CN115137721A - Application of citrulline or pharmaceutically acceptable salt thereof in preparation of medicine for improving immunity - Google Patents
Application of citrulline or pharmaceutically acceptable salt thereof in preparation of medicine for improving immunity Download PDFInfo
- Publication number
- CN115137721A CN115137721A CN202210892692.XA CN202210892692A CN115137721A CN 115137721 A CN115137721 A CN 115137721A CN 202210892692 A CN202210892692 A CN 202210892692A CN 115137721 A CN115137721 A CN 115137721A
- Authority
- CN
- China
- Prior art keywords
- citrulline
- pharmaceutically acceptable
- acceptable salt
- matrix metalloproteinase
- immunity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention provides application of citrulline or pharmaceutically acceptable salt thereof in preparing medicines, a method for improving the activity of matrix metalloproteinase 7, a method for up-regulating the gene expression level of coded matrix metalloproteinase 7 and a pharmaceutical composition for improving immunity, wherein the citrulline or pharmaceutically acceptable salt thereof can effectively improve the immunity, and has important research value and clinical application value for improving the immunity.
Description
Technical Field
The present invention relates to the field of medicine. Specifically, the invention relates to application of citrulline or pharmaceutically acceptable salt thereof in preparing a medicine for improving immunity.
Background
In the case of young animals or humans, physical weakness, diseases, stress, pathogenic infection, etc., the immunity is liable to be lowered, and secondary infection (mixed infection of bacteria or viruses) occurs, causing inflammatory reaction (red, heat, swelling, pain, etc.) and intestinal dysfunction. At present, for the treatment of infection, the traditional and commonly used prevention and treatment strategy is to use antibiotics and hormone anti-inflammatory drugs (such as hydrocortisone, dexamethasone and the like), although the traditional and commonly used prevention and treatment strategy can effectively control infectious inflammation and non-infectious inflammation, the continuous use can cause various side effects: such as serious disorders of water and salt metabolism and sugar, fat and protein metabolism, and cause deterioration of adrenal cortex function, complications of digestive system or aggravated infection.
Therefore, the stability of the immune function of the human body is the key to maintaining the stability of the environment in the organism, and has very important physiological significance for the normal exertion of various functions of the organism. At present, drugs for improving immunity are still to be researched.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the invention provides the application of citrulline or pharmaceutically acceptable salt thereof in preparing medicines, a method for improving the activity of matrix metalloproteinase 7, a method for up-regulating the gene expression level of coded matrix metalloproteinase 7 and a pharmaceutical composition for improving immunity, wherein the citrulline or pharmaceutically acceptable salt thereof can effectively improve the immunity, and has important research value and clinical application value for improving the immunity.
In one aspect of the invention, the invention proposes the use of citrulline or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. According to an embodiment of the invention, the medicament is for enhancing immunity.
In another aspect of the invention, the invention features a method for increasing the activity of matrix metalloproteinase 7. According to an embodiment of the invention, the method comprises: contacting a matrix metalloproteinase with citrulline or a pharmaceutically acceptable salt thereof.
In still another aspect of the present invention, the present invention provides a method for up-regulating the expression level of a gene encoding matrix metalloproteinase 7. According to an embodiment of the invention, the method comprises: citrulline or a pharmaceutically acceptable salt thereof is co-cultured with cells or tissue containing a gene encoding matrix metalloproteinase 7.
In yet another aspect of the present invention, the present invention provides a pharmaceutical composition for enhancing immunity. According to an embodiment of the invention, the pharmaceutical composition comprises citrulline or a pharmaceutically acceptable salt thereof.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows a small intestine MMP7 immunohistochemistry for wild type and mtDNA mutant mice according to example 1 of the present invention;
FIG. 2 shows a small intestinal metabolite detection map of wild type and mtDNA mutant mice according to example 1 of the present invention (n.gtoreq.4,. Sup.p < 0.05, independent t-test);
fig. 3 shows a small intestine MMP7 immunohistochemistry map after citrulline administration to mtDNA mutant mice according to example 2 of the present invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.
The invention provides application of citrulline or pharmaceutically acceptable salt thereof in preparing medicines, a method for improving the activity of matrix metalloproteinase 7, a method for up-regulating the expression level of a gene encoding matrix metalloproteinase 7 and a pharmaceutical composition for improving immunity, which are respectively described in detail below.
Application of citrulline in preparation of medicine
In one aspect of the invention, the invention proposes the use of citrulline, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. According to an embodiment of the invention, the medicament is for enhancing immunity.
The POLG mutant mouse has a D257A mutation at the position of POLG exonuclease so that the exonuclease activity of the POLG mutant mouse is lost, correction defects in the mtDNA replication process are caused, mtDNA mutation is caused, and the POLG mutant mouse is a well-known mouse model for researching mtDNA mutation, and the mtDNA mutant mouse model can generate low immunity symptoms and is reflected in that the expression level of matrix metalloproteinase 7 (MMP 7) is reduced. MMP7 is mainly a precursor of shearing defensins, thereby producing functional defensins, regulating intestinal mucosal reaction through antibacterial reaction, and maintaining intestinal-intestinal microbial balance. The reduction of MMP7 expression level will result in the imbalance of intestinal flora in mice.
Further, the inventors conducted metabolomics studies on the small intestine of mtDNA mutant mouse models, and found that the small intestine citrulline specificity was decreased in the mouse models. Further, by administering citrulline to mtDNA mutant mouse model, MMP7 expression was significantly increased. Therefore, citrulline can improve MMP7 expression level and is beneficial to improving the immunity of the organism. At the same time, anxiety symptoms were alleviated in mtDNA mutant mice.
The stability of human immune function is the key to maintaining the stability of the environment in the body, the occurrence of a plurality of diseases is related to low immunity, and citrulline and pharmaceutically acceptable salts thereof are further helpful for preventing or treating Alzheimer's disease, parkinson's disease and cancers, such as breast cancer, lung cancer, nasopharyngeal cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, melanoma, skin cancer, prostate cancer, cervical cancer, leukemia, thyroid cancer, lymphoma, bladder cancer, kidney cancer, uterine body cancer, ovarian cancer, gallbladder cancer, oral cancer, laryngeal cancer, bone cancer, testicular cancer or brain cancer and the like on the basis of improving the immunity.
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
According to an embodiment of the invention, the medicament is for the prevention or treatment of a disturbance of the intestinal flora. As described above, citrulline or a pharmaceutically acceptable salt thereof can increase the MMP7 expression level, and thus can contribute to the prevention or treatment of intestinal dysbacteriosis.
According to an embodiment of the present invention, the medicament is for increasing the activity of matrix metalloproteinase 7 or up-regulating the expression level of a gene encoding matrix metalloproteinase 7.
According to an embodiment of the invention, the drug is targeted to the brain-gut axis. The brain-gut axis (brain-gut axis) refers to a two-way information communication network between the brain and the gut, and broadly includes neural interaction pathways, neuroendocrine and neuroimmune pathways, gut microbiota, and the like. The inventor carries out detection and analysis on mouse metabolites with low immunity and finds that citrulline in small intestine is reduced, and the small intestine is directly related to the brain intestinal axis. After the citrulline is given to the mice, the low immunity of the mice is relieved, so that the action target point of the citrulline is shown to be the brain-intestine axis.
According to an embodiment of the present invention, the administration mode of the drug is oral or enema. As mentioned above, citrulline can improve immunity by targeting the brain-intestine axis, so that the citrulline can act on the brain-intestine axis to better exert drug effect by adopting an oral administration mode or an enema mode.
The administration frequency and dose of the inventive drug can be determined by a variety of relevant factors, including the type of disease to be treated, the administration route, the age, sex, body weight and severity of the disease of the patient, and the type of drug as an active ingredient. According to some embodiments of the invention, the daily dose may be divided into 1, 2 or more doses in a suitable form for administration 1, 2 or more times over the entire period, as long as a therapeutically effective amount is achieved.
Method for increasing activity of matrix metalloproteinase 7
In another aspect of the invention, the invention features a method of increasing the activity of matrix metalloproteinase 7. According to an embodiment of the invention, the method comprises: contacting matrix metalloproteinase 7 with citrulline or a pharmaceutically acceptable salt thereof. By contacting citrulline or a pharmaceutically acceptable salt thereof with matrix metalloproteinase 7, the activity of matrix metalloproteinase 7 can be increased, thereby facilitating scientific research on matrix metalloproteinase 7.
Method for up-regulating gene expression level of coded matrix metalloproteinase 7
In still another aspect of the present invention, the present invention provides a method for up-regulating the expression level of a gene encoding matrix metalloproteinase 7. According to an embodiment of the invention, the method comprises: citrulline or a pharmaceutically acceptable salt thereof is co-cultured with cells or tissue containing a gene encoding matrix metalloproteinase 7. Under the condition suitable for cell or tissue culture, citrulline can effectively improve the expression level of the gene coding the matrix metalloproteinase 7, thereby being beneficial to scientific research on the matrix metalloproteinase 7 and the coding gene thereof.
Pharmaceutical composition for improving immunity
In yet another aspect of the present invention, the present invention provides a pharmaceutical composition for enhancing immunity. According to an embodiment of the invention, the pharmaceutical composition comprises citrulline or a pharmaceutically acceptable salt thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises: pharmaceutically acceptable auxiliary materials.
The invention does not strictly limit the types of the auxiliary materials and can flexibly select the auxiliary materials according to the conditions. For injectable formulations, pharmaceutically acceptable carriers may include buffers, preservatives, analgesics, solubilizers, isotonic agents (isotonicagents) and stabilizers. For formulations for topical administration, pharmaceutically acceptable carriers may include bases, excipients, lubricants, and preservatives. The pharmaceutical composition of the present invention may be prepared in various dosage forms in combination with the above pharmaceutically acceptable carrier. For injectable preparations, the pharmaceutical compositions may be prepared in ampoules, e.g. in single dose dosage form, or in unit dosage forms, e.g. in multidose containers. The pharmaceutical compositions may also be formulated as solutions, suspensions, tablets, pills, capsules and depot preparations. Among the excipients and diluents suitable for pharmaceutical formulations according to some embodiments of the present invention may be, among others: lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. According to other embodiments of the present invention, the adjuvants of the present invention may further comprise fillers, anticoagulants, lubricants, moisturizers, fragrances, and preservatives.
The scheme of the invention will be explained with reference to the following examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
1. In this example, a wild mouse 8 months old and an mtDNA mutant mouse were selected, and expression of intestinal MMP7 was detected by an immunohistochemical experiment, which included the following steps:
(1) The materials are obtained. Taking a small intestine section of about 3-5cm, flushing chyme in the small intestine section by using a cold PBS solution, and paying attention to flushing strength to avoid damaging the small intestine structure. The sections were then completely soaked in 4% paraformaldehyde and fixed for 2 days.
(2) Dewaxing and hydrating. The following treatments were performed on the slices in sequence: the xylene is soaked twice, and new xylene is replaced each time, and each time lasts for five minutes; soaking with 100% alcohol twice, and replacing with new 100% alcohol each time for 3 min each time; soaking in 90% alcohol for 3 min; soaking in 80% alcohol for 3 min; soaking in 70% alcohol for 3 min; soaking in distilled water for 1 minute; three times for 5 minutes each, in Phosphate Buffered Saline (PBS).
(3) And (3) performing microwave antigen retrieval. The EDTA antigen retrieval solution (50X, pH 9) was diluted to 1X with PBS, the sections were immersed in 1X EDTA antigen retrieval solution, heated in a microwave oven with 100 firepower at high temperature for 10 minutes and 50 firepower at low temperature for 10 minutes in this order, and then the slides were taken out and allowed to cool naturally. After cooling, the sections were soaked three times in PBS solution. Each time for 5 minutes. A hydrophobic circle is drawn on the tissue block using the organized strokes. The next step will be performed using a two-step immunohistochemistry kit (cat # E-IR-R217-18 mL) from Irelet. 50 μ l of E-IR-R217C (3% H2O 2) reagent was added dropwise to the hydrophobic ring at room temperature for 10min to inactivate endogenous enzymes. Sections were soaked in PBS solution three times, each time with a new PBS solution for 3 minutes. E-IR-R217A (normal goat serum) was added dropwise to the hydrophobic ring and blocked at 37 ℃ for 30 minutes. After the sealing is finished, the excess liquid is thrown off. MMP7 antibody (cat # 3801S) diluted with E-IR-R217A (normal goat serum) (1. The sections were soaked in PBS solution three times, each time with a new PBS solution for 3 minutes. E-IR-R217B (Polyperoxidase-anti-Mouse/Rabbit IgG) is dripped into a hydrophobic ring, the incubation is carried out for 30 minutes at 37 ℃, the section is soaked in PBS solution for three times, and the PBS solution is replaced by new PBS solution each time for 3 minutes. Adding 50 mu L of E-IR-R217D (DAB concentrated solution) into 1mL of E-IR-R217E (DAB substrate solution), uniformly mixing to obtain DAB working solution, dropwise adding 50 mu of LDAB working solution into a hydrophobic ring, and incubating for 5 minutes at room temperature in a dark place. The color development was stopped by washing with tap water for 5 minutes.
(4) Hematoxylin counterstain, differentiation, and bluing. The sections were soaked in hematoxylin dye for 30 seconds and rinsed with tap water for 2 minutes. The slices were soaked in 1% alcohol hydrochloride dye for 5 seconds, and then placed in dilute aqueous lithium carbonate solution for 2 minutes. The mixture was rinsed with tap water for 3 minutes.
(5) Dehydrating and transparent. Soaking in 70%, 80%, 90% and 100% (twice) alcohol for 3 min, and soaking in xylene for 3 min and 2 min.
(6) And (5) sealing the neutral resin.
(7) Slide reading was performed using a 3D HISTECHPANNORMIC 250FLASH slide, 3D HISTECHCSASE viewer.
As shown in FIG. 1, the expression level of MMP7 in mtDNA mutant mice is reduced, the intestinal flora is disordered, and the antibacterial immune response is weakened.
2. In order to search for a potential mechanism for regulating the brain-intestinal axis function and detect the small intestine metabolomics of mtDNA mutant mice, the method comprises the following specific steps:
(1) Taking small intestine, taking small intestine and middle intestine sections of about 3-5cm, washing chyme in the intestine sections by using cold PBS solution, paying attention to washing strength to avoid damaging small intestine structures, and quickly freezing by using liquid nitrogen. Taking out the sample from a refrigerator at the temperature of-80 ℃, unfreezing the sample on ice, weighing 50mg of the sample in a 2mL EP tube after unfreezing, and adding 500uL of 70% methanol water internal standard extracting solution precooled at the temperature of-20 ℃.
(2) One small steel ball was added and homogenized at 30Hz for 4 times, 30s each time.
(3) After homogenizing, oscillating at 1500r/min for 5min, and standing on ice for 15min.
(4) Centrifugation was carried out at 10min,4 ℃ and 12000r/min.
(5) 200uL of the supernatant was taken and loaded into the corresponding vial liner for LC-MS/MS analysis.
The results are shown in fig. 2, the specificity of small intestine citrulline in mtDNA mutant mice is reduced, suggesting that citrulline plays an important role in the brain-intestine axis.
Example 2
200mg L-citrulline is weighed and added to 250mLSPF grade animal drinking water, mixed well and dissolved. The 8-month-old mtDNA mutant mice were weighed and divided equally into two groups by weight, one group was 250 mlsff-grade animal drinking water (control group) and the other group was 250 mlsff-grade animal drinking water containing 200mg L-type citrulline (experimental group). Water was supplied continuously for 14 days. After 14 days of uninterrupted water supply, the MMP level of the small intestine was detected by immunohistochemical experiments.
As a result, as shown in fig. 3, citrulline increased MMP7 expression in mtDNA mutant mice after administration, contributing to improvement of immunity.
In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (9)
1. Use of citrulline, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for enhancing immunity.
2. Use according to claim 1, characterized in that the medicament is for the prevention or treatment of a disturbance of the intestinal flora.
3. The use according to claim 1, wherein the medicament is for increasing the activity of matrix metalloproteinase 7 or for up-regulating the expression of a gene encoding matrix metalloproteinase 7.
4. The use according to claim 1, wherein the drug is targeted to the brain-gut axis.
5. The use according to claim 1, wherein the medicament is administered orally or as an enema.
6. A method of increasing the activity of matrix metalloproteinase 7, comprising: contacting matrix metalloproteinase 7 with citrulline or a pharmaceutically acceptable salt thereof.
7. A method for up-regulating the expression level of a gene encoding matrix metalloproteinase 7, comprising:
citrulline or a pharmaceutically acceptable salt thereof is co-cultured with cells or tissue containing a gene encoding matrix metalloproteinase 7.
8. A pharmaceutical composition for enhancing immunity, comprising citrulline or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical composition of claim 8, further comprising: pharmaceutically acceptable adjuvants.
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| Title |
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| 李晓斌等: "L-瓜氨酸对小鼠体重及肠道菌群多样性的影响", 《动物营养学报》, vol. 31, no. 9, pages 4235 - 4241 * |
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