Application of pharmaceutical composition composed of full eucommia ulmoides capsules and tripterygium glycosides tablets in toxicity reduction and efficacy enhancement

Abstract

The invention discloses application of a pharmaceutical composition consisting of a full eucommia ulmoides capsule and a tripterygium glycosides tablet to preparation of a medicine for reducing reproductive injury caused by the tripterygium glycosides tablet and enhancing the curative effect of the tripterygium glycosides tablet on preventing and / or treating osteoarthritis. The invention finds that when being matched with tripterygium glycosides tablets for treating arthritis, the full eucommia ulmoides capsules can play a role in enhancing efficacy and reducing toxicity, effectively improve the adverse effects of sperm quality reduction, reproductive target organ quality reduction and the like caused by the tripterygium glycosides tablets on reproductive systems, regulate HPG axis hormone level disorder, and improve spermatogenesis and maturation related factors and protein expression.

Description

Technical Field

[0001] The invention relates to the technical field of medicine, and in particular to a use of a pharmaceutical composition consisting of whole eucommia capsules and tripterygium wilfordii polyglycoside tablets for reducing toxicity and increasing efficacy. Background Art

[0002] Tripterygium wilfordii polyglycosides tablets are a traditional Chinese medicine preparation commonly used to treat autoimmune diseases such as rheumatoid arthritis and nephrotic syndrome. The prior art does not find the use of the pharmaceutical composition of the present invention consisting of whole eucommia capsules and tripterygium wilfordii polyglycosides tablets for reducing toxicity and increasing efficacy. Summary of the invention

[0003] Based on this, the present invention provides a use of a pharmaceutical composition consisting of whole Eucommia capsules and Tripterygium wilfordii polyglycosides tablets in the preparation of a drug for reducing reproductive damage caused by Tripterygium wilfordii polyglycosides tablets while enhancing the efficacy of Tripterygium wilfordii polyglycosides tablets in preventing and / or treating osteoarthritis.

[0004] Furthermore, the osteoarthritis is osteoarthritis caused by aging, obesity, joint damage and / or trauma.

[0005] Further, the bone joint is selected from one or more of the following: hip joint, knee joint, shoulder joint, ankle joint, interphalangeal joint and intertoe joint.

[0006] According to another aspect of the present invention, there is provided a use of whole Eucommia capsules in preparing a medicament for preventing and treating oligospermia and / or asthenospermia.

[0007] Furthermore, the pharmaceutical composition reduces the effect of the reproductive damage caused by Tripterygium Wilfordii Polyglycosides Tablets or the effect of the whole Eucommia Capsules in preventing and treating oligospermia and / or asthenospermia in one or more of the following ways: improving sperm quality, increasing the visceral-brain coefficient of reproductive organs, improving organ structure, improving the hormone level of the hypothalamus-pituitary-gonadal axis, and improving spermatogenesis and maturation.

[0008] Furthermore, the improvement of sperm quality includes increasing sperm concentration, increasing sperm motility, increasing sperm dynamic parameters and / or reducing sperm deformity rate.

[0009] Furthermore, the visceral-brain coefficient is the ratio of the visceral organ mass to the total brain mass.

[0010] Furthermore, the reproductive organ visceral-brain coefficient includes a testicular visceral-brain coefficient and / or an epididymal visceral-brain coefficient.

[0011] Furthermore, the improvement of organ structure includes improving pathological abnormalities of organ tissue and / or improving ultrastructural abnormalities of organ tissue.

[0012] Furthermore, the improvement of organ tissue pathological abnormalities is selected from one or more of the following: increasing the number of spermatogenic cells, increasing the number of sperm, regular arrangement of spermatogenic cells, reducing the spacing between seminiferous tubules, thickening of the epididymal duct epithelium, reducing the shedding of epididymal duct epithelial cells, and reducing the spacing between epididymal ducts and increasing the number of linear sperm.

[0013] Furthermore, the improvement of organ tissue ultrastructural abnormalities includes alleviating testicular tissue cell membrane damage, improving organelle swelling and / or reducing endoplasmic reticulum expansion.

[0014] Furthermore, the improvement of the hormone level of the hypothalamus-pituitary-gonadal axis is selected from one or more of the following: increasing the serum CYP11A1 level, increasing the serum gonadotropin-releasing hormone level, increasing the serum testosterone level, decreasing the serum CYP19A1 level, decreasing the serum follicle-stimulating hormone level, and decreasing the serum luteinizing hormone level.

[0015] Furthermore, the improvement in spermatogenesis and maturation is selected from one or more of the following: increased expression of testicular neural epidermoid growth factor 2, increased expression of c-ros sarcoma carcinogen-receptor tyrosine kinase in epididymal tissue, increased expression of epididymal phospholipase 2, and increased expression of sperm surface transmembrane protein metallopeptidase 3.

[0016] Furthermore, the pharmaceutical composition has a synergistic effect on the prevention and / or treatment of osteoarthritis in one or more of the following ways: improving pathological joint damage, reducing osteoarthritis scores, reducing immune organ brain coefficients, and reducing serum inflammatory factor levels.

[0017] Furthermore, the visceral-brain coefficient is the ratio of the visceral organ mass to the total brain mass.

[0018] Furthermore, the immune organ visceral-brain coefficient includes a spleen-brain coefficient and / or a thymus-brain coefficient.

[0019] Furthermore, the inflammatory factors include TNF-α and / or 1L-1β.

[0020] Furthermore, the pharmaceutical composition further comprises one or more drugs for preventing and / or treating osteoarthritis.

[0021] Furthermore, the drug is selected from one or more of the following: acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, serotonin norepinephrine reuptake inhibitors, tetrandrine tablets and joint cartilage protectors.

[0022] Further, the non-steroidal anti-inflammatory drug is selected from one or more of the following: ibuprofen, diclofenac, loxoprofen, sulindac, celecoxib, nimesulide, etoricoxib and etoricoxib.

[0023] Further, the opioid is selected from one or more of the following: morphine, oxycodone, fentanyl, codeine, buprenorphine, tramadol, buprenorphine, dihydrocodeine, codeine acetaminophen and oxycodone acetaminophen.

[0024] Further, the serotonin norepinephrine reuptake inhibitor is selected from one or more of the following: duloxetine, venlafaxine and milnaprim.

[0025] Furthermore, the joint cartilage protective agent is selected from one or more of the following: diacerein, glucosamine and chondroitin.

[0026] Furthermore, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0027] Furthermore, the auxiliary material is selected from one or more of the following: diluent, wetting agent, binder, disintegrant, inclusion agent, flavoring agent, sustained-release agent, glidant, lubricant, dispersant, plasticizer, opacifier and antioxidant.

[0028] Furthermore, the pharmaceutical composition is in the form of tablets, pills, capsules, powders, injections, films, lozenges, granules or oral solutions.

[0029] Beneficial effects of the present invention:

[0030] When used in combination with Tripterygium wilfordii glycosides to treat arthritis, Whole Eucommia Capsules can enhance efficacy and reduce toxicity, effectively improving adverse effects on the reproductive system such as decreased sperm quality and decreased quality of reproductive target organs caused by Tripterygium wilfordii glycosides, regulating the disorder of HPG axis hormone levels, and improving the expression of factors and proteins related to spermatogenesis and maturation. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without exceeding the scope of protection required by the present invention.

[0032] Figure 1 Schematic diagram of sperm quality monitoring results of Example 1. (A) Sperm density example diagram; (B) Sperm morphology example diagram, Note: a-normal, b-coiled body, c-curved neck, d-folded body, e-folded tail, f-headless; (C) Sperm count; (D) Sperm deformity rate; (E) Sperm motility; (F) Sperm motility; (G) Sperm dynamics parameters; (H) Sperm in vitro fertilization and sperm-egg combination; (I) In vitro fertilization rate; (J) In vitro fertilization deformity rate.

[0033] Figure 2The diagram is a schematic diagram of the kidney tissue morphology and the visceral-brain coefficient results of Example 1. Among them, (A) kidney tissue morphology; (B) kidney-brain coefficient; (C) testis-brain coefficient.

[0034] Figure 3 Schematic diagram of the results of rat histopathological characteristics in Example 1. (A) HE pathology of kidney, testis, and epididymis; (B) electron microscopic ultrastructure of testis, Note: Supporting cells (SC), myoid cells (My), damaged areas (marked with "↓"), mitochondria (M), rough endoplasmic reticulum (RER), Golgi apparatus (Go), lipid droplets (LD), autophagosomes (AP), primary spermatocytes (PS), spermatogonia (SG), lysosomes (Ly), autophagolysosomes (ASS).

[0035] Figure 4 This is a schematic diagram of the change results of the HPG axis hormone levels in rat serum in Example 1. Among them, (AD) are GnRH, LH, FSH, and T levels, respectively.

[0036] Figure 5 This is a schematic diagram of the key factors and protein expression results of spermatogenesis and maturation in rats with kidney yang deficiency and oligoasthenospermia in Example 1. Among them, (A, D) testicular signal factor NELL2 expression; (B, E) epididymal epithelial cell receptor ROS1 expression; (C, F) epididymal secretory protein OVCH2 expression; (G) sperm surface processing protein ADAM3 expression.

[0037] Figure 6 This is a schematic diagram of the monitoring results of arthritis indicators of CIA rats in Example 2. Among them, (A) rat paw example picture and joint HE pathology; (B) arthritis score statistics; (C) immune organ-spleen and thymus example picture; (DE) spleen and thymus visceral brain coefficient; (FG) inflammatory factor level.

[0038] Figure 7 This is a schematic diagram of the sperm quality monitoring results of Example 2. Among them, (A) sperm density example diagram; (B) sperm count; (D) sperm deformity rate; (E) sperm motility; (G) sperm dynamics parameter VCL.

[0039] Figure 8 This is a schematic diagram of the results of the reproductive target organ brain coefficient in Example 2. Among them, (A) testis-brain coefficient; (B) epididymis-brain coefficient.

[0040] Fig. 9 Schematic diagram of the histopathological characteristics of rats in Example 2. (A) HE pathology of testis and epididymis; (B) electron microscopic ultrastructure of testis.

[0041] Fig.10This is a schematic diagram of the changes in the HPG axis hormone levels in rat serum in Example 2. Among them, (AF) are the levels of CYP11A1, CYP19A1, GnRH, LH, FSH, and T, respectively.

[0042] Fig.11 This is a schematic diagram of the key factors and protein expression results of rat spermatogenesis and maturation in Example 2. Among them, (A, D) testicular signaling factor NELL2 expression; (B, E) epididymal epithelial cell receptor ROS1 expression; (C, F) epididymal secretory protein OVCH2 expression; (G) sperm surface processing protein ADAM3 expression. DETAILED DESCRIPTION

[0043] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0044] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by those of ordinary skill in the field of the invention or the field in which the terms are used. Although any methods, conditions, substances or materials similar to or equivalent to those disclosed herein may be used in the practice of the present invention, preferred methods, conditions, substances or materials are described herein.

[0045] The present invention is intended to encompass all alternatives, variations and equivalents that may be included in the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0046] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0047] In the present invention, the term "comprising" is synonymous with "including". As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0048] As described in the background technology section, the use of a pharmaceutical composition composed of whole Eucommia capsules and Tripterygium wilfordii polyglycosides tablets of the present invention for reducing toxicity and increasing efficacy has not been found in the prior art. In order to solve the above problems, the present invention provides a use of a pharmaceutical composition composed of whole Eucommia capsules and Tripterygium wilfordii polyglycosides tablets in the preparation of a drug for reducing reproductive damage caused by Tripterygium wilfordii polyglycosides tablets while enhancing the efficacy of Tripterygium wilfordii polyglycosides tablets in preventing and / or treating osteoarthritis.

[0049] In a preferred embodiment, the osteoarthritis is osteoarthritis caused by aging, obesity, joint injury and / or trauma.

[0050] In a preferred embodiment, the bone joint is selected from one or more of the following: hip joint, knee joint, shoulder joint, ankle joint, interphalangeal joint and intertoe joint.

[0051] According to another aspect of the present invention, there is provided a use of whole Eucommia capsules in preparing a medicament for preventing and treating oligospermia and / or asthenospermia.

[0052] In a preferred embodiment, the pharmaceutical composition reduces the effect of Tripterygium Wilfordii Polyglycosides Tablets on reproductive damage or the effect of Eucommia ulmoides capsules on preventing and treating oligospermia and / or asthenospermia in one or more of the following ways: improving sperm quality, increasing the visceral-brain coefficient of reproductive organs, improving organ structure, improving hormone levels of the hypothalamus-pituitary-gonadal axis, and improving spermatogenesis and maturation.

[0053] In a preferred embodiment, the improvement of sperm quality includes increasing sperm concentration, increasing sperm motility, increasing sperm kinetic parameters and / or reducing sperm deformity rate.

[0054] In a preferred embodiment, the visceral-brain coefficient is the ratio of the visceral organ mass to the whole brain mass.

[0055] In a preferred embodiment, the reproductive organ visceral-brain coefficient includes the testicular visceral-brain coefficient and / or the epididymal visceral-brain coefficient.

[0056] In a preferred embodiment, the improvement of organ structure includes improving pathological abnormalities of organ tissue and / or improving ultrastructural abnormalities of organ tissue.

[0057] In a preferred embodiment, the improvement of organ tissue pathological abnormalities is selected from one or more of the following: increasing the number of spermatogenic cells, increasing the number of sperm, regular arrangement of spermatogenic cells, reducing the spacing between seminiferous tubules, thickening of the epididymal duct epithelium, reducing the shedding of epididymal duct epithelial cells, and reducing the spacing between epididymal ducts and increasing the number of linear sperm.

[0058] In a preferred embodiment, the improvement of ultrastructural abnormalities of organ tissues includes alleviating damage to testicular tissue cell membranes, improving organelle swelling and / or reducing endoplasmic reticulum expansion.

[0059] In a preferred embodiment, the improvement of hypothalamus-pituitary-gonadal axis hormone levels is selected from one or more of the following: increasing serum CYP11A1 levels, increasing serum gonadotropin-releasing hormone levels, increasing serum testosterone levels, decreasing serum CYP19A1 levels, decreasing serum follicle-stimulating hormone levels, and decreasing serum luteinizing hormone levels.

[0060] In a preferred embodiment, the improvement in spermatogenesis and maturation is selected from one or more of the following: increased expression of neural epidermoid growth factor 2 in testicular tissue, increased expression of c-ros sarcoma carcinogen-receptor tyrosine kinase in epididymal tissue, increased expression of phospholipase 2 in epididymal tissue, and increased expression of transmembrane protein metallopeptidase 3 on sperm surface.

[0061] In a preferred embodiment, the pharmaceutical composition has a synergistic effect on the prevention and / or treatment of osteoarthritis in one or more of the following ways: improving pathological joint damage, reducing osteoarthritis scores, reducing immune organ brain coefficients, and reducing serum inflammatory factor levels.

[0062] In a preferred embodiment, the visceral-brain coefficient is the ratio of the visceral organ mass to the whole brain mass.

[0063] In a preferred embodiment, the immune organ visceral-brain coefficient includes the spleen-brain coefficient and / or the thymus-brain coefficient.

[0064] In a preferred embodiment, the inflammatory factors include TNF-α and / or 1L-1β.

[0065] In a preferred embodiment, the pharmaceutical composition further comprises one or more drugs for preventing and / or treating osteoarthritis.

[0066] In a preferred embodiment, the drug is selected from one or more of the following: acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, serotonin norepinephrine reuptake inhibitors, tetrandrine tablets and joint cartilage protectors.

[0067] In a preferred embodiment, the nonsteroidal anti-inflammatory drug is selected from one or more of the following: ibuprofen, diclofenac, loxoprofen, sulindac, celecoxib, nimesulide, etoricoxib and etoricoxib.

[0068] In a preferred embodiment, the opioid is selected from one or more of the following: morphine, oxycodone, fentanyl, codeine, buprenorphine, tramadol, buprenorphine, dihydrocodeine, codeine acetaminophen and oxycodone acetaminophen.

[0069] In a preferred embodiment, the serotonin norepinephrine reuptake inhibitor is selected from one or more of the following: duloxetine, venlafaxine and milnaprim.

[0070] In a preferred embodiment, the joint cartilage protective agent is selected from one or more of the following: diacerein, glucosamine and chondroitin.

[0071] In a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0072] In a preferred embodiment, the auxiliary material is selected from one or more of the following: diluents, wetting agents, binders, disintegrants, inclusion agents, flavoring agents, sustained-release agents, glidants, lubricants, dispersants, plasticizers, opacifiers and antioxidants.

[0073] In a preferred embodiment, the pharmaceutical composition is in the form of tablets, pills, capsules, powders, injections, films, lozenges, granules or oral solutions.

[0074] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out according to conventional conditions or conditions recommended by the manufacturer.

[0075] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0076] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in this patent specification can be used in combination with any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0077] Embodiment 1

[0078] 1. Experimental Materials

[0079] 1.1 Experimental Animals

[0080] Sixty SPF grade 6-week-old male SD rats, weighing (180±10) g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., animal license number: SCXK (Beijing) 2021-0006. The animals were kept in the Experimental Animal Center of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, with constant temperature and humidity, natural circadian rhythm lighting, free drinking water and food, and the experiment began after 7 days of adaptive feeding. The animal experiment passed the ethical review of experimental animal welfare of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences (ethical approval number 2024B078).

[0081] 1.2. Drugs and Reagents

[0082] Eucommia ulmoides capsules (Jiangxi Puzheng Pharmaceutical Co., Ltd., batch number 231401); Clomiphene citrate tablets (Gott Pharmaceutical Co., Ltd., batch number S1103); Adenine (BioFroxx, Germany, batch number E27890C450); Hematoxylin and eosin (HE) staining kit (Biyuntian, batch number C0105S); NELL2, ROS1, OVCH2 antibodies (ImmunoWay, USA, batch numbers YT7088, YN0013, YN3162); ADAM3 antibody (Santa Clara, USA Cruz Company, batch number sc-365288); goat anti-rabbit / mouse secondary antibody (Wuhan Boster Biotechnology Co., Ltd., batch number BA1133, BA1127); ELISA kits GnRH, LH, FSH, T, CYP19A, CYP11A1 (Shanghai ELISA Biotechnology Co., Ltd., batch numbers ml1003038, ml1002860, ml1002872, ml1002868, ml660318, ml660978).

[0083] 1.3 Experimental instruments

[0084] Inverted fluorescence microscope (Shenzhen Sinico Optical Instrument Co., Ltd., batch number XK-SW40FLT); BSA224S balance (Sartorius Scientific Instrument Co., Ltd.); BX60 upright microscope (Olympus, Japan); Multiskan FC microplate reader (Thermo, USA).

[0085] 2. Experimental methods

[0086] 2.1 Grouping and Dosing

[0087] Sixty rats were randomly divided into 6 groups: control group, model group, low (QDZ-L, 0.5 times clinical equivalent dose 0.13g / kg / d), medium (QDZ-M, 1 times clinical equivalent dose 0.26g / kg / d), high (QDZ-H, 2 times clinical equivalent dose 0.52g / kg / d) dose groups of whole Eucommia capsule, and Clomiphene Citrate positive group (Clomiphene Citrate, CC, dose 4.5mg / kg / d), 10 rats in each group. Except for the control group, the rest of the groups were given adenine dissolved in 0.3% sodium carboxymethylcellulose (dose 150mg / kg / d) by gavage for 14 consecutive days to establish the model of oligoasthenozoospermia of kidney yang deficiency. After 2 hours of modeling, except for the control group and model group, the rest of the groups were given continuous gavage for 42 days.

[0088] 2.2. Sperm quality testing

[0089] 2.2.1. Detection of sperm concentration and sperm dynamic parameters

[0090] The rat epididymis tail was taken, placed in HBSS (preheated at 37°C), cut into pieces, shaken thoroughly, and incubated in a 37°C water bath to allow all sperm to swim out of the epididymis. The sperm suspension was dropped on a glass slide, and computer assisted sperm analysis (CASA) technology was used to detect sperm concentration, sperm motility, and sperm dynamic parameters, including curve velocity (VCL), linear velocity (VSL), progressiveness (STR), and whipping frequency (BCF).

[0091] 2.2.2. Sperm motility test

[0092] Take the sperm suspension, stain it according to the instructions of the dead cell staining kit, and detect it under the oil lens of the confocal microscope. If the sperm head, body, and tail all show green fluorescence, it means that the sperm is alive. If the tip of the sperm head shows green fluorescence and the back end shows red fluorescence, and the body shows obvious green fluorescence, it means that the sperm is in the transition period between survival and death; the head of the dead sperm will show red fluorescence completely. Calculate the sperm viability, that is, the ratio of the sum of the number of surviving sperm and transitional sperm to the total number of sperm.

[0093] 2.2.3. Sperm deformity rate detection

[0094] Take the sperm suspension and inactivate it at high temperature, draw a small amount of the suspension and drop it onto the slide, and spread the slide evenly. Then fix it with methanol, stain it with eosin, rinse it with running water, and let it stand to dry. Count the number of abnormal sperm in every 200 sperm in different fields under a microscope, and calculate the sperm abnormality rate.

[0095] 2.2.4. Sperm in vitro fertilization rate detection

[0096] Healthy adult female rats were selected. COCs were obtained from female rats after superovulation treated with gonadotropin and matured and cultured. Sperm from male rats in the model group and QDZ-H group were obtained and centrifuged, treated with capacitation medium and incubated for capacitation. Capacitation sperm and mature eggs were placed in a culture dish containing appropriate culture medium in a certain proportion and incubated in a carbon dioxide incubator. After incubation, the sperm-egg binding was observed under a microscope and the sperm-egg binding rate was calculated. The fertilized eggs were continued to be cultured to observe their developmental stages and calculate the deformity rate.

[0097] 2.3. Observation of organ coefficient

[0098] Kidneys, testicles, epididymis, and whole brain were taken, their masses were weighed, and the visceral brain coefficient was calculated. Visceral brain coefficient = organ mass / whole brain mass.

[0099] 2.4 Pathological tissue and ultrastructural observation

[0100] After routine fixation, the kidney, testis, and epididymis tissues were dehydrated and permeabilized, embedded in paraffin, and 2-5 μm white slices were made according to the steps of "trimming, cutting, unfolding, pasting, and baking". After HE staining, the slices were sealed with neutral resin, and the images were observed, analyzed, and collected under an OLYPUS microscope.

[0101] Testicular tissue was pretreated and fixed with 3% glutaraldehyde and 1% osmium tetroxide, then dehydrated with serial acetone and embedded in epoxy resin 812. Sections were stained with methylene blue, and ultrathin sections were stained with uranyl acetate and lead citrate. Sections were examined using a HT7800 transmission electron microscope.

[0102] 2.5. Hypothalamus-pituitary-gonadal axis (HPG) hormone level detection

[0103] The levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) in the "hypothalamus-pituitary-gonadal axis" (HPG) in rat serum were detected by ELISA kits.

[0104] 2.6. Detection of key factors and protein expression levels of spermatogenesis and sperm maturation

[0105] After routine fixation, the testis and epididymis tissues were dehydrated and permeabilized, embedded in paraffin, and 2-5 μm white slices were made according to the steps of "trimming, cutting, unfolding, pasting, and baking". Then, the slices were dewaxed to water, and the slices were restored to a hydrated state by treating with xylene and different concentrations of ethanol. After antigen repair, blocking, incubation with primary antibodies of NELL2 (1:200), ROS1 (1:100), and OVCH2 (1:50) at 4°C overnight, incubation with corresponding secondary antibodies (1:300), and sealing, and observation under a fluorescence microscope, the location and expression of the antigen were determined based on the color and distribution of the fluorescent markers.

[0106] According to the basic Western Blot operation, protein extraction, quantification, sample loading, electrophoresis, transfer, blocking, ADAM3 (1:500) primary antibody incubation at 4 ° C overnight, corresponding secondary antibody (1:2000) incubation, color development and other analysis of protein expression levels were performed.

[0107] 2.7 Statistical Analysis

[0108] All data were statistically analyzed and plotted using GraphPad Prism 7.0, and one-way ANOVA was used for comparison among groups. # P<0.05, ## P<0.01, ### P<0.001; significant differences between the model group and the model group were indicated by * P<0.05, ** P<0.01, *** P<0.001.

[0109] 3. Experimental results

[0110] 3.1 Effect of Eucommia ulmoides capsule on sperm quality in rats with oligoasthenospermia of kidney-yang deficiency type

[0111] like Figure 1 As shown in AG, compared with the control group, the model group significantly reduced the sperm concentration, viability, motility and sperm dynamics parameters VCL, VSL, STR, BCF of rats, and significantly increased the sperm deformity rate (P < 0.001). Compared with the model group, QDZ-L, M, and H can increase the sperm concentration, viability, motility and sperm dynamics parameters to varying degrees (P < 0.05, 0.01, 0.001), and reduce the sperm deformity rate (P < 0.05, 0.001). The positive drug CC can significantly increase the sperm concentration, viability, motility and sperm dynamics parameters VCL and VSL (P < 0.05, 0.001), reduce the sperm deformity rate (P < 0.001), and can also increase the sperm dynamics parameters STR and BCF, but not significantly. As Figure 1 As shown in HJ, compared with the model group, QDZ treatment could significantly increase the sperm in vitro fertilization rate and reduce the sperm in vitro fertilization deformity rate (P<0.05).

[0112] 3.2 Effect of Eucommia ulmoides capsule on renal morphology and reproductive target organ coefficients in rats with oligoasthenospermia of kidney yang deficiency type

[0113] like Figure 2As shown in A-2B, the kidneys of rats in the control group were light pink and no abnormalities were observed; compared with the control group, the kidneys in the model group were enlarged, with a white surface and a sense of solidification, showing a "large white kidney", and the kidney-brain coefficient was significantly increased (P < 0.001); compared with the model group, after the intervention of QDZ-L, M, H and the positive drug CC, the kidneys gradually returned to normal size, the white part gradually turned into light pink, and the kidney-brain coefficient was significantly reduced (P < 0.001).

[0114] like Figure 2 As shown in C, compared with the control group, the testicles of the rats in the model group were atrophied, and their visceral-brain coefficient was significantly decreased (P < 0.01); compared with the model group, the testicular visceral-brain coefficients of the QDZ-L, M, and H groups were significantly increased (P < 0.05, 0.01, 0.001), and the positive drug CC could increase the testicular visceral-brain coefficient, but without significance.

[0115] 3.3 Effects of Eucommia ulmoides capsule on pathology and ultrastructure of reproductive target tissues in rats with oligoasthenospermia of kidney-yang deficiency type

[0116] like Figure 3 A shows the pathological tissues of kidney, testis and epididymis. In the kidney, compared with the control group, the glomeruli in the model group were atrophied, the tubular lumen was enlarged, the inflammatory cells in the interstitium were accumulated in large numbers, and the tubulointerstitial fibrosis was observed. Compared with the model group, the number of inflammatory cell infiltration in the tubulointerstitium of the QDZ-L, M, H and positive drug CC groups decreased, the number of fibroblasts decreased, and the tubules tended to be normal. In the testis, compared with the control group, the testis in the model group was atrophied, the diameter of the seminiferous tubules became smaller, the arrangement was sparse, the arrangement of spermatogenic cells at all levels in the tubules was disordered, and the number of sperm in the tubular lumen decreased. Compared with the model group, the testicular tissue and seminiferous tubule structure of rats in the QDZ-L, M, H and positive drug CC groups tended to be normal, among which the arrangement of spermatogenic cells at all levels in the seminiferous tubules of the QDZ-H group tended to be regular. In terms of epididymis, compared with the control group, the epididymal duct wall thickened, loosely arranged, interstitial enlargement, sperm in the cavity aggregated into clusters, the number decreased, and irregular arrangement in the model group. Compared with the model group, the thickening of the epididymal duct wall in the QDZ-L, M, and H groups was significantly improved, tightly arranged, and the amount of sperm in the cavity increased and was evenly distributed; the positive drug CC group had an increase in the amount of sperm in the cavity and was evenly distributed, but the epididymal duct wall thickened, loosely arranged, and the lumen proliferated and atrophied.

[0117] like Figure 3 B shows the ultrastructural characteristics of testicular tissue. In the control group, the supporting cell membrane structure was intact, the cytoplasm was concentrated, and the organelle damage was low; compared with the control group, the model group had edema, local cell membrane damage, and reduced cytoplasm density; compared with the model group, the QDZ-L, M, H groups and the positive drug CC group had slightly lighter damage, intact cell membrane structure, clear cell membrane boundaries, uniform cytoplasm density, low organelle damage, and low autophagy level.

[0118] 3.4 Effect of Eucommia ulmoides capsule on the levels of HPG axis hormones GnRH, LH, FSH and T in rats with oligoasthenospermia of kidney yang deficiency type

[0119] The hormone levels of the HPG axis directly reflect changes in the reproductive endocrine system. Figure 4 As shown in the results, compared with the control group, the hypothalamic secretion of GnRH and the level of T in the testis of the rats in the model group were significantly decreased (P<0.01, 0.001), and the FSH and LH released by the pituitary gland increased compensatorily (P<0.001). Compared with the model group, the QDZ-L, M, H groups and the positive drug CC group could promote the secretion of GnRH by the hypothalamus and the release of T by the testis of the rats to varying degrees (P<0.05, 0.01), and significantly reduced the compensatory increase of FSH and LH (P<0.001, 0.01).

[0120] 3.5 Effect of Eucommia ulmoides capsule on the expression levels of key factors and proteins in spermatogenesis and maturation in rats with oligoasthenospermia of kidney-yang deficiency type

[0121] like Figure 5 AF immunofluorescence analysis showed that compared with the control group, the expression of NELL2 in the testis, ROS1 and OVCH2 in the epididymis of the model group rats was significantly reduced (P < 0.01, 0.001, 0.05); compared with the model group, QDZ treatment significantly increased the expression of NELL2, ROS1 and OVCH2 (P < 0.001, 0.05), and positive western medicine CC treatment significantly increased the expression of NELL2 and ROS1 (P < 0.001, 0.01), and increased the expression of OVCH2, but not significantly. Figure 5 G Western blot analysis showed that compared with the control group, the expression of sperm surface processing protein ADAM3 in the model group was decreased, and the expression of ADAM3 was increased after treatment with QDZ or positive drug CC.

[0122] Embodiment 2

[0123] 1. Experimental Materials

[0124] 1.1 Experimental Animals

[0125] 70 SPF grade 6-week-old male SD rats, weighing (200±10) g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., animal license number: SCXK (Beijing) 2021-0011. The animals were kept in the Experimental Animal Center of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, with constant temperature and humidity, natural circadian rhythm lighting, free drinking water and food, and the experiment began after 7 days of adaptive feeding. The animal experiment passed the ethical review of experimental animal welfare of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences (ethical approval number 2024B107).

[0126] 1.2. Drugs and Reagents

[0127] Eucommia capsules (Jiangxi Puzheng Pharmaceutical Co., Ltd., batch number 231401); Tripterygium wilfordii polyglycosides tablets (Zhejiang Deende Pharmaceutical Co., Ltd., batch number 2312124B); L-carnitine oral solution (Northeast Pharmaceutical Group Shenyang First Pharmaceutical Co., Ltd., batch number 2312124B); bovine type II collagen acetic acid solution, incomplete Freund's adjuvant (Chondrex, USA, batch numbers 230479, 240086); eosin staining solution (Beijing Solebow Technology Co., Ltd., batch number 240003002), Calcein / PI cell activity and cytotoxicity detection kit (Biyuntian, batch number C2015S). The remaining antibodies and ELISA kits are the same as in Example 1, part 1.2.

[0128] 1.3 Experimental instruments

[0129] Same as part 1.3 of Example 1.

[0130] 2. Experimental methods

[0131] 2.1 Grouping and Dosing

[0132] Eighty rats were randomly divided into 7 groups: control group, CIA model group, tripterygium wilfordii polyglycosides group (TGT), low, medium and high doses of whole Eucommia capsule combined with tripterygium wilfordii polyglycosides group (QT-L, 0.5 times the clinical equivalent dose of 0.13g / kg / d combined with tripterygium wilfordii polyglycosides; QT-M, 1 times the clinical equivalent dose of 0.26g / kg / d combined with tripterygium wilfordii polyglycosides; QT-H, 2 times the clinical equivalent dose of 0.52g / kg / d combined with tripterygium wilfordii polyglycosides), positive drug L-carnitine combined with tripterygium wilfordii polyglycosides group (LC, 1 times the clinical equivalent dose of 200mg / kg / d), with 10 rats in each group. Equal volumes of bovine type II collagen acetic acid solution and incomplete Freund's adjuvant were emulsified, and 0.2mL / rat was subcutaneously injected at the base of the tail of the rat, and 0.1mL / rat was injected with the same emulsifier on the 7th day to stimulate immunity. The drugs were administered orally according to the dose on the day of the first immunization. The control group and CIA model group were administered with an equal volume of distilled water, and the drug administration lasted for 28 days.

[0133] 2.2. Arthritis index detection

[0134] 2.2.1. Joint pathology detection

[0135] The knee and ankle joints were fixed with paraformaldehyde, slowly decalcified with 10% EDTA, and then embedded in paraffin and sliced ​​for later use. The slices were placed on a slicer and baked at 60°C for 30 minutes. The slices were dewaxed in xylene and gradient ethanol until they were hydrated. The slices were then placed in hematoxylin and eosin dye solutions, stained, rinsed with running water, differentiated with differentiation solution, and then blued with 0.5% ammonia water. Finally, they were rinsed with running water again. After the slices were slightly dried, they were sealed with neutral resin and observed and photographed under a microscope.

[0136] 2.2.2 Arthritis score

[0137] Each group was scored according to the rat arthritis scoring standard. The scoring standard is: 1 point for any one of the following: slight swelling of the dorsum of the foot, swelling of the ankle joint, and slight swelling of the toes; 2 points for swelling of the dorsum of the foot and swelling of the ankle joint, or swelling of the toes; 3 points for swelling of the dorsum of the foot, swelling of the ankle joint, and swelling of the toes at the same time, or swelling of the dorsum of the foot and swelling of the ankle joint at the same time and the degree of swelling is significantly higher than the corresponding standard of 2 points; 4 points for swelling of the dorsum of the foot, swelling of the ankle joint, and swelling of the toes are particularly severe.

[0138] 2.2.3. Immune organ coefficient

[0139] Take the spleen, thymus and whole brain, weigh them and calculate the visceral brain coefficient. Visceral brain coefficient = organ mass / whole brain mass.

[0140] 2.3. Sperm quality testing

[0141] Same as Section 2.2.1-2.2.3 of Example 1.

[0142] 2.4. Organ coefficient observation

[0143] Same as in part 2.3 of Example 1.

[0144] 2.5 Pathological tissue and ultrastructural observation

[0145] Same as part 2.4 of Example 1.

[0146] 2.6. Hypothalamic-pituitary-gonadal axis (HPG) hormone level detection

[0147] Same as part 2.5 of Example 1.

[0148] 2.7. Detection of key factors and protein expression levels of spermatogenesis and sperm maturation

[0149] Same as in section 2.6 of Example 1.

[0150] 2.8 Statistical Analysis

[0151] All data were statistically analyzed and plotted using GraphPad Prism 7.0, and one-way ANOVA was used for comparison among groups. # P<0.05, ## P<0.01, ### P<0.001; significant difference between the CIA group and the * P<0.05, ** P<0.01, ***P<0.001; significant difference between the TGT group and the & P<0.05, && P<0.01, &&& P<0.001.

[0152] 3. Experimental results

[0153] 3.1 Effects of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on arthritis indices in CIA rats

[0154] like Figure 6 As shown in AB, except for the control group, the other groups began to develop joint redness and swelling symptoms on the 7th day after the first immunization, and the swelling gradually worsened, the toes were deformed, the skin was congested, and the movement of some joints was limited. TGT, QT-L, M, and H groups can effectively improve the severe hyperplasia of synovial connective tissue in the ankle and knee joints of CIA rats, the infiltration of a large number of inflammatory cells, and the erosion of articular cartilage and multiple bones by hyperplastic connective tissue. QT-L, M, and H groups are better than TGT in improving the pathological injuries of the ankle and knee joints of CIA rats. At the same time, the arthritis scores of TGT, QT-L, M, and H groups were lower than those of the CIA group.

[0155] like Figure 6 As shown in CE, compared with the control group, the spleen and thymus visceral-brain coefficients of the rats in the CIA group were significantly increased (P < 0.001); compared with the CIA group, the spleen and thymus visceral-brain coefficients of the rats in the TGT, QT-L, M, and HC groups were significantly decreased (P < 0.05, 0.01, 0.001); compared with the TGT group, the spleen and thymus visceral-brain coefficients of the rats in the QT-H group were significantly decreased (P < 0.05).

[0156] like Figure 6 As shown in FG, compared with those in control group, the serum TNF-α and 1L-1β levels of rats in CIA group were significantly increased (P<0.001); compared with those in CIA group, the serum TNF-α and 1L-1β levels of rats in TGT, QT-L, M and H groups were significantly decreased (P<0.05, 0.01 and 0.001); compared with TGT group, the serum TNF-α and 1L-1β levels of rats in QT-M and H groups were decreased to different degrees (P<0.05).

[0157] In summary, the CIA group showed obvious arthritis symptoms and immune system activation, while the treatment groups (TGT, QT-L, QT-M, QT-H) alleviated arthritis symptoms and indicators to varying degrees, and had a certain regulatory effect on the immune system. It can be seen that the combination of whole Eucommia Capsules and Tripterygium Wilfordii Polyglycosides Tablets can enhance the effect of Tripterygium Wilfordii Polyglycosides Tablets in treating arthritis and play a "synergistic" role.

[0158] 3.2 Effect of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on sperm quality in CIA rats

[0159] like Figure 7 As shown in the results, compared with the CIA group, the sperm concentration, motility, and sperm dynamics parameter VCL of rats in the TGT group were significantly reduced, and the sperm deformity rate was significantly increased (P < 0.001); compared with the TGT group, the QT-L, M, H, and positive drug LC groups could significantly increase the sperm concentration, motility, and sperm dynamics parameter VCL of rats to varying degrees, and reduce the sperm deformity rate (P < 0.001, 0.01, 0.05). It can be seen that the combination of whole Eucommia capsule and Tripterygium wilfordii polyglycosides tablets can effectively improve the reduction in sperm quality caused by Tripterygium wilfordii polyglycosides tablets in the treatment of arthritis.

[0160] 3.3 Effects of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on the organ coefficients of reproductive target organs in CIA rats

[0161] like Figure 8 As shown in the figure, compared with the CIA group, the TGT group can significantly reduce the testicular and epididymal visceral-brain coefficients (P < 0.05, 0.001); compared with the TGT group, the QT-L, M, H and positive drug LC groups can increase the testicular and epididymal visceral-brain coefficients to varying degrees (P < 0.001, 0.01, 0.05). It can be seen that the combination of whole Eucommia Capsules and Tripterygium Wilfordii Polyglycosides Tablets can improve the reduction in reproductive target organ quality caused by Tripterygium Wilfordii Polyglycosides Tablets in the treatment of arthritis.

[0162] 3.4 Effects of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on pathology and ultrastructure of reproductive target tissues in CIA rats

[0163] like Fig. 9 A Pathological HE showed that the testicular seminiferous tubules of the control group were round or oval with normal morphology, the walls of the seminiferous tubules were intact and thick, the spermatogenic cells at all levels were arranged regularly and tightly, the layers were clear, the cell bodies were filled, mature sperms were seen in some cavities, and no exfoliated cells were seen; the epididymal ducts were larger in diameter and longer in length, a large number of linear sperms were seen in the cavities, and only a small number of exfoliated cells were seen. Compared with the control group, the testicles and epididymis of the CIA group showed histopathological changes, the testicular seminiferous tubules had irregular tissue structure, reduced cross-sectional area, slightly increased abnormal structures, increased intertubular spaces, interstitial cell damage, and exfoliated cell blocks were seen in some cavities; the epididymal ducts showed reduced diameters, slightly increased intertubular spaces, and exfoliated cell blocks of the epididymal duct epithelium in the ductal lumen. Compared with the CIA group, the TGT group could cause obvious pathological damage to the testicular and epididymal tissues, with disordered spermatogenic cells, reduced and unclear layers, increased exfoliated cell blocks in the epididymal ducts, and significantly reduced linear sperm. Compared with TCT group, spermatogenic cells and sperm at all levels in the testis of rats in QT-L, M, H and positive drug LC groups showed an obvious proliferation trend, spermatogenic cells were stably arranged, the spacing between seminiferous tubules was reduced, the epididymal tubule epithelium was thickened, the number of exfoliated cell blocks decreased, the spacing between tubules decreased, and the number of linear sperm was significantly increased.

[0164] like Fig. 9 B. Testis tissue electron microscopy showed that the control and CIA groups had no obvious damage, with clear cell membrane boundaries, uniform cytoplasm, slightly swollen mitochondria, no expansion of the endoplasmic reticulum, and no typical autophagy structure; the TGT group had the most serious damage, mainly with swelling of organelles and cytoplasm, intact cell membrane structure, sparse cytoplasm, cavitation of mitochondria, and slightly expanded rough endoplasmic reticulum. The QT-L, M, H and positive drug LC groups had mild damage, with slightly damaged cell membrane structure, and low swelling and expansion of organelles.

[0165] 3.5 Effects of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on the levels of HPG axis hormones in CIA rats

[0166] like Fig.10 As shown, compared with the CIA group, the TGT group significantly decreased the levels of CYP11A1, GnRH, and T (P < 0.05, 0.001), and significantly increased the levels of CYP19A1, LH, and FSH (P < 0.001, 0.05). Compared with the TGT group, the QT-M, H, and positive drug LC groups increased the levels of CYP11A1, GnRH, and T to varying degrees, and decreased the levels of CYP19A1, FSH, and LH (P < 0.001, 0.01, 0.05).

[0167] 3.6 Effects of whole Eucommia capsule combined with Tripterygium wilfordii polyglycosides tablets on the expression levels of key factors and proteins in spermatogenesis and maturation in CIA rats

[0168] like Fig.11 As shown in AF, compared with the control group, there was no significant change in the expression of NELL2 in the testis and ROS1 and OVCH2 in the epididymis of the CIA group; compared with the CIA group, the expression of NELL2, ROS1, and OVCH2 in the TGT group was significantly reduced (P < 0.001, 0.05); compared with the TGT group, QT and positive drug LC treatment could significantly increase the expression of NELL2, ROS1, and OVCH2 (P < 0.001, 0.05). Fig.11 As shown in G, there was no significant change in the expression of sperm surface processing protein ADAM3 between the control group and the CIA group; compared with the CIA group, the expression of ADAM3 increased after QT treatment.

[0169] The embodiments of the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, changes or deformations made by those skilled in the art based on the ideas of the present invention, the specific implementation methods and application scope of the present invention, all belong to the scope of protection of the present invention. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. Use of a pharmaceutical composition consisting of whole Eucommia capsules and tripterygium wilfordii polyglycosides tablets in the preparation of a drug for reducing reproductive damage caused by tripterygium wilfordii polyglycosides tablets while enhancing the efficacy of tripterygium wilfordii polyglycosides tablets in preventing and / or treating osteoarthritis.

2. The use according to claim 1, characterized in that The osteoarthritis is osteoarthritis caused by aging, obesity, joint injury and / or trauma; Preferably, the bone joint is selected from one or more of the following: hip joint, knee joint, shoulder joint, ankle joint, interphalangeal joint and intertoe joint.

3. Use of whole Eucommia capsule in preparing medicine for preventing and treating oligospermia and / or asthenospermia.

4. The use according to any one of claims 1 to 3, characterized in that The pharmaceutical composition reduces the effect of reproductive damage caused by Tripterygium wilfordii polyglycosides tablets or the effect of whole Eucommia ulmoides capsule in preventing and treating oligospermia and / or asthenospermia in one or more of the following ways: improving sperm quality, increasing the visceral-brain coefficient of reproductive organs, improving organ structure, improving the hormone level of the hypothalamus-pituitary-gonad axis, and improving spermatogenesis and maturation.

5. The use according to claim 4, characterized in that Improving sperm quality includes increasing sperm concentration, increasing sperm motility, increasing sperm dynamics parameters and / or reducing sperm deformity rate; Preferably, the visceral brain coefficient is the ratio of the visceral organ mass to the whole brain mass; Preferably, the reproductive organ visceral brain coefficient includes the testicular visceral brain coefficient and / or the epididymal visceral brain coefficient; Preferably, the improving the organ structure includes improving pathological abnormalities of organ tissue and / or improving ultrastructural abnormalities of organ tissue; More preferably, the improvement of pathological abnormalities in organ tissues is selected from one or more of the following: increasing the number of spermatogenic cells, increasing the number of spermatozoa, regular arrangement of spermatogenic cells, reducing the spacing between seminiferous tubules, thickening of epididymal tubule epithelium, reducing epididymal tubule epithelial cell shedding, and reducing the spacing between epididymal tubules and increasing the number of linear spermatozoa; More preferably, the improvement of organ tissue ultrastructural abnormalities includes alleviating testicular tissue cell membrane damage, improving organelle swelling and / or reducing endoplasmic reticulum expansion; Preferably, the improvement of the hormone level of the hypothalamus-pituitary-gonadal axis is selected from one or more of the following: increasing serum CYP11A1 level, increasing serum gonadotropin-releasing hormone level, increasing serum testosterone level, decreasing serum CYP19A1 level, decreasing serum follicle-stimulating hormone level, and decreasing serum luteinizing hormone level; Preferably, the improvement in spermatogenesis and maturation is selected from one or more of the following: increased expression of neuroepidermoid growth factor 2 in testicular tissue, increased expression of c-ros sarcoma carcinogen-receptor tyrosine kinase in epididymal tissue, increased expression of phospholipase 2 in epididymal tissue, and increased expression of transmembrane protein metallopeptidase 3 on sperm surface.

6. The use according to claim 1, characterized in that: The pharmaceutical composition enhances the prevention and / or treatment of osteoarthritis in one or more of the following ways: improving pathological joint damage, reducing osteoarthritis scores, reducing immune organ brain coefficients, and reducing serum inflammatory factor levels.

7. The use according to claim 6, characterized in that The visceral brain coefficient is the ratio of the organ mass to the total brain mass; Preferably, the immune organ visceral-brain coefficient includes the spleen-brain coefficient and / or the thymus-brain coefficient; Preferably, the inflammatory factors include TNF-α and / or 1L-1β.

8. The use according to claim 1, characterized in that The pharmaceutical composition further comprises one or more drugs for preventing and / or treating osteoarthritis; Preferably, the drug is selected from one or more of the following: acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, serotonin norepinephrine reuptake inhibitors, tetrandrine tablets and joint cartilage protectors.

9. The use according to claim 8, characterized in that The nonsteroidal anti-inflammatory drug is selected from one or more of the following: ibuprofen, diclofenac, loxoprofen, sulindac, celecoxib, nimesulide, etoricoxib and etoricoxib; Preferably, the opioid is selected from one or more of the following: morphine, oxycodone, fentanyl, codeine, buprenorphine, tramadol, buprenorphine, dihydrocodeine, codeine acetaminophen and oxycodone acetaminophen; Preferably, the serotonin norepinephrine reuptake inhibitor is selected from one or more of the following: duloxetine, venlafaxine and milnaprim; Preferably, the joint cartilage protective agent is selected from one or more of the following: diacerein, glucosamine and chondroitin.

10. The use according to claim 1, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable excipient; Preferably, the excipient is selected from one or more of the following: diluent, wetting agent, binder, disintegrant, inclusion agent, flavoring agent, sustained-release agent, glidant, lubricant, dispersant, plasticizer, opacifier and antioxidant; More preferably, the pharmaceutical composition is in the form of tablets, pills, capsules, powders, injections, films, lozenges, granules or oral solutions.

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