CN112755055B - Application of lactobacillus plantarum NA136 and cannabidiol monomer combination in preparation of product for treating rheumatoid arthritis - Google Patents
Application of lactobacillus plantarum NA136 and cannabidiol monomer combination in preparation of product for treating rheumatoid arthritis Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The application of the combination of lactobacillus plantarum NA136 and cannabidiol monomer in the preparation of products for treating rheumatoid arthritis belongs to the field of functional food microorganisms. Wherein the concentration of Lactobacillus plantarum NA136 is 2 × 10 9 ～2×10 10 A CFU; the concentration of cannabidiol monomer is 2.4mg/mL; lactobacillus plantarum NA136 was used separately from cannabidiol monomer. Experiments prove that the joint application of the lactobacillus plantarum NA136 strain and the cannabidiol monomer can relieve the arthritis symptom of rats; reducing bone erosion and cartilage degradation; reducing inflammatory reaction, reducing the level of inflammatory factors IL-17 and TNF-alpha, and improving the level of anti-inflammatory factors IL-10; reducing the content of lipopolysaccharide in serum; immunoglobulin IgG levels were reduced during the onset of rheumatoid arthritis. The invention has the function of preventing and/or treating rheumatoid arthritis.
Description
Technical Field
The invention belongs to the technical field of functional food microorganisms, and particularly relates to an application of lactobacillus plantarum NA136 and cannabidiol monomer in preparation of a product for treating rheumatoid arthritis.
Background
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease, with joint pain, joint capsule swelling, lesions, etc. as the main manifestations. The occurrence and development of RA are related to the release of a large number of inflammatory cytokines and inflammatory mediators, and the main pathological change is chronic synovitis which gradually shows cartilage and bone destruction, and finally causes joint deformity and even joint function loss of patients. Epidemiological investigation shows that about 0.5 to 1 percent of people worldwide suffer from rheumatoid arthritis, and the prevalence rate of China is about 0.32 to 0.36 percent.
At present, no medicament for fundamentally treating RA exists in clinic. At present, the western medicine mainly adopts methods such as drug therapy, gene therapy and the like. The common western medicines mainly comprise non-steroidal anti-inflammatory drugs, glucocorticoids, immunosuppressants, biological agents and the like. Although these drugs can improve the symptoms of RA to some extent and inhibit bone destruction, they have strong toxic and side effects, such as inhibiting the immune function of the body and inducing severe adverse reactions such as infection of RA patients, when used for a long time. Therefore, the search for safe and effective drugs for treating RA is of great significance.
Disclosure of Invention
The invention aims to provide application of lactobacillus plantarum NA136 and cannabidiol monomer in preparation of a product for treating rheumatoid arthritis, so as to solve the problems in the existing rheumatoid arthritis treatment process.
The technical scheme adopted by the invention for solving the technical problem is as follows:
the lactobacillus plantarum NA136 and the cannabidiol monomer are combined to be applied to preparation of products for treating rheumatoid arthritis.
In a preferred embodiment, the concentration of Lactobacillus plantarum NA136 is 2X 10 9 ～2×10 10 A CFU; the concentration of the cannabidiol monomer is 2.4mg/mL; the lactobacillus plantarum NA136 and cannabidiol monomers were used separately.
As a preferred embodiment, the lactobacillus plantarum NA136 has been deposited in the chinese collection of type cultures on 11/3/2018 under the following accession number: CCTCC NO: M2018112.
In a preferred embodiment, the Lactobacillus plantarum NA136 is used by suspending it in 2% Tween-80 physiological saline at a concentration of 2X 10 9 ～2×10 10 CFU。
In a preferred embodiment, the cannabidiol monomer is dissolved in 2% tween-80 saline at a concentration of 2.4mg/mL when used.
In a preferred embodiment, the cannabidiol monomer has a purity of 99% or greater.
As a preferred embodiment, the cannabidiol monomer is prepared using the following method:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting twice, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing the water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
As a preferred embodiment, the product is a pharmaceutical product.
As a more preferred embodiment, the product functions as at least one of (1) to (7):
(1) Alleviating the symptoms of arthritis;
(2) Reduction of bone erosion and cartilage degradation;
(3) Reducing the level of inflammatory factor IL-17;
(4) Reducing the level of inflammatory factor TNF-alpha;
(5) Increasing the level of anti-inflammatory factor IL-10;
(6) Reducing the content of lipopolysaccharide in serum;
(7) Reduces immunoglobulin IgG levels.
The invention has the beneficial effects that:
the invention adopts a collagen type rheumatoid arthritis rat model, and the combined application of the lactobacillus plantarum (L.plantarum) NA136 strain, the cannabidiol monomer, the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer is administered for 28 days through gastric lavage, so that the treatment effect of the combined application of the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer on the collagen type rheumatoid arthritis rat model is discussed. Research results show that the combined application of the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer can relieve arthritis symptoms; reducing bone erosion and cartilage degradation; reducing inflammatory reaction, reducing the level of inflammatory factors IL-17 and TNF-alpha, and increasing the level of anti-inflammatory factors IL-10; reducing the content of Lipopolysaccharide (LPS) in serum; immunoglobulin IgG levels were reduced during the onset of rheumatoid arthritis.
Therefore, the lactobacillus plantarum (L.plantarum) NA136 strain provided by the invention and the cannabidiol monomer are jointly applied, so that the effect of preventing and/or treating rheumatoid arthritis is achieved, the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer can be used for preparing products for resisting rheumatoid arthritis, including medicines and the like, and the composition of the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer provided by the invention can be applied to the fields of medicines and the like, so that the application prospect is very wide.
Drawings
FIG. 1 shows the results of arthritis scoring in collagen-type arthritis rats.
FIG. 2 shows the results of histopathological analysis of collagen arthritis rat joints. In the figure, A is a control group; b is a model group; c is Lactobacillus plantarum NA136 group; d is a cannabidiol monomer group; e is the NA136+ cannabidiol monomer group.
FIG. 3 shows the measurement results of LPS content in rat serum.
FIG. 4 shows the measurement results of IgG content in rat serum.
Detailed Description
The invention relates to an application of lactobacillus plantarum NA136 (L.plantarum) and cannabidiol monomer in preparation of a product for treating rheumatoid arthritis.
Preferably, the concentration of Lactobacillus plantarum NA136 (L.plantarum) is 2X 10 9 ～2×10 10 CFU; the concentration of cannabidiol monomer is 2.4mg/mL; lactobacillus plantarum NA136 (l.plantarum) and cannabidiol monomer were used separately.
Preferably, lactobacillus plantarum NA136 (l.plantarum) has been deposited in the chinese collection of type cultures on day 11, 3/2018 at the address: eight-path Wuhan university school (Wuhan university collection center) 299 in Wuchang area, wuhan city, hubei province has the collection number: CCTCC NO of M2018112.
Preferably, lactobacillus plantarum NA136, when used, is suspended in 2% Tween-80 physiological saline at a concentration of 2X 10 9 ～2×10 10 CFU。
Preferably, cannabidiol monomer, when used, is dissolved in 2% tween-80 saline at a concentration of 2.4mg/mL.
Preferably, the purity of the cannabidiol monomer is more than or equal to 99%.
Preferably, the cannabidiol monomer is prepared by the following method:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting twice, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
Preferably, the product is a pharmaceutical product.
More preferably, said product has at least one of the functions (1) to (7):
(1) Alleviating the symptoms of arthritis;
(2) Reduction of bone erosion and cartilage degradation;
(3) Reducing the level of inflammatory factor IL-17;
(4) Reducing the level of inflammatory factor TNF-alpha;
(5) Increasing the level of anti-inflammatory factor IL-10;
(6) Reducing the content of lipopolysaccharide in serum;
(7) Reduces immunoglobulin IgG levels.
The lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer are taken in daily time intervals, namely, are not taken at the same time to replace the medicine for treating rheumatoid arthritis, so that the diameter of the ankle joint of a rat can be reduced; reduction of bone erosion and cartilage degradation; reducing inflammatory reaction, reducing the level of inflammatory factors IL-17 and TNF-alpha, and increasing the level of anti-inflammatory factors IL-10; reducing the content of Lipopolysaccharide (LPS) in serum; immunoglobulin IgG levels were reduced during the onset of rheumatoid arthritis. Has effects of preventing and treating rheumatoid arthritis, and has advantages of safety and no adverse side effects.
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The test materials used in the following examples were obtained from conventional biochemicals unless otherwise specified. In the quantitative tests in the following examples, three replicates were set up and the results averaged.
Experimental materials:
liquid MRS medium: the solvent is water, and contains peptone 10g/L, beef extract 10g/L, yeast extract 5g/L, KH 2 PO 4 2g/L, sodium acetate 5g/L, sodium citrate 5g/L, mgSO 4 ·7H 2 O 0.2g/L、MnSO 4 ·4H 2 O0.05 g/L, tween-80 mL/L, glucose 20g/L; pH6.6.
SD rats (body weight 180-220 g): cincha Changchun city Yinshi laboratory animal technology, inc.
Basic feed: changchun city yi si laboratory animal technology Limited liability company.
Cannabidiol monomer: selecting fresh industrial hemp flowers and leaves, air-drying, weighing 500g of the air-dried industrial hemp flowers and leaves, adding 20 times of food-grade ethanol (95%), heating, refluxing and extracting twice, filtering, combining filtrates, and recovering a solvent under reduced pressure to obtain an extract containing cannabidiol; putting the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, discarding the water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol, separating cannabidiol with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
Detecting the content of TNF-alpha in serum by adopting a Jiangsu enzyme-labeled rat tumor necrosis factor (TNF-alpha) ELISA kit; detecting the content of IL-17 in serum by adopting a Jiangsu enzyme-labeled rat interleukin 1 beta (IL-1 beta) ELISA kit; detecting the content of IL-10 in serum by adopting a Jiangsu enzyme-labeled rat interleukin 10 (IL-10) ELISA kit; detecting the content of IgG in serum by adopting a Jiangsu enzyme-labeled rat immunoglobulin IgG (IgG) ELISA kit; and (3) detecting the content of LPS in serum by adopting an ELISA kit of Jiangsu enzyme-labeled rat endotoxin (LPS).
Among them, freund's complete adjuvant was purchased from Sigma, USA, and type II collagen was purchased from Beijing Boleigdeko technology development Co.
Example 1 Effect of Lactobacillus plantarum NA136 Strain, cannabidiol monomer, lactobacillus plantarum NA136 Strain in combination with cannabidiol monomer on collagen arthritis model rats
1. Establishment and grouping of animal models
Fully emulsifying the calf cartilage type II collagen with Freund's incomplete adjuvant to obtain a modeling agent, dissolving 20mg of the calf cartilage type II collagen in 10mL of acetic acid with the concentration of 0.1mol/L, and fully emulsifying with the same amount of complete Freund's adjuvant after overnight at 4 ℃.
First immunization: 150. Mu.L/rat of the model agent was injected subcutaneously at a distance of 1.5cm from the root of the rat tail.
And (3) second immunization: after 7d, the same procedure was used for boosting, i.e., 150. Mu.L/mouse of the model agent was injected subcutaneously 2.0cm from the root of the rat tail. The red swelling status of the paw and ankle of the rat was observed one week after the booster immunization to score the arthritis clinical symptoms.
The arthritis clinical symptom scoring criteria were as follows: 0 minute: the joints were free of erythema and swelling; 1 minute: swelling and/or redness of 1 joint; and 2, dividing: swelling or redness of 2 joints; dividing into: greater than 2 joints swelling or redness; and 4, dividing: inflammation of the red joints of the entire paw is severe. One rat scored 4 paws separately with a maximum score of 16 per rat.
The standard that the arthritis index score is more than or equal to 4 is used as the standard for judging the success of the model. 40 successfully modeled male SD rats were randomly divided into 4 groups: model group, NA136 group, cannabidiol monomer group, NA136+ cannabidiol monomer group, 10 per group; the control group was 10 unmodeled male SD rats. The injection is carried out 7d after the second immunization, and the control group and the model group are respectively injected with 2% Tween-80 physiological saline 2mL/d at 9 and 16 per day; the NA136 group is perfused with 2% tween-80 normal saline 2mL/d at 00 per day, and the bacterial strain NA1362mL/d at 00 per day is perfused with 16; the cannabidiol monomer group comprises 2mL/d of 9; the NA136+ cannabidiol monomer group was administered for 28 days at 2mL/d for 9 00 gavage cannabidiol monomer solution, 2mL/d for 16. After the test is finished, the heart of each group of rats is bled, centrifuged at 3000r/min for 15min, and serum is collected.
2. Rat ankle joint clinical symptomatic inflammation scoring and joint pathological section
The arthritis indexes of the four limbs of the rats are scored by using a five-grade scoring standard of the arthritis indexes, and the scoring results are shown in figure 1. The result shows that the lactobacillus plantarum NA136 or cannabidiol monomer is perfused for 4 weeks continuously, and the arthritis index score of the rat is reduced; after the lactobacillus plantarum NA136 and the cannabidiol monomer are used in a combined interference mode, the arthritis index score of a rat is reduced most obviously, the foot swelling of the rat is basically eliminated, and the activity is flexible.
Reference to a of fig. 2 is a control group. After the second immunization, the joints of the model group rheumatoid arthritis rats exhibited inflammatory cell recruitment, significant bone erosion and synovial cell layer destruction (as indicated by the arrows in B of fig. 2). After gavage with lactobacillus plantarum NA136 or cannabidiol monomer 28D, the synovial tissue was significantly improved (as shown in fig. 2C and fig. 2D). The synovial tissue was substantially restored to normal following the combined use of lactobacillus plantarum NA136 and cannabidiol monomer intervention (as shown in E of figure 2).
3. Detection of related indexes in serum
RA onset is associated with intestinal flora disturbance. Disturbance of the intestinal flora causes an increase of LPS, which crosses the intestinal wall, causing an inflammatory reaction. As shown in FIG. 3, the LPS content in the serum of the model group was 41.67EU/L, which was nearly two-fold higher than that in the serum of the control group (22.80 EU/L). There was a reduction in LPS following lactobacillus plantarum NA136 or cannabidiol monomer intervention. After the combination of Lactobacillus plantarum NA136 and cannabidiol monomer dry-out, the value of LPS in serum was reduced to 25.82EU/L, which is 38.03% lower than that in the model group, and the difference is very significant (p < 0.01). The results are shown in Table 1.
TABLE 1 Effect of Lactobacillus plantarum NA136 in combination with cannabidiol monomer on inflammatory factors in serum of collagen type arthritic rats
| Group of | TNF-α(pg/mL) | IL-17(pg/mL) | IL-10(pg/mL) |
| Control group | 66.77±4.31 ** | 2.13±0.33 ** | 90.26±4.21 ** |
| Model set | 223.98±9.16 | 3.70±0.28 | 20.98±5.93 |
| NA136 group | 113.98±4.55 ** | 2.65±0.17 ** | 64.31±3.88 ** |
| Cannabidiol monomer group | 110.99±8.77 ** | 2.31±0.22 ** | 57.39±4.64 ** |
| NA136+ cannabidiol monomer set | 78.10±5.93 ** | 2.23±0.14 ** | 87.73±6.35 ** |
* Differences were very significant compared to the model group (p < 0.01).
During the onset of RA, the levels of inflammatory cytokines such as TNF- α, IL-17, etc., are elevated and the levels of the anti-inflammatory cytokine IL-10 are reduced, which aggravate the inflammatory response and cause damage to the synovial membrane and articular cartilage. The content change of three cytokines which have key effects in the RA attack is detected, the lactobacillus plantarum NA136 and the cannabidiol monomer are combined to have anti-inflammatory effect, so that the levels of TNF-alpha and IL-17 of collagen arthritis rats are reduced, and the difference is very obvious (p is less than 0.01); the level of the IL-10 which is reduced pathologically is increased, the difference is very obvious (p is less than 0.01), thereby the disease condition is relieved, and the disease degree is reduced.
The initiation factor inducing RA can make the organism produce IgG antibody and change the molecular structure of the IgG antibody, thereby stimulating the formation of rheumatoid factor. As shown in fig. 4, the immune index IgG of the model group rats was significantly increased, and the expression of IgG was reduced after the intervention of lactobacillus plantarum NA136 or cannabidiol monomer. After the lactobacillus plantarum NA136 and cannabidiol monomer are combined for use, the IgG value in the serum is reduced to 0.82mg/mL, and the difference is very obvious (p is less than 0.01).
In conclusion, the lactobacillus plantarum (L.plantarum) NA136 strain and the cannabidiol monomer are taken in daily time intervals to replace the medicine for treating rheumatoid arthritis, so that the arthritis symptoms can be relieved; reducing bone erosion and cartilage degradation; reducing inflammatory reaction, reducing the level of inflammatory factors IL-17 and TNF-alpha, and improving the level of anti-inflammatory factors IL-10; reducing the content of Lipopolysaccharide (LPS) in serum; immunoglobulin IgG levels were reduced during the onset of rheumatoid arthritis. Has effects of preventing and treating rheumatoid arthritis, and has advantages of safety and no adverse side effects.
The invention discloses application of lactobacillus plantarum NA136 and cannabidiol monomer in preparation of a product for treating rheumatoid arthritis. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that the technology can be practiced and applied by modifying or appropriately combining the products described herein without departing from the spirit and scope of the invention.
Claims (5)
1. The application of the combination of lactobacillus plantarum NA136 and cannabidiol monomer in the preparation of medicaments for treating rheumatoid arthritis; the lactobacillus plantarum NA136 is preserved in the China center for type culture Collection in 2018, 3 and 11 months, and the preservation numbers are as follows: CCTCC NO: M2018112.
2. The use of claim 1 wherein cannabidiol monomer, when used, is dissolved in 2% tween-80 saline at a concentration of 2.4mg/mL.
3. The use of claim 1, wherein the cannabidiol monomer is at least 99% pure.
4. The use of claim 1, wherein the cannabidiol monomer is prepared by:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp flower leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting for two times, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
5. The use according to claim 1, wherein the function of the drug is at least one of (1) to (7):
(1) Alleviating the symptoms of arthritis;
(2) Reduction of bone erosion and cartilage degradation;
(3) Reducing the level of inflammatory factor IL-17;
(4) Reducing the level of inflammatory factor TNF-alpha;
(5) Increasing the level of anti-inflammatory factor IL-10;
(6) Reducing the content of lipopolysaccharide in serum;
(7) Reduces immunoglobulin IgG levels.
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