CN117159668B - Application of dampness-resolving toxin-vanquishing particles in preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone - Google Patents
Application of dampness-resolving toxin-vanquishing particles in preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone Download PDFInfo
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of anti-skeletal muscle atrophy medicines, and particularly relates to application of dampness-resolving and toxicity-removing particles in preparation of medicines for improving skeletal muscle-related adverse reactions caused by dexamethasone. The dampness resolving and toxin resolving particles are applied to the preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone, so that the problem of large side effects on skeletal muscle related aspects of dexamethasone can be solved, and the safety and effectiveness of dexamethasone in clinical use can be improved.
Description
Technical Field
The invention belongs to the technical field of anti-skeletal muscle atrophy medicines, and particularly relates to application of dampness-resolving toxin-vanquishing particles in preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone.
Background
Dexamethasone (DEX) has pharmacological activity of improving lung function, reducing inflammatory reaction, etc., however, the drug is accompanied with various adverse reactions such as: osteoporosis, skeletal muscle atrophy, immunosuppression, hyperglycemic dyslipidemia, and the like. During SARS, some patients receive large doses of dexamethasone, and after healing, drug sequelae are left, mainly including skeletal muscle dysfunction, femoral head necrosis, walking disorder, bone pain caused by osteoporosis, and the like. Wherein, skeletal muscle is the main target tissue of glucocorticoid, and dexamethasone can directly promote skeletal muscle protein catabolism to strengthen and inhibit skeletal muscle protein synthesis, so that skeletal muscle protein is subjected to net degradation, and skeletal muscle atrophy is caused. The long-term use of dexamethasone can bring serious consequences of skeletal muscle atrophy, cause muscle strength reduction and mobility impairment, and increase risk factors of patient fall and fracture. That is, dexamethasone has a problem in that side effects in skeletal muscle are large.
If the medicine capable of improving skeletal muscle related adverse reactions caused by dexamethasone can be provided, the medicine safety of dexamethasone can be improved, and the medicine has important research value.
Disclosure of Invention
The invention aims to provide the application of dampness resolving and toxin resolving particles in the preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone, so as to solve the problem of large side effects of dexamethasone in skeletal muscle related aspects, and improve the medication safety of dexamethasone.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the application of dampness resolving and toxin resolving particles in preparing medicines for improving skeletal muscle related adverse reactions caused by dexamethasone. The preparation raw materials of the dampness resolving and toxin resolving granule comprise 14 traditional Chinese medicines. The inventor finds that the dampness-resolving toxin-vanquishing particles can improve skeletal muscle related adverse reactions caused by dexamethasone, meanwhile, the dampness-resolving toxin-vanquishing particles can not reduce the anti-inflammatory efficacy of dexamethasone, the dampness-resolving toxin-vanquishing particles can inhibit secretion of inflammatory factors, and the dampness-resolving toxin-vanquishing particles have anti-inflammatory effects equivalent to those of dexamethasone. The dampness resolving and toxin resolving particles are applied to the preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone, so that the problem of large side effects on skeletal muscle related aspects of dexamethasone can be solved, and the safety and effectiveness of dexamethasone in clinical use can be improved.
As a further improvement, the skeletal muscle related side effects include skeletal muscle atrophy. The dampness-resolving toxin-vanquishing granule has the effect of improving skeletal muscle atrophy, and can further improve the safety of dexamethasone in clinical use.
As a further improvement, the skeletal muscle atrophy includes at least one of weight loss, skeletal muscle strength loss, and skeletal muscle loss. The dampness-resolving toxin-vanquishing granule has the effects of improving weight reduction, improving skeletal muscle strength reduction and skeletal muscle loss, and can further improve the safety of dexamethasone in clinical use.
As a further improvement, the skeletal muscle related side effects include at least one of myotube cell injury, myotube cell atrophy. The dampness-resolving toxin-vanquishing particles have the effect of improving myotube cell injury, and the dampness-resolving toxin-vanquishing particles also have the effect of improving myotube cell atrophy, so that the safety of dexamethasone in clinical use can be further improved.
As a further improvement, the skeletal muscle related side effects include a decrease in skeletal muscle atrophy related enzyme activity. The dampness-resolving toxin-vanquishing particles can obviously enhance the activity of skeletal muscle atrophy related enzymes, can solve the problem of large side effects on skeletal muscle related caused by using dexamethasone, and further improve the safety of dexamethasone in clinical use.
As a further improvement, the skeletal muscle atrophy-related enzyme includes SIRT1 enzyme. Dexamethasone can cause the decrease of SIRT1 enzyme activity, the decrease of SIRT1 enzyme activity can cause skeletal muscle related adverse reaction, dampness resolving and toxin removing particles can obviously enhance the activity of SIRT1 enzyme, can improve the side effect on skeletal muscle related caused by dexamethasone, and further improves the safety of dexamethasone in clinical use.
Drawings
FIG. 1 is a graph showing the relative amounts of NO in control, model, Q-14, and DEX groups in experiments of the effect of DEX and Q-14 on LPS-induced NO release from A549 cells;
FIG. 2 is a graph of the relationship between different concentrations of Q-14 and C2C12 myotube cell viability in experiments in which different concentrations of Q-14 and DEX drugs have an effect on C2C12 myotube cell viability;
FIG. 3 is a graph of the effect of different concentrations of Q-14 and DEX drugs on C2C12 myotube cell viability in experiments where different concentrations of DEX and C2C12 myotube cell viability;
FIG. 4 is a graph showing comparison of C2C12 myotube cell viability in the control group, the DEX group, and the Q-14 improved group (Q-14+DEX) in experiments on the effect of DEX, Q-14, radix Paeoniae Rubra, and Glycyrrhrizae radix on C2C12 myotube cell viability;
FIG. 5 is a graph showing comparison of cell viability of C2C12 myotubes of the control group, the DEX group, the red peony root-modified group (red peony+DEX), and the licorice-modified group (licorice+DEX) in experiments on the effect of DEX, Q-14, red peony root, and licorice on cell viability of C2C12 myotubes;
FIG. 6 is a graph showing Western blot results of control, DEX, and Q-14 modified (Q-14+DEX) groups in experiments of the effects of DEX, Q-14, radix Paeoniae Rubra, and Glycyrrhrizae radix on C2C12 myotube cell atrophy;
FIG. 7 is a graph showing Western blot results of control, DEX, paeonia lactiflora (radix Paeoniae Rubra+DEX), and Glycyrrhiza uralensis (radix Glycyrrhizae+DEX) in experiments of the effects of DEX, Q-14, paeonia lactiflora and Glycyrrhiza uralensis on C2C12 myotube cell atrophy;
FIG. 8 is a graph of comparison of body weights of mice in the control group, the DEX group, and the Q-14 modified group (Q-14+DEX) in experiments on the effect of DEX and Q-14 on the body weights of mice;
FIG. 9 is a graph comparing the mouse grip of the control group, the DEX group, and the Q-14 modified group (Q-14+DEX) in experiments on the effect of DEX, Q-14 on skeletal muscle strength of mice;
FIG. 10 is a graph comparing SIRT1 enzyme activities of a control group, a Q-14 group, a DEX group, and a Q-14 modified group (Q-14+DEX) in experiments on the effect of DEX and Q-14 on SIRT1 enzyme activities;
in the figure: the sum of the ∈and the ∈indicates significant differences from the control group, +.i indicates that P.ltoreq.0.05, +.i indicates that P.ltoreq.0.01, # and # indicate significant differences from the DEX group, # indicates that P.ltoreq.0.05, # indicates that P.ltoreq.0.01.
Detailed Description
Dexamethasone (DEX) has pharmacological activity for reducing inflammatory response, but DEX also has a problem of great skeletal muscle related side effects. The inventor finds that the dampness-resolving toxin-vanquishing particles (Q-14) can improve the problem of large skeletal muscle related side effects caused by Dexamethasone (DEX), and meanwhile, the dampness-resolving toxin-vanquishing particles also have anti-inflammatory effects equivalent to those of dexamethasone. The dampness resolving and toxin resolving particles are applied to the preparation of medicines for improving skeletal muscle related adverse reactions caused by dexamethasone, so that the problem of large side effects on skeletal muscle related aspects of dexamethasone can be solved, and the safety and effectiveness of dexamethasone in clinical use can be improved.
The technical scheme of the invention is further described in detail below with reference to specific embodiments.
Pharmacodynamic experiments are carried out on the dampness-resolving toxin-vanquishing particles, and the anti-inflammatory effect and the anti-skeletal atrophy effect of the dampness-resolving toxin-vanquishing particles are verified. The specific experimental procedure is as follows.
Experimental reagent
Dampness resolving and toxin resolving granule (Guangdong party pharmaceutical Co., ltd.); lipopolysaccharide (LPS) (Sigma-Aldrich); DMEM medium (Gibco); F-12K medium (Gibco); fetal bovine serum (Gibco); horse serum (Gibco); TNF-alpha, IL-1 beta, IL-6 ELISA kit (Jiang Lai Biotechnology Co., ltd.). CCK-8 kit, SIRT1 nitric oxide detection kit (Biyun Tian Biotechnology Co., ltd.); enzyme activity detection kit (Abcam); the liquorice extract particles (purchased from Tongzhimen Hospital of Beijing traditional Chinese medicine university) contain the following liquorice: 1.28g licorice/g licorice extract granule, red peony root extract granule (purchased from Dongzhimen hospital of Beijing traditional Chinese medicine university), the red peony root content in the granule is: 1.28g radix Paeoniae Rubra/g radix Paeoniae Rubra extract granule.
Experimental instrument
An electronic balance, a mertretolide Shanghai electronic balance; a tabletop centrifuge (Thermo Scientific ST R); an electric heating constant temperature water bath pot, shanghai-a constant scientific instrument limited company; tecan microplate reader (switzerland dinken); microscope (Olympus, japan).
1. Anti-inflammatory effect research of dampness-resolving toxin-vanquishing particles
Cell culture and grouping
A549 (human non-small cell lung cancer cells) were obtained from ATCC cell banks using F-12K medium (Gibco) containing 10% FBS at 37℃with 5% CO 2 Culturing in an incubator. Passaging for 1 time every 2 to 3 days according to the cell growth state, changing liquid, and taking cells in logarithmic growth phase for subsequent experiments.
LPS stock solution: 100mg of LPS powder was dissolved in 100mL of PBS to a concentration of 1mg/mL and stored at-20℃in a refrigerator.
1.1 experiments on the Effect of LPS, DEX and Q-14 drugs on A549 cell survival
A549 cells were expressed as 1×10 5 The density of each mL was inoculated in 96-well plates at 100. Mu.L per well. After the cells adhere to the wall, the cells are molded and grouped. Only A549 cells exist in the blank group, and LPS is added into the A549 cells by 1.0 mg/mL to act on the A549 cells for 24 hours; the DEX group was prepared by adding 1.0. 1.0 mg/mL of LPS and 10. Mu.M of DEX (dexamethasone) to A549 cells, and allowing them to act on the A549 cells for 24 hours; the Q-14 group was prepared by adding 1.0. 1.0 mg/mL of LPS and 10 mg/mL of Q-14 (damp-resolving toxin-resolving particles) to A549 cells, and allowing the mixture to act on the A549 cells for 24 hours. CCK-8 assay A549 cell viability, 90. Mu.L of culture broth and 10. Mu.L of CCK-8 reagent (CCK 8, biyun Tian, C0038) were added to each well, and after incubation of 1.5. 1.5 h in the cell incubator, absorbance was measured (A450) with a fluorescent microplate reader at a wavelength of 450 nm, and cell viability was calculated according to the following formula:
cell viability (%) = treatment group a 450/control group a450 x 100%.
Wherein, the treatment group refers to LPS group, DEX group and Q-14 group, and the control group refers to blank group.
The A549 cell survival rates in the blank group, the LPS group, the DEX group and the Q-14 group are detected, and the detection results show that compared with the blank group, the LPS, DEX, Q-14 can not influence the A549 cell survival rate. Therefore, the above drugs do not cause a549 cytotoxicity in the above concentrations, and subsequent experiments can be performed safely and effectively.
1.2 experiments on the effect of DEX, Q-14 on LPS-induced NO Release from A549 cells
A control group, a model group, a Q-14 group and a DEX group are arranged, wherein the control group comprises A549 cells, the model group comprises A549 cells and LPS, the Q-14 group comprises A549 cells and Q-14, and the DEX group comprises A549 cells and DEX.
NO levels were determined using Griess: each set of cell supernatants and standards was added to the ELISA plate at 50. Mu.L per well, and 50. Mu. L Griess Reagent I and 50. Mu. L Griess Reagent II, which had been allowed to stand at room temperature, were added to each well. After shaking and mixing, the mixture reacts for 10 min in dark, and the absorbance D (A540) value is measured by an enzyme-labeled instrument. And determining the NO content in the sample according to the measured standard curve.
The relative amounts of NO in the control group, model group, Q-14 group, and DEX group are shown in FIG. 1, and can be seen in FIG. 1: compared with the control group, the addition of LPS in the model group can cause obvious increase of the NO release level, and the NO content of the DEX group and the Q-14 group is lower than that of the model group, so that the NO release level of the A549 cells can be reduced by the DEX and the Q-14, the NO release of the A549 cells induced by the LPS can be inhibited by the DEX and the Q-14, and the DEX and the Q-14 have anti-inflammatory effects. The NO content of DEX group was equivalent to that of Q-14 group, indicating that the anti-inflammatory effect of Q-14 was equivalent to that of DEX.
1.3 experiments on the Effect of DEX, Q-14 on LPS-induced secretion of cytokines TNF- α, IL-1β, IL-6
A control group, a model group, a Q-14 group and a DEX group were set, wherein the control group only had A549 cells, the model group was prepared by adding 1.0 mg/mL of LPS to the A549 cells, the LPS was allowed to act on the A549 cells for 24 hours, the Q-14 group was prepared by adding 1.0 mg/mL of LPS to the A549 cells and 10 mg/mL of Q-14 (damp-resolving toxin resolving particles), the DEX group was prepared by adding 1.0 mg/mL of LPS to the A549 cells and 10. Mu.M of DEX (dexamethasone) to the A549 cells, and the DEX group was prepared by adding 1.0 mg/mL of LPS to the A549 cells and 10. Mu.M of DEX to the A549 cells for 24 hours.
Determination of inflammatory factors TNF- α, IL-1β, IL-6 levels by ELISA: according to ELISA kit instructions, detecting tumor necrosis factor (TNF alpha), interleukin 6 (IL-6) and interleukin 1 beta (IL-1 beta) in each group specifically comprises: incubation, washing, adding biotinylated antibody, incubation, washing, adding enzyme, incubation, washing, developing color, stopping reaction, and detecting absorbance by an enzyme-labeled instrument. The concentrations of inflammatory factors TNF-alpha, IL-1 beta and IL-6 were determined according to standard curves, respectively.
The detection results show that compared with the control group, the model group, the Q-14 group and the DEX group, the secretion concentration of the inflammatory factor TNF-alpha can be obviously increased by adding LPS in the model group, the secretion concentration of the TNF-alpha in the DEX group and the secretion concentration of the TNF-alpha in the Q-14 group are lower than the secretion concentration of the TNF-alpha in the model group, so that the DEX and the Q-14 can reduce the concentration of the inflammatory factor TNF-alpha of the A549 cells, and the DEX and the Q-14 can inhibit the secretion of the inflammatory factor TNF-alpha, namely the DEX and the Q-14 have anti-inflammatory effects. The secretion concentration of TNF- α in the DEX group was equivalent to that in the Q-14 group, indicating that the anti-inflammatory effect of Q-14 was equivalent to that of DEX.
The detection results show that compared with the control group, the model group, the Q-14 group and the DEX group, the addition of LPS in the model group can cause the obvious increase of the secretion concentration of the inflammatory factor IL-1 beta, the secretion concentration of the IL-1 beta in the DEX group and the secretion concentration of the IL-1 beta in the Q-14 group are lower than the secretion concentration of the IL-1 beta in the model group, which indicates that the DEX and the Q-14 can both reduce the concentration of the inflammatory factor IL-1 beta of the A549 cells, and the DEX and the Q-14 can both inhibit the secretion of the inflammatory factor IL-1 beta, namely the DEX and the Q-14 have anti-inflammatory effect. The secretion concentration of IL-1β in the DEX group was equivalent to that of IL-1β in the Q-14 group, indicating that the anti-inflammatory effect of Q-14 was equivalent to that of DEX.
The detection results show that compared with the control group, the model group, the Q-14 group and the DEX group, the addition of LPS in the model group can cause the obvious increase of the secretion concentration of inflammatory factors IL-6, the secretion concentration of IL-6 in the DEX group and the secretion concentration of IL-6 in the Q-14 group are lower than the secretion concentration of IL-6 in the model group, and the detection results show that DEX and Q-14 can reduce the concentration of inflammatory factors IL-6 of A549 cells, and that DEX and Q-14 can inhibit the secretion of inflammatory factors IL-6, namely, the DEX and Q-14 have anti-inflammatory effects. The secretion concentration of IL-6 in the DEX group was equivalent to that of IL-6 in the Q-14 group, indicating that the anti-inflammatory effect of Q-14 was equivalent to that of DEX.
2. Damp-resolving toxin-vanquishing particles (Q-14) for improving C2C12 myofibroblast injury research caused by Dexamethasone (DEX)
Cell culture and grouping: C2C12 myoblasts with good growth state at 10 5 The individual/hole cell density is inoculated into a 96-well plate, the cell induction culture medium containing 2% horse serum is replaced when the cells are fused by 70-80%, the culture is continued for 6 days, and the cells are used for subsequent experiments when the cells are differentiated into mature myotube cells.
2.1 experiments on the Effect of different concentrations of Q-14 and DEX drugs on C2C12 myotube cell viability
Modeling and grouping the differentiated and mature myotube cells, wherein only the differentiated and mature C2C12 myotube cells exist in a blank group; DEX groups are prepared by adding different concentrations (5-20 μm) of DEX (dexamethasone) into differentiated mature C2C12 myotube cells, and allowing the mixture to act for 24 hours; the group Q-14 is prepared by adding different concentrations (5-160 mg/mL) of Q-14 (damp-resolving and toxin-resolving particles) into differentiated and mature C2C12 myotube cells, and allowing the mixture to act for 24 hours. The viability of C2C12 cells was measured using CCK-8 and was the same as 1.1.
The comparison of the survival rate of the C2C12 myotube cells with different concentrations of Q-14 is shown in FIG. 2, and the survival rate of the C2C12 myotube cells is tested after each group of Q-14 in FIG. 2 has been applied to the C2C12 myotube cells for 24 hours at different doses. As can be seen from FIG. 2, Q-14 was administered to C2C12 cells for 24 hours at a concentration of less than 20 mg/ml without cytotoxicity, at a safe dose of Q-14 at a concentration of less than 20 mg/ml. Q-14 in the experiment of the invention is carried out within a safe dosage range, has no cytotoxicity of C2C12 myotubes, and can safely and effectively carry out subsequent experiments.
The relationship between the different concentrations of DEX and the survival rate of C2C12 myotube cells is shown in FIG. 3, and the survival rate of C2C12 myotube cells is tested after each group of DEX in FIG. 3 has been applied to C2C12 myotube cells for 24 hours at different doses. As can be seen from FIG. 3, DEX showed partial cytotoxicity to C2C12 myotube cells at 10. Mu.M.
2.2 experiments on the Effect of DEX, Q-14, radix Paeoniae Rubra, glycyrrhrizae radix on the survival rate of C2C12 myotube cells
Reference 2.1 method for culturing cells, grouping, wherein the control group: adding serum-free DMEM medium into the C2C12 myotube cells; DEX group: adding 10 mu M DEX into C2C12 myotube cells, and allowing the mixture to act for 24 hours by taking a serum-free DMEM culture medium as a solvent; q-14 improvement group (Q-14+dex): adding 10 mg/mL of Q-14 and 10 mu M of DEX into C2C12 myotube cells, and allowing the mixture to act for 24 hours by taking a serum-free DMEM culture medium as a solvent; red peony improvement group (red peony+dex): adding 10 mg/mL radix Paeoniae Rubra extract particles and 10 μm DEX into C2C12 myotube cells, and allowing the mixture to act for 24 hours with serum-free DMEM medium as solvent; licorice improvement group (licorice+dex): 10 mg/mL of licorice extract particles and 10 mu M of DEX were added to C2C12 myotube cells, and the mixture was allowed to act for 24 hours in a serum-free DMEM medium as a solvent, and used for the subsequent experiments. The above procedure was followed using serum-free DMEM medium as solvent, followed by testing the viability of C2C12 myotube cells in each group separately using CCK-8.
The cell viability of the control group, the DEX group, and the Q-14 improved group (Q-14+DEX) is shown in FIG. 4, and it can be seen from FIG. 4 that the cell viability of the DEX group is smaller than that of the control group, indicating that DEX causes a decrease in the cell viability of the C2C12 myotubes. The cell viability of the Q-14 improved group (Q-14+DEX) was greater than that of the C2C12 myotube of the DEX group, i.e., Q-14 and DEX were simultaneously applied to the C2C12 myotube cells, and the C2C12 myotube cell viability was increased, indicating that Q-14 could effectively ameliorate the problem of DEX-induced C2C12 cell injury.
The cell viability of the control group, the DEX group, the red peony root-modified group (red peony root+dex) and the licorice root-modified group (licorice root+dex) is shown in fig. 5, and as can be seen from fig. 5, the cell viability of the red peony root-modified group (red peony root+dex) and the cell viability of the licorice root-modified group (licorice root+dex) are equivalent to those of the DEX group, indicating that the red peony root extract and the licorice root extract have no protective activity on C2C12 myotube cells.
2.3 experiments on the Effect of DEX, Q-14, radix Paeoniae Rubra, and Glycyrrhrizae radix on C2C12 myotube cell atrophy
MuRF-1 and atrogin1 are 2 important ubiquitin-protein ligases and can be used as important molecular markers for skeletal muscle atrophy.
Detection of skeletal muscle protein degradation marker protein MuRF-1 and atrogin1 by Western blot: C2C12 cells were plated at 5X 10 4 Density of individual/mL was inoculated in 6 wellsA plate. After the C2C12 cells differentiated into mature myotube cells, modeling was performed as above. A control group, a DEX group, a Q-14 modified group (Q-14+DEX), which included C2C12 myotube cells and 10. Mu.M DEX, a Q-14 modified group (Q-14+DEX) which included C2C12 myotube cells, 10. Mu.M DEX and 10 mg/mL Q-14, a red peony root modified group (red peony root+DEX) which included C2C12 myotube cells, 10. Mu.M DEX and 10 mg/mL radix paeoniae rubra extract particles, and a licorice modified group (licorice+DEX) which included C2C12 myotube cells, 10. Mu.M DEX and 10 mg/mL licorice extract particles, were set. And collecting protein lysate, and carrying out Western blot detection.
The Western blot experiment results of the control group, the DEX group and the Q-14 improvement group (Q-14+DEX) are shown in FIG. 6, and can be seen from FIG. 6: increased expression of MuRF-1 and atrogin1 proteins in the DEX group compared to the control group, indicating that DEX may cause increased expression of MuRF-1 and atrogin1 proteins; the reduced expression of MuRF-1 and atrogin1 proteins in the Q-14 improved group (Q-14+DEX) compared to the DEX group, i.e., simultaneous action of Q-14 and DEX on C2C12 myotube cells effectively down-regulates protein expression of MuRF-1 and atrogin1 in C2C12 myotube cells, i.e., Q-14 improves DEX-induced atrophy of C2C12 myotube cells.
The Western blot experiment results of the control group, the DEX group, the red peony root improvement group (red peony+DEX) and the licorice improvement group (licorice+DEX) are shown in FIG. 7, and can be seen from FIG. 7: the expression of MuRF-1 and atrogin1 proteins was not reduced in the radix Paeoniae Rubra modified group (radix Paeoniae Rubra+DEX) and the Glycyrrhrizae radix modified group (Glycyrrhrizae radix+DEX) compared with the DEX group, indicating that: the radix Paeoniae Rubra extract and Glycyrrhrizae radix extract can not improve the problem of increased protein decomposition of C2C12 myotube cell caused by DEX, and the radix Paeoniae Rubra extract and Glycyrrhrizae radix extract have no skeletal muscle cell protecting activity.
3. Experiment of Effect of DEX, Q-14 on mouse muscle atrophy
Experimental animal
C57BL/6 mice, SPF grade, male, offered by Peking Vitreton Lihua laboratory animal technologies Co. The temperature of the animal house is 22+/-1 ℃, the humidity is 40-70%, and drinking water is taken freely in 12 hours of day and night period.
Experimental grouping and experimental method
Grouping and administration: a control group, a DEX group, and a Q-14 improvement group (Q-14+DEX) were set. Control group: 6 mice were given the same volume of physiological saline by oral gavage for 10 days. DEX group: 6 mice, each of which was dosed with DEX; DEX mice were dosed at 25 mg/kg, formulated with 0.5% CMC-Na, and 0.1ml/10g were given by intraperitoneal injection, 1 time a day, with the same volume of saline administered orally by gavage; q-14 improvement group (Q-14+dex): 6 mice, each of which was dosed with DEX and Q-14, and the dose of DEX in the Q-14 modified group (Q-14+DEX) was identical to the dose and mode of dosing of DEX in the DEX group, and the dose of Q-14 in the Q-14 modified group (Q-14+DEX) was: 50mg/kg, formulated with 0.5% CMC-Na, and administered orally 2 times a day at 0.1ml/10 g.
In clinical practice, the most commonly used administration mode of DEX (dexamethasone) for patients with new crown infection is injection administration, and the administration mode of Q-14 (damp-resolving and toxin-vanquishing particles) is oral administration, so that the invention adopts the same administration mode as clinical practice for experiments in a more limited reduction clinical experiment.
3.1 experiments on the influence of DEX, Q-14 on the weight of mice
The control group, DEX group, Q-14 modified group (Q-14+DEX) were dosed continuously for 10 days, and the body weights of the mice were recorded before daily dosing. The time of dosing was recorded as a function of the body weight of mice in the control, DEX, and Q-14 modified groups (Q-14+DEX).
The body weight of the mice is an important index for affecting skeletal muscle function of the mice, changes in body weight of each group of mice are recorded before daily administration, and the body weights of the mice at different times are counted. Muscle atrophy is one of the major side effects of the large number of DEX-use, and the weight pairs of control, DEX, and Q-14 modified (Q-14+DEX) mice are shown in FIG. 8, and as can be seen in FIG. 8, the weight of the DEX mice is lower than that of the control mice, indicating that DEX causes weight loss and muscle loss; the weight of the mice in the Q-14 improvement group (Q-14+DEX) was higher than that of the mice in the DEX group, indicating that Q-14 significantly improved the DEX-induced weight loss and muscle loss problems.
3.2 experiments on the influence of DEX, Q-14 on skeletal muscle strength in mice
The control group, DEX group, and Q-14 modified group (Q-14+DEX) were tested for their mouse grip. Specifically, the holding power of each group of mice is detected by a holding power measurement experiment using an animal holding power instrument. After 30 minutes each time following dosing, mice were tested for grip every 2 days interval and the grip determination experiments were repeated 3 times. The animal holding power instrument is provided by Jiangsu Sago Biotechnology Co., ltd, and the product model is SANS, SA-417.
The comparison of the mouse holding power of the control group, DEX group and Q-14 improvement group (Q-14+DEX) is shown in FIG. 9, and can be seen from FIG. 9: the mouse holding power of the DEX group is lower than that of the control group, which indicates that the DEX can cause the muscle weakness of the mice and the obvious reduction of the mouse holding power; the improvement of the Q-14 group (Q-14+DEX) showed that the holding power of the mice was higher than that of the DEX group, indicating that Q-14 significantly improved the problems of reduced skeletal muscle strength, reduced muscle strength and reduced holding power of the mice caused by DEX. Thus, Q-14 has the effect of improving muscle function and muscle strength, and Q-14 can be used to alleviate DEX-induced decline in muscle function and decline in muscle strength.
3.3 experiments on the Effect of DEX, Q-14 on skeletal muscle loss in mice
Mouse gastrocnemius muscle separation and detection: mice in the control group, the DEX group and the Q-14 improvement group (Q-14+DEX) were weighed and treated, then muscles at each part of the mice were precisely isolated, the muscles at each part were rinsed clean with pre-chilled physiological saline, residual water was removed by suction, gastrocnemius was taken, precisely weighed and recorded, and then the ratio of gastrocnemius mass to body weight, i.e., gastrocnemius index, was calculated. The gastrocnemius index was calculated as follows:
gastrocnemius index = mouse gastrocnemius weight g/mouse body weight g x 100%.
The results of comparison of skeletal muscle loss in mice of the control group, DEX group, and Q-14 modified group (Q-14+DEX) are shown in Table 1, and can be seen from Table 1: the difference in the gastrocnemius index of the mice in the DEX group and the control group was significant, and the difference in the gastrocnemius index of the mice in the Q-14 improvement group (Q-14+DEX) and the gastrocnemius index of the mice in the DEX group was significant. The gastrocnemius index of mice in the DEX group was lower than that of the control group, indicating that DEX caused skeletal muscle loss in mice; the gastrocnemius index of the mice in the Q-14 improvement group (Q-14+DEX) is higher than that of the mice in the DEX group, which indicates that Q-14 can obviously improve the problem of skeletal muscle loss caused by DEX and obviously increase the wet weight of the muscle.
TABLE 1 comparison of skeletal muscle loss in mice of control, DEX, Q-14 modified (Q-14+DEX) group
| Group of | Wet weight of gastrocnemius (g) | Mouse body weight (g) | Gastrocnemius index (%) |
| Control group | 0.170±0.013 | 23.24±0.316 | 0.730 ±0.058 |
| DEX group | 0.135±0.006★ | 21.03±0.850★ | 0.641 ±0.037★ |
| Q-14 improvement group | 0.156±0.005# | 21.93±0.513# | 0.713±0.027# |
Where ∈ represents significant differences from the control group, # represents significant differences from the DEX group.
4. Effect of DEX, Q-14 on SIRT1 enzyme Activity experiments
Grouping and administration: a control group, a Q-14 group, a DEX group, a Q-14 improvement group (Q-14+DEX) was set, wherein the control group: 6 mice were given the same volume of physiological saline by oral gavage for 10 days. DEX group: 6 mice, each of which was given DEX at a dose of 25 mg/kg, formulated with 0.5% CMC-Na, and given by intraperitoneal injection, 0.1ml/10g, 1 time a day, with the same volume of physiological saline administered orally by gavage; group Q-14: 6 mice, each of which was dosed with Q-14, Q-14 in Q-14 groups at a dose of 50mg/kg, formulated with 0.5% CMC-Na, and dosed orally 2 times a day at 0.1ml/10 g. Q-14 improvement group (Q-14+dex): 6 mice, each of which was dosed with DEX and Q-14, and the dose of DEX in the Q-14 modified group (Q-14+DEX) was the same as the dose of DEX in the DEX group, and the dose of Q-14 in the Q-14 modified group (Q-14+DEX) was 50mg/kg, formulated with 0.5% CMC-Na, and dosed orally 2 times a day at 0.1ml/10 g.
Experimental method
SIRT1 deacetylase activity was quantified using fluorescence, fluorescence intensity was measured using a SpectraMax M5 microplate reader, the excitation wavelength of fluorescence intensity was 355nm, the emission wavelength was 450 and nm, and concentration was calculated from the standard curve by protein content calibration, operating under the instruction of SIRT1 detection kit (Sigma-Aldrich) kit instructions.
Experimental results
A comparison of SIRT1 enzyme activities of the control group, the Q-14 group, the DEX group, and the Q-14 improved group (Q-14+DEX) is shown in FIG. 10, and can be seen in FIG. 10: the SIRT1 enzyme activity of the Q-14 group is obviously higher than that of the control group, which shows that the Q-14 can obviously enhance the SIRT1 enzyme activity. The SIRT1 enzyme activity of the DEX group was lower than that of the control group, indicating that DEX caused a decrease in SIRT1 enzyme activity. The SIRT1 enzyme activity of the Q-14 improved group (Q-14+DEX) was higher than that of the DEX group, indicating that Q-14 can improve the problem of reduced SIRT1 deacetylase activity caused by DEX. SIRT1 enzyme activity is associated with skeletal muscle atrophy, with higher SIRT1 enzyme activity leading to better resistance to skeletal muscle atrophy. Thus, Q-14 can improve skeletal muscle atrophy induced by DEX by increasing the SIRT1 enzyme activity of the body.
Claims (3)
1. Use of dampness-resolving and toxin-vanquishing particles for the preparation of a medicament for improving skeletal muscle-related side effects caused by dexamethasone, wherein the skeletal muscle-related side effects are at least one of skeletal muscle atrophy and myotube cell injury.
2. Use of granules according to claim 1 for the preparation of a medicament for ameliorating skeletal muscle related side effects caused by dexamethasone, wherein skeletal muscle atrophy is manifested as at least one of reduced skeletal muscle strength and loss of skeletal muscle.
3. Use of dampness resolving and toxin resolving granule for preparing medicine for improving skeletal muscle related adverse reaction caused by dexamethasone, wherein the skeletal muscle related adverse reaction is SIRT1 enzyme activity reduction.
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| KR950000152A (en) * | 1993-06-28 | 1995-01-03 | 고창순 | Osteoporsis and skeletal muscle atrophy inhibitors based on dehydroepiandrosterone and methods of using the same |
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| CN114426568A (en) * | 2022-01-11 | 2022-05-03 | 安帝康（无锡）生物科技有限公司 | 2-oxo-3-pyrrolidinylpropionitrile compound, and pharmaceutical composition and application thereof |
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