of physiological saline; (3-7) each monosaccharide group; (8) a small dose monosaccharide composition group; (9) a medium-dose monosaccharide composition group; (10) a group of high dose monosaccharide compositions; (11) and (4) a positive drug group.
The monosaccharide and the compound dosage are as follows:
l-arabinose: 1.2 g/kg;
d-mannose: 0.26/kg;
d-xylose: 0.24 g/kg;
d-psicose: 0.24/kg;
d-tagatose: 0.06 g/kg;
monosaccharide composition small dose group: monosaccharide composition dosage: 0.5g/kg of L-arabinose (0.3g), D-mannose (0.065g), D-xylose (0.06g), D-psicose (0.06g) and D-tagatose (0.015g) per kg of body weight;
dose groups in monosaccharide compositions: monosaccharide composition dosage: 1g/kg of each kilogram of body weight contains L-arabinose (0.6g), D-mannose (0.13g), D-xylose (0.12g), D-psicose (0.12g) and D-tagatose (0.03 g);
monosaccharide composition large dose group: monosaccharide composition dosage: 2g/kg of each kilogram of body weight contains L-arabinose (1.2g), D-mannose (0.26g), D-xylose (0.24g), D-psicose (0.24g) and D-tagatose (0.06 g);
positive control group: rosiglitazone (3mg/kg, RGZ) was selected and administered by gavage for 1 dose per day.
(II) results
1. Influence on blood sugar and glucose tolerance of diabetic model rats
After 4 weeks of continuous administration, the blood sugar of rats in the model control group has no obvious change, and L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose which are independently gazed have the function of slightly reducing the blood sugar in the experimental group. The blood sugar of rats with small, medium and large dosages of the monosaccharide combination is obviously reduced, the effect of the monosaccharide combination is greater than that of the monosaccharides, but the blood sugar reducing effect of the monosaccharide combination is obviously weaker than that of RGZ positive control groups (table 2).
TABLE 2 SD model rat Fasting Blood Glucose (FBG) variance (mean. + -. SEM)
n＝8，##p<0.01 compared to normal group; p<0.05，**p<0.01 was compared to the T2DM model group.
Rats were subjected to an Oral Glucose Tolerance Test (OGTT) at the end of 4 weeks of dosing. Blood glucose values of the OGTT of the rats in the T2DM model group at all time points are obviously higher than those of the normal group, and the rat is indicated to have abnormal glucose tolerance. The obtained results are shown in figure 1, the monosaccharide composition provided by the invention has the advantages that the blood sugar of rats with small, medium and large doses in various time points is obviously reduced, and the blood sugar reducing effect is better than that of the individual components. Compared with the positive control group RGZ, the monosaccharide composition has weaker effect.
FIG. 1 Effect of individual monosaccharides and monosaccharide combinations on glucose tolerance, RGZ, as a positive control drug. n is 8, mean ± sem,. p<0.05 compared to normal group;#p<0.05 was compared to the T2DM model group.
2. Influence on blood glucose and glucose tolerance of normal rats
After the monosaccharide composition of each dose group is continuously administered to normal rats for 4 weeks, only L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose are observed to have slight blood sugar reducing effect in the test group by intragastric gavage. The blood sugar of the monosaccharide composition in the medium and small dose groups is not remarkably reduced, the medium and large doses can realize the effect of reducing the fasting blood sugar of rats, and the blood sugar reducing effect of the monosaccharide composition in the large dose group is superior to that of the monosaccharide composition fed with L-arabinose alone. Meanwhile, the hypoglycemic effect is weaker than that of the RGZ positive control group (table 3).
TABLE 3 change in fasting plasma glucose (FBG) in Normal SD rats (mean. + -. SEM)
n-8, p <0.05 compared to the normal group.
Normal rats were subjected to Oral Glucose Tolerance Test (OGTT) at the end of 4 weeks of treatment. The results are shown in FIG. 2, and there was no significant difference between the groups of blood glucose values at each time point in the OGTT of rats.
FIG. 2 Effect of individual monosaccharides and monosaccharide combinations on glucose tolerance, RGZ as a positive control drug. n-8, mean ± sem.
(III) conclusion
After each monosaccharide and the monosaccharide composition provided by the invention are continuously administered for 4 weeks, only L-arabinose in a monosaccharide single administration group has the effect of reducing blood sugar in normal rats; the blood sugar of a small-dose group in each monosaccharide combination is not remarkably reduced, and the fasting blood sugar of a rat can be slightly reduced by medium and large doses without remarkable influence on the sugar tolerance; however, in the diabetes model rat, after the monosaccharide compound is continuously given for 4 weeks, each dosage of the monosaccharide composition group can slightly reduce the fasting blood glucose of the rat, correct abnormal glucose tolerance, reduce postprandial blood glucose and realize effective control on the blood glucose.
The result shows that the monosaccharide composition provided by the invention can effectively reduce the blood sugar of normal animals and diabetes model animals and improve the sugar tolerance of the diabetes model animals.
EXAMPLE 7 Effect of monosaccharide compositions on immunomodulation
Treg cells and Th17 cells have opposite roles in autoimmune and inflammatory diseases. Th17 cells promote autoimmunity, which Treg cells control. Thus, tregs pass control of CD4+The expansion and activation of T effector cells play an important self-tolerizing role in the pathological mechanisms of autoimmunity. Maintaining the Treg/Th17 cell balance plays a key role in the development of this type of disease. This example examines the effect of the monosaccharide compositions provided by the invention on immune modulation.
(I) Experimental method
1. Mouse model for rheumatoid arthritis
Balb/c male mice, weighing 25.3 + -2.4 g, were acclimatized for 1 week and were randomized: normal control group and rheumatoid arthritis mouse model group. The collagen II type of the model group mice is dissolved in 5mol/L acetic acid according to 0.1mg/0.1mL, the same volume of incomplete Freund's adjuvant is dripped in ice bath to prepare emulsion, subcutaneous injection is carried out on the abdomen, the back and the tail root of the mice at the dosage of 0.1 mL/mouse, injection is carried out every day in the whole experimental process, basic immunization is carried out, and the day is marked as day 1. The same procedure was used for boosting on day 21. On day 42, the success of model replication was evaluated using the joint swelling score criteria.
2. Joint swelling degree score
And (3) adopting a 0-4 grade scoring calculation method:
0 point, normal or no inflammation of toes;
1 point, swollen or mild redness of toe joints;
2 points, redness and swelling of the toe joints and toes;
3 points, redness and swelling of the entire paw below the ankle joint;
at 4 points, the ankle was severely red and swollen with evidence of deformity in the joint.
The cumulative sum of the limb joint scores was the polyarthritis index (AI) for each mouse. The AI value of more than or equal to 4 indicates the success of molding.
3. Flow cytometry detection of mouse peripheral blood Th17 and Treg
After administration, each group of mice was subjected to eye ball picking and blood sampling, peripheral blood of the mice was detected by a flow cytometer, and the ratio of Th17 cells and Treg cells in the peripheral blood was detected, and the method was completely performed according to the kit instructions. The kit used was a product of Becton, Dickinson and Company (BD) in the United states.
4. Experiment grouping
Normal mice, which had been identified as arthritis models, were grouped:
(1) normal animal group, given equal volume of normal saline;
(2) model animal group, given equal volume of physiological saline;
(3-7) each monosaccharide group;
(8) a small dose monosaccharide composition group;
(9) a medium-dose monosaccharide composition group;
(10) a high dose monosaccharide combination group;
(11) and (4) a positive drug group. The intragastric monosaccharide compound and the positive control drug are continuously given for 2 weeks. The treatment group was administered 2 times daily, 1 intragastrically at AM9:00 and PM5:00, respectively, the positive control group was administered hydrocortisone (10mg/kg) by intraperitoneal injection for 1 time per day, and the negative control group and the model group were administered 2 times daily with an equal volume of physiological saline.
The dosages of each component of the monosaccharide composition and the monosaccharide composition are as follows:
l-arabinose: 1.2 g/kg;
d-mannose: 0.26/kg;
d-xylose: 0.24 g/kg;
d-psicose: 0.24/kg;
d-tagatose: 0.06 g/kg;
monosaccharide composition small dose group: 0.5g/kg monosaccharide composition, wherein per kg body weight contains L-arabinose (0.3g), D-mannose (0.065g), D-xylose (0.06g), D-psicose (0.06g) and D-tagatose (0.015 g);
dose groups in monosaccharide compositions: 1g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (0.6g), D-mannose (0.13g), D-xylose (0.12g), D-psicose (0.12g) and D-tagatose (0.03 g);
monosaccharide composition large dose group: 2g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (1.2g), D-mannose (0.26g), D-xylose (0.24g), D-psicose (0.24g) and D-tagatose (0.06 g);
positive control group: hydrocortisone (10mg/kg) was selected for intraperitoneal injection 1 time/day.
(II) results
1. Influence on joint swelling of rheumatoid arthritis mice
From the 422 th day of modeling, after 2 weeks of continuous model administration, the results are shown in FIG. 3, and as can be seen from FIG. 3, only D-mannose was found to have a slight effect of suppressing the swelling of joints in the experimental group of L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose by gavage alone. The joint swelling degree of mice in each group with small, medium and large dosages of monosaccharide combination is obviously reduced, but the effect is obviously weaker than that of a positive control hydrocortisone group.
Effect of monosaccharides and combinations on joint swelling scores, hydrocortisone as a positive control drug. n-8, mean ± sem, × p <0.05, × p <0.01 were compared to the model group.
2. Influence on the ratio of TH17 cells to Treg cells of mice with rheumatoid arthritis
Compared with the normal group, the proportion of the mouse peripheral blood Th17 cells and the Treg cells is increased, the proportion of the model group mouse peripheral blood Th17 cells is increased, and the proportion of the Treg cells is reduced. In the experimental group of independently gavage L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose, only D-mannose is found to reduce the proportion of Th17 cells and increase the proportion of Treg cells. After the treatment of the small, medium and large dose groups of the monosaccharide composition, the Th17 cell proportion of each dose group is reduced to different degrees and the Treg cell proportion is increased compared with the model group, but the effect is weaker compared with the positive control medicament hydrocortisone. But the effect was much better than the results obtained with the monosaccharide composition alone, see table 4.
TABLE 4 Effect of Normal arthritic mice TH17 on Treg cells (mean. + -. SEM)
n＝8，##p<0.01 compared to normal group; p<0.05，**p<0.01 was compared to the model group.
As can be seen from table 4, the inhibitory effect of TH17 cell ratio was much lower than that of the monosaccharide composition provided by the present invention when each substance was used alone in the monosaccharide composition provided by the present invention. In the proliferation effect on Treg cells, the proportion of Treg cells of L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose is lower than that of each dosage group of the monosaccharide composition provided by the invention. The components in the monosaccharide composition provided by the invention exert synergistic effects, and the effects of the monosaccharide composition on TH17 cells and Treg cells are enhanced. The monosaccharide composition provided by the invention has a good control effect on arthritis and other inflammation related to motor skeletal muscle.
(III) conclusion
Treg cells are involved in the pathogenesis of a number of autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroiditis, autoimmune liver diseases, various kidney diseases, and the like. Treg cells have important significance for the occurrence and development of autoimmune diseases. After the rats continuously give the monosaccharide compound for 2 weeks, the D-mannose can reduce the proportion of Th17 cells and increase the proportion of Treg cells; the small, medium and large dose groups of the monosaccharide composition can slightly reduce the joint swelling degree of a joint rheumatoid arthritis mouse, recover abnormal proportion of TH17 cells and Treg cells in an inflammatory state, and obviously enhance the effect compared with the effect of D-mannose monosaccharide with an immunoregulation effect when being used alone. The study shows that the monosaccharide combination has obvious immunoregulation effect.
EXAMPLE 8 the effects of monosaccharide compositions on improving gut micro-ecology and modulating beneficial gut bacteria
The L-arabinose and the D-xylose in the monosaccharide composition provided by the invention have the functions of improving intestinal microorganisms and proliferating intestinal beneficial bacteria. The L-arabinose can promote the growth of beneficial intestinal flora such as bifidobacterium, lactobacillus and the like, promote the absorption of calcium by organisms, enhance the capability of the organisms to discharge toxic substances and inhibit the proliferation of harmful microorganisms by acidifying the intestinal tracts; meanwhile, nutrients such as vitamin B1, vitamin B2, vitamin B12, nicotinic acid, folic acid and the like can be generated in the metabolism process of the bifidobacterium, and the health-care function of various nutrients of a human body is realized. This example examines the effect of the monosaccharide compositions provided by the present invention on the intestinal flora.
(I) Experimental method
1. Mouse intestinal flora disorder model
Selecting Balb/c male mice with the body weight of 25.83 +/-2.2 g, adaptively feeding for 1 week, and randomly dividing into: normal control group and intestinal flora disorder to be modeled. Except 8 mice in the normal group, the other 40 mice were subjected to intragastric gavage with lincomycin for 0.3 mL/time, 2 times/d and 3 days continuously to prepare a mouse intestinal dysbacteriosis model. After the model is successfully prepared, the normal group of mice and the model group of mice are subjected to intragastric lavage by using normal saline with equal volume, and the positive control medicament is Lizhu Changle. The administration was continued for 14 days.
2. Preparation and culture of intestinal bacteria liquid
After the administration of each group, 0.1g of mouse feces is aseptically collected, diluted by 10 times in a dry sterilized test tube to prepare a suspension, centrifuged to obtain an intestinal bacterial solution, and inoculated on various selective culture media. After the culture, the number of bacteria in each gram of excrement is calculated by counting the number of bacterial colonies according to the colony morphology, gram staining microscopy, biochemical reaction and the like, and then the statistical treatment is carried out. The four gut bacteria culture conditions are listed in table 5:
TABLE 5 intestinal flora culture Medium and culture conditions
3. Experiment grouping
Normal mice and mice that will have been identified as models of disturbed intestinal flora were grouped:
(1) normal animal group, given equal volume of normal saline;
(2) model animal group, given equal volume of physiological saline;
(3-7) each monosaccharide group;
(8) a small dose monosaccharide composition group;
(9) a medium-dose monosaccharide composition group;
(10) a group of high dose monosaccharide compositions;
(11) and (4) a positive drug group. The gavage monosaccharide composition and the positive control drug were administered continuously for 2 weeks. The treatment group was gavaged 2 times daily at AM9:00 and PM5:00 times 1 each, Lizhu Changle (35mg/kg) was selected as a positive control, and an equal volume of physiological saline was given 2 times daily to the negative control group and the model group.
The dosages of each component of the monosaccharide composition and the monosaccharide composition are as follows: l-arabinose: 1.2 g/kg;
d-mannose: 0.26/kg;
d-xylose: 0.24 g/kg;
d-psicose: 0.24/kg;
d-tagatose: 0.06 g/kg;
monosaccharide composition small dose group: 0.5g/kg monosaccharide composition, wherein per kg body weight contains L-arabinose (0.3g), D-mannose (0.065g), D-xylose (0.06g), D-psicose (0.06g) and D-tagatose (0.015 g);
dose groups in monosaccharide compositions: 1g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (0.6g), D-mannose (0.13g), D-xylose (0.12g), D-psicose (0.12g) and D-tagatose (0.03 g);
monosaccharide composition large dose group: 2g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (1.2g), D-mannose (0.26g), D-xylose (0.24g), D-psicose (0.24g) and D-tagatose (0.06 g);
positive control group: lizhu Changle (35mg/kg) was selected for oral administration 1 time per day.
(II) results
After the monosaccharide compositions of the groups with small, medium and large doses and the monosaccharide compositions of the groups are treated, compared with the model group, the gavage of L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose is independently performed, and the gavage of L-arabinose and D-tagatose can promote the proliferation of beneficial flora and inhibit the proliferation of harmful bacteria; each dosage group of the monosaccharide composition can increase the number of bifidobacteria and lactobacilli in intestinal tracts, and the middle and large dosage groups can reduce the number of enterobacteria and enterococci, wherein the large dosage group is equivalent to the positive control medicament lizhulele. See table 6.
TABLE 6 variation of intestinal flora in mice (relative number, mean. + -. SEM under equal dilution conditions)
n＝8，*p<0.05，**p<0.01 compared to model set;##p<0.01 comparison with Normal group
As can be seen from table 6, the effect on the intestinal flora of mice when each substance in the monosaccharide composition provided by the present invention is used alone is much lower than that of the large dose group in the monosaccharide composition provided by the present invention. Particularly, in the inhibition effect on enterobacter, the monosaccharide composition provided by the invention has an obvious proliferation effect, and the proliferation effect on other beneficial bacteria is far better than that of each substance used alone.
(III) conclusion
The model that intestinal flora imbalance of mice is caused by lincomycin is used, and monosaccharide and compound are given for 2 weeks, so that the fact that the L-arabinose and the D-tagatose which are separately gazed can promote the proliferation of beneficial flora and inhibit the proliferation of harmful bacteria is found; the small, medium and large dosages of the monosaccharide combination have the function of regulating the intestinal flora of mice, can promote the proliferation of beneficial flora and limit the proliferation of harmful flora, and the function of the monosaccharide combination is obviously enhanced compared with the independent use of L-arabinose and D-tagatose monosaccharide with the flora regulating function. The effect of the large-dose group is equivalent to that of the positive control medicament Lizhu Changle.
EXAMPLE 9 Effect of monosaccharide compositions on controlling blood lipids
This example examines the effect of monosaccharide compositions on the blood lipids of rats in the hyperlipidemic model.
(I) Experimental method
1. Rat model with hyperlipidemia
SD (Spraque-Dawley) male rats are selected, aged about 10 weeks and have the body weight of 258 +/-22 g, and are randomly divided into a normal control group and a metabolic syndrome model-building group after being adaptively fed for 1 week. The groups were randomly divided into a normal control group (n-8) and a metabolic syndrome group (n-40).
During modeling, the rats in the normal control group are fed with basal feed, and the rats in the metabolic syndrome group are fed with high-sugar, high-fat and high-salt feed, free water and food intake. After 146w, rats of metabolic syndrome groups (40 successful) which are successfully molded are screened according to the body weight, the blood sugar level, the blood pressure level and the blood fat level. The rat basal feed formula comprises: crude protein is more than or equal to 18.0 percent, crude fat is more than or equal to 4.0 percent, crude fiber is less than or equal to 5.0 percent, water is less than or equal to 10.0 percent, ash is less than or equal to 8.0 percent, and calcium is 1.0 to 1.8 percent. And (3) high-fat feed formula: 63.8% of basal feed, 15% of lard oil, 10% of cane sugar, 1% of cholesterol, 0.2% of sodium cholate and 10% of egg yolk powder. Intervention 6w after the rats are fasted for 12h, the abdominal aorta is bled, the blood sample is stood for 2h at room temperature, centrifuged for 10min at 3800rpm, and the upper layer serum is taken and stored at-80 ℃ for later use. The serum Triglyceride (TG), Total Cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) determination kit is purchased from Nanjing institute of bioengineering.
2. Experiment grouping
Normal mice and hyperlipidemic rats were grouped:
(1) normal animal group, given equal volume of normal saline;
(2) model animal group, given equal volume of physiological saline;
(3-7) each monosaccharide group;
(8) a small dose monosaccharide composition group;
(9) a medium-dose monosaccharide composition group;
(10) a group of high dose monosaccharide compositions;
(11) and (4) a positive drug group. All groups were fed with high-sugar, high-fat diet simultaneously, and the gavage monosaccharide composition and the positive control drug were administered continuously for 6 weeks.
The treatment group was gavaged 2 times daily at AM9:00 and PM5:00 times, respectively, 1 gavage was performed for the positive control, simvastatin (2.5mg/kg, RGZ) was selected for the positive control, and 2 times daily equal volume of physiological saline was administered for the negative control and model groups. The preparation method and the composition of each material of the monosaccharide composition were the same as in example 6.
The dosages of each component of the monosaccharide composition and the monosaccharide composition are as follows:
l-arabinose: 1.2 g/kg;
d-mannose: 0.26/kg;
d-xylose: 0.24 g/kg;
d-psicose: 0.24/kg;
d-tagatose: 0.06 g/kg;
monosaccharide composition small dose group: 0.5g/kg monosaccharide composition, wherein per kg body weight contains L-arabinose (0.3g), D-mannose (0.065g), D-xylose (0.06g), D-psicose (0.06g) and D-tagatose (0.015 g);
dose groups in monosaccharide compositions: 1g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (0.6g), D-mannose (0.13g), D-xylose (0.12g), D-psicose (0.12g) and D-tagatose (0.03 g);
monosaccharide composition large dose group: 2g/kg of monosaccharide composition, wherein each kg of body weight contains L-arabinose (1.2g), D-mannose (0.26g), D-xylose (0.24g), D-psicose (0.24g) and D-tagatose (0.06 g);
positive control group: simvastatin (2.5mg/kg) was selected for intragastric administration 1 time/day.
(II) results
The model control group rats have obvious blood fat height, and after continuous administration for 6 weeks, L-arabinose and D-psicose in the monosaccharide group show certain lipid-lowering effect; the blood lipid of rats in small, medium and large doses of the monosaccharide composition is obviously reduced, but the blood lipid reducing effect is obviously weaker than that of simvastatin as a positive control (table 7).
TABLE 7 SD model rat blood lipid profile (mean. + -. SEM, mmol/L)
n＝8，*p<0.05，**p<0.01 compared to model set;##p<0.01 comparison with Normal group
As can be seen from table 7, the effect of each substance in the monosaccharide composition provided by the present invention on rat blood lipids is much lower than that of the large dose group in the monosaccharide composition provided by the present invention when used alone.
(III) conclusion
After the monosaccharide composition is fed to a high-fat fed rat model for 6 weeks, small, medium and large doses of the monosaccharide composition are found to have the function of regulating the blood fat of the rat, remarkably reduce total cholesterol, total triglyceride and low-density lipoprotein cholesterol, and improve the blood fat composition. The effect is obviously enhanced compared with the independent use of L-arabinose monosaccharide and D-psicose monosaccharide with the effect of reducing blood fat.
The above description is only for the purpose of illustrating the present invention and is not intended to limit the present invention in any way, and the present invention is not limited to the above description, but rather should be construed as being limited to the scope of the present invention.
Claims (11)
1. A monosaccharide composition consisting of L-arabinose, D-mannose, D-xylose, D-psicose and D-tagatose;
wherein L-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is 1-20: 1-20: 1-20: 1-20: 1.
2. the monosaccharide composition according to claim 1,
l-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is 1-10: 1-10: 1-10: 1-10: 1.
3. the monosaccharide composition according to claim 1,
l-arabinose: d-mannose: d-xylose: d-psicose: the mass ratio of the D-tagatose is 3-10: 1-10: 1-10: 1-10: 1.
4. a pharmaceutical formulation of a monosaccharide composition, comprising: a monosaccharide composition according to any one of claims 1 to 3 which has an L-arabinose content of from 1 to 15g per unit formulation.
5. The pharmaceutical formulation of claim 4,
the monosaccharide composition has an L-arabinose content of 1-5g per unit preparation.
6. Use of a monosaccharide composition for the preparation of a medicament for the prevention and/or treatment of diabetes mellitus, wherein the monosaccharide composition is according to any one of claims 1 to 3.
7. The use according to claim 6, wherein the monosaccharide composition is administered in an amount of 30 to 120mg/kg body weight of L-arabinose.
8. Use of a monosaccharide composition for the manufacture of a medicament for controlling postprandial blood glucose, wherein the monosaccharide composition is according to any one of claims 1 to 3.
9. The use according to claim 8,
the monosaccharide composition is calculated by the dosage of L-arabinose of 30-120 mg/kg body weight.
10. Use of a monosaccharide composition for the preparation of a medicament for immunomodulation, wherein the monosaccharide composition is according to any one of claims 1 to 3.
11. The use according to claim 10, wherein the monosaccharide composition is administered in an amount of 30 to 120mg/kg body weight of L-arabinose.
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