CN113616647A - Use of berberine in treating glucocorticoid-induced metabolic disorder - Google Patents
Use of berberine in treating glucocorticoid-induced metabolic disorder Download PDFInfo
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- CN113616647A CN113616647A CN202010388831.6A CN202010388831A CN113616647A CN 113616647 A CN113616647 A CN 113616647A CN 202010388831 A CN202010388831 A CN 202010388831A CN 113616647 A CN113616647 A CN 113616647A
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- Prior art keywords
- acid
- berberine
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- dexamethasone
- glucocorticoid
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- 229940093265 berberine Drugs 0.000 title claims abstract description 40
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 title claims abstract description 40
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The invention belongs to the technical field of pharmacy, and particularly discloses an application of berberine or a pharmaceutically acceptable salt thereof in preparing a medicament for treating metabolic disorder diseases caused by glucocorticoid. The research firstly proves that the berberine or the berberine hydrochloride can reduce the visceral fat accumulation caused by the glucocorticoid dexamethasone and improve the blood fat level, the blood sugar level and the like of the model mouse.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to application of berberine and a salt thereof in visceral fat accumulation and abnormal blood lipid and blood glucose metabolism caused by glucocorticoid.
Background
Glucocorticoids such as Dexamethasone (Dexamethasone, Dex) have multiple effects of resisting inflammation, allergy, shock and nonspecific suppression of immunity, and are mainly used for treating allergic and autoimmune diseases clinically. When used for a long time or in a large dose, the composition often causes muscular atrophy[1]Hyperglycemia and hyperlipidemia[2,3]Central obesity[4,5]And the like, which have adverse effects on the body of a patient, and no effective treatment method exists at present. Therefore, research and development of drugs capable of relieving side effects such as blood sugar and dyslipidemia caused by hormones are of great significance.
Berberine is a traditional natural product medicine, is mainly used for treating diarrhea clinically, is a main component in plants such as phellodendron amurense, coptis chinensis, barberry, Indian barberry and the like, and belongs to benzyl isoquinoline quaternary ammonium protoberberineBasic (II)[6]. Research shows that the berberine has the functions of reducing blood sugar and resisting inflammation[7,8]Reducing blood fat[9]Antimicrobial agent[10]Anti-tumor and intestinal bacteria regulating effects[11,12]And the like.
Through the retrieval of patent documents at home and abroad and the published journal articles, the inventor does not find that the berberine is used for treating side effects such as glycolipid metabolism abnormality caused by glucocorticoid, and does not find reports or documents related to the invention. Disclosure of Invention
The invention aims to solve the technical problem of providing a new application of a natural product medicament berberine (the chemical name of the berberine is 5, 6-dihydro-9, 10-dimethoxybenzo [ g ] -1, 3-benzodioxolane [5, 6-alpha ] quinolizine), namely the application of the berberine or pharmaceutically acceptable salts thereof in medicaments for preventing and/or treating metabolic disorders caused by glucocorticoid. In particular to a new application of berberine or berberine hydrochloride in the drugs for preventing and/or treating diseases caused by glucocorticoid, such as blood fat, blood sugar metabolism disorder, visceral fat accumulation and the like, or provides a new treatment indication of berberine or berberine hydrochloride. Based on experiments such as molecular biology, cell biology and animal models, the inventor finds that berberine has the effect of reducing visceral fat accumulation, hyperlipidemia and hyperglycemia caused by glucocorticoid dexamethasone (the chemical name of dexamethasone is (11 beta, 16 alpha) -9-fluoro-11, 17, 21-trihydroxy-16-methyl pregnene-1, 4-diene-3, 20-dione), and has the effect of treating glucocorticoid-induced metabolic disorder.
The pharmaceutically acceptable salt is selected from the salt formed by berberine and organic acid or inorganic acid. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, and the like, and the organic acid is selected from oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, phthalic acid or p-toluenesulfonic acid, and the like.
The glucocorticoid is dexamethasone or pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is selected from dexamethasone acetate or dexamethasone sodium phosphate and the like.
The metabolic disorder mainly refers to blood sugar, blood fat metabolic disorder and visceral fat accumulation. The disorder of lipid metabolism is high low density lipoprotein-cholesterol, high total cholesterol, high low density lipoprotein-cholesterol, high triglyceride or low high density lipoprotein-cholesterol. The disorder of blood glucose metabolism is hyperglycemia.
Berberine hydrochloride berberine
Dexamethasone disodium phosphate
The inventor proves that the berberine and the berberine hydrochloride have the effects of treating glucose and lipid metabolism disorder and visceral fat accumulation induced by glucocorticoid dexamethasone through extensive and intensive research and experiments. In a mouse model with dexamethasone long-term action, the oral administration of berberine is found to reduce visceral fat accumulation and effectively regulate blood fat and blood sugar levels; in vitro cell experiments, berberine dose-dependently inhibits the differentiation of preadipocytes 3T3-L1, and reduces the lipid content in adipocytes. Compared with the vacancy of drugs for treating the side effect of glucocorticoid drugs in clinical application and the higher biological safety of berberine, research results show that berberine is a drug with great research and application values in the treatment of the side effect of glucocorticoid drugs.
The invention establishes a glucocorticoid mouse model by subcutaneously implanting an osmotic pump with dexamethasone solution as a content. Recording the weight gain, the change of limb muscles, the body fat content and the visceral fat content of the animals; determining blood glucose (Glu), Triglyceride (TG), Cholesterol (CHO), low density lipoprotein-cholesterol (LDL-c), high density lipoprotein-cholesterol (HDL-c) levels in plasma of the model animal; and measuring the expression levels of PPAR gamma and AMPK genes in the adipose tissues and the adipose cells of the animals.
The experimental result shows that berberine (100 mg/kg. day) can remarkably reduce visceral fat accumulation of mice caused by glucocorticoid dexamethasone, and reduce levels of glucose (Glu), Triglyceride (TG), Cholesterol (CHO), and low-density lipoprotein-cholesterol (LDL-c) in plasma; increasing plasma high density lipoprotein-cholesterol (HDL-c) levels; increase the muscle weight of the limbs. The berberine can obviously increase the AMPK expression level in the adipose tissue of a glucocorticoid mouse; reduce PPAR γ expression level.
In vitro cell experiments show that berberine dose-dependently inhibits the differentiation of preadipocytes 3T3-L1 and reduces the lipid content in adipocytes.
The present invention can draw the following conclusions: the berberine or berberine hydrochloride oral administration can obviously reduce visceral fat accumulation caused by glucocorticoid dexamethasone, improve blood fat and blood sugar level, and the action mechanism is related to inhibiting differentiation of preadipocytes and regulating expression of energy metabolism related genes in vivo.
The compound may exist in prodrug form. Prodrugs of the compounds are chemically altered under physiological conditions to yield the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an in vitro environment. Variations of prodrug derivatives are known in the art, e.g., based on hydrolysis or oxidation of the prodrug. Without being limited thereto, the precursors of the compounds encompassed by the present invention may be in their salified form, which, after being metabolized in vivo, form active quaternary ammonium, aldehyde and alcohol compounds.
The compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and both are intended to be encompassed within the scope of the present invention.
The compounds of the present invention exist in polymorphic or amorphous form. In general, the physical forms in which the compounds of the present invention may exist are equivalent when used and are intended to be within the scope of the present invention.
The presence of asymmetric carbon atoms (chiral centers) or double bonds, enantiomers, diastereomers, and stereoisomers of particular compounds of the invention are included within the scope of the invention.
The invention therefore also relates to pharmaceutical compositions containing as active ingredient a compound according to the invention. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form useful as human or veterinary medicaments by combining them with one or more pharmaceutically acceptable solid, semi-solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by oral route.
Compositions for administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, unit dosage forms are provided in the compositions to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes or pills of the liquid composition, tablets, capsules, lozenges or similar solid compositions.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. For example, the liquid dosage form can be a solution (including true solution, colloidal solution), a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Solid dosage forms such as tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, intragastric floating tablet, and orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule, and gastric soluble capsule), dripping pill, powder, granule, and lyophilized powder for injection.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems. For example, the compounds of the present invention may be formulated in sustained or controlled release systems such as diffusion systems (e.g., storage devices, matrix devices, diffusion control implants and transdermal patches) and encapsulation and matrix dissolution systems, disintegrating products, osmotically disintegrating systems, ion exchange resins, and the like.
In order to prepare the unit dosage form into tablets, various carriers well known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants, and the like. The diluent can be starch, dextrin, calcium sulfate, lactose, mannitol, sorbitol, xylitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be glycerol, polyethylene glycol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; the disintegrating agent can be pregelatinized starch, cross-linked polyvinylpyrrolidone, alginate, agar powder, brown algae starch, sodium bicarbonate, citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For example, to encapsulate the administration unit, the active ingredient of the compounds of the invention is mixed with the various carriers mentioned above and the mixture thus obtained is placed directly in hard gelatin capsules or soft gelatin capsules. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.
The dosage of the drug of the present invention to be administered may be adjusted, for example, according to the patient's needs and the nature and severity of the disease, the sex, age, body weight, character and individual response of the patient or animal. Generally, the dosage of the pharmaceutical ingredients of the present invention used is well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount.
The compounds of the invention are administered orally to humans in a dose range of 0.2 to 1.0 g/day. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms which is limited by the clinical experience of the administering physician and by dosage regimens which include the use of other therapeutic means.
The total dose required for each treatment can be divided into multiple doses or administered as a single dose. The compound of the invention can be taken alone, or combined with other therapeutic drugs or symptomatic drugs and dosage is adjusted, and the administration mode of the compound is mainly oral. For the skilled clinician, the treatment regimen (e.g., the dosage of the drug and the number of administrations) may be adjusted according to the particular circumstances, such as the observed patient response to the administered drug and the observed changes in the degree of disease after administration.
The beneficial technical effects are as follows:
our research first proves that berberine and berberine hydrochloride can reduce visceral fat accumulation caused by glucocorticoid dexamethasone, and improve blood lipid and blood glucose levels of model mice. And further verifies that the berberine can generate the effects by inhibiting the differentiation of preadipocytes into adipocytes and regulating the expression of genes related to sugar and lipid metabolism in vivo and in vitro of animals.
Drawings
FIG. 1 shows the oil red staining pattern of adipocytes (a blank control group, b solvent control group, c differentiation group, d berberine 2.5. mu. mol. L-1E berberine 5. mu. mol. L-1F berberine 10. mu. mol. L-1)
FIG. 2 quantitative comparison of fat cell oil red
FIG. 3 animal model construction
FIG. 4 is a graph showing the change in body weight of mice
FIG. 5 comparison of mouse feed consumption
FIG. 6 comparison of body fat percentage in mice
FIG. 7 comparison of the ratio of the length of the soleus muscle to the tibia in the right hind limb of a mouse
FIG. 8 shows the comparison of blood sugar and blood fat levels of mice in different groups after intervention
FIG. 9 comparison of the expression level of mRNA for adipocyte mechanistic factor after termination of intervention
FIG. 10 comparison of the expression levels of adipocyte mechanistic factor proteins after the end of intervention
FIG. 11 comparison of the expression levels of the mechanism factor mRNA in adipose tissue of various groups of mice after the termination of intervention
FIG. 12 comparison of the expression levels of the mechanism factor protein in adipose tissues of various groups of mice after termination of intervention
Detailed Description
The following examples are presented to assist those skilled in the art in providing a more complete understanding of the present invention, but are not intended to limit the invention in any way, and it is to be understood that these examples are provided for illustration only and are not intended to limit the scope of the invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the teachings of the present invention, and such equivalents also fall within the scope of the appended claims.
The berberine hydrochloride is obtained from Nanjing Zealand Biotech, Inc., and berberine is obtained from Shanghai Mecline Biotech, Inc.
First, Experimental example 1
In vitro experiment design:
mouse preadipocytes 3T3-L1 were cultured in DMEM high-sugar medium containing 10% fetal bovine serum at 37 ℃ in 5% CO2In a saturated humidity constant temperature incubator, when the cell fusion degree reaches 70 to 80 percent, pancreatin containing 0.02 percent EDTA is used for digestion and passage. By 4 x 104mL-1The cell suspension of (2) was cultured in a 6-well plate, and a blank control group (DMEM), a solvent control group (CON), and a differentiation group (DM) were added to the plate, followed by differentiation to give a drug (2.5. mu. mol. L)-1,5μmol·L-1,10μmol·L-1BBR). After the cells were confluent and in contact with the cells for 2 days, differentiation wells were filled with a differentiation-inducing solution (90% DMEM, 10% FBS, 1.0. mu. mol. L)-1Dexamethasone, 0.5mmol·L-1IBMX、1.0μg·mL-1Insulin) for 2 days, and then with a differentiation maintenance solution (90% DMEM, 10% FBS, 1.0. mu.g. mL)-1Insulin) for 7-15 days, replacing fresh culture medium in blank control wells and replacing culture medium in solvent control groups with the same amount of solvent as the solution used in differentiation wells each time the solution is replaced in differentiation wells. After the cell differentiation was completed, the cells were used with a medium containing 2.5. mu. mol. L-1,5μmol·L-1,10μmol·L-1Culturing in complete culture medium for 24 hr.
Preparing 60% oil red dye by using double distilled water, and filtering to obtain clear oil red dye solution. The culture medium is discarded from the six-hole plate after the drug treatment, PBS is washed twice, 4% paraformaldehyde is used for fixing for 15min, the PBS is washed once after the fixing is finished, 1.2mL of oil red dye solution is added into each hole, the six-hole plate is dyed for 15min in a dark place, the PBS is washed for several times, and a microscope is used for photographing.
Adding 500 μ L isopropanol into each culture well after oil red staining, shaking to dissolve the dye in isopropanol, collecting in 1.5mL centrifugal tube, and collecting at 800 r.min-1Centrifuging for 5min, collecting supernatant 100 μ L, adding into 96-well plate, setting parallel wells in each group for 3, zeroing with isopropanol, measuring OD value of each well with microplate reader at 490nm wavelength, and quantitatively comparing oil red staining conditions.
Extracting cell protein and RNA which have the same treatment mode and are not stained by oil red.
Secondly, the influence of berberine on the differentiation of preadipocytes
FIG. 1 shows that 3T3-L1 cells used after differentiation were 2.5. mu. mol. L-1,5μmol·L-1,10μmol·L-1After the berberine is cultured in a complete culture medium for 24 hours, the result of oil red staining shows that the generation of intracellular lipid drops of differentiated preadipocytes is increased obviously, and the coloring area of the oil red is reduced along with the increase of the administration concentration. Figure 2 shows that the quantification of oil red decreases after administration. The berberine is shown to inhibit the differentiation of mouse preadipocytes to mature adipocytes in a dose-dependent manner and reduce the generation of adipose tissues. The oil red quantification is shown in table 1.
TABLE 1 oil Red quantification OD values
Thirdly, in vivo experimental design:
clean grade C57 mice 18 (male, 6 weeks old, 20-22g in weight) were purchased from experimental animals technology ltd, viton, beijing. Animals are raised in the animal center of the institute of pharmaceutical research of Chinese academy of medical science under constant temperature of 23 + -2 deg.C and moderate temperature of 50-70%, and sterilized padding, free diet and water are replaced twice per week. The administration and treatment of mice were as follows:
after the animals were acclimated in the animal room for one week, the C57 mice were randomly divided into a control group, a model group and a berberine hydrochloride group, 6 mice per group, and fed with normal maintenance feed. Mice were acclimatized for one week and then subcutaneously implanted with osmotic pressure pump (2004 type, 0.25 μ L/h, 4 weeks old, available from Alzet, USA) to control group containing normal saline and model group and berberine hydrochloride group containing dexamethasone disodium phosphate solution (1.4ug day)-1) Antibiotics were injected three consecutive days after surgery, and the animal model is shown in fig. 3. The berberine hydrochloride group mice were gavaged at 100mg/kg/day for 4 weeks. The body weight and food intake of the mice were measured weekly during the period. And (3) taking out the osmotic pump after the administration is finished, carrying out body fat detection by small animal nuclear magnetic imaging after the mouse state is recovered every other day, then taking blood from eyeballs, taking out epididymis adipose tissues of the mouse after the neck is removed and the mouse is killed, and carrying out subsequent molecular biology experiments.
Fourthly, the change of the berberine hydrochloride dry prognosis animal growth condition
1. Weight change of each group of mice during berberine hydrochloride intervention period
The body weight of the mice was recorded weekly during the experiment, and the body weight change is shown in fig. 6, n-6,
comparison of representation to model group P<0.05. As can be clearly seen from the figure, the body weight of the model group after receiving the effect of dexamethasone is obviously reduced compared with that of the control group of mice; the weight of the berberine hydrochloride group mice has no significant difference compared with the model group.
2. Comparison of feed consumption of groups of mice during berberine hydrochloride intervention
The feed consumption of each group of mice was recorded weekly during the experiment and the daily average consumption of each mouse was calculated for each group. The weight change is shown in fig. 4, n is 6,
and comparing with the model group. As is clear from FIG. 5, there is no significant difference in the amount of feed consumed by the mice in each group C57, so that the weight change of the mice in the model group and the berberine hydrochloride gavage group relative to the control group is independent of the food intake.
3. Comparison of systemic, subcutaneous and visceral fat percentage of mice after berberine hydrochloride intervention
Fig. 6 is a comparison of body fat percentage data and MRI images of mice in each group after berberine hydrochloride drying, wherein white area is in vivo adipose tissue, n is 6,
comparison of representation to model set p<0.05, p is compared to the model set<0.01, p is compared to the model set<0.001. After the model group continuously acts on the hormone for 4 weeks, imaging shows that visceral fat accumulation of the mice in the group is obviously increased compared with a control group, subcutaneous fat has no significant change, the visceral fat content is reduced by about 33.3 percent after the berberine hydrochloride is perfused, and the body fat rate is reduced. Specific values are shown in Table 2.
TABLE 2 mouse visceral, subcutaneous and whole body fat values (%)
4. Comparison of the length ratio of the mouse's hindlimb soleus muscle to the tibia after berberine hydrochloride intervention
Fig. 7 is a graph of the change in the ratio of the muscle length to the tibia length of the posterior limb soleus in mice following berberine hydrochloride intervention, n-6,
comparison of representation to model set p<0.05. The ratio of the soleus muscle weight to the tibia length is used as an index of muscle atrophy, and comparison shows that the ratio of the soleus muscle weight to the tibia length is remarkably reduced compared with that of a control group, namely, after a C57 mouse receives dexamethasone for a long time, the muscle atrophy appears, the physiological change generated by long-term stimulation of glucocorticoid is met, and berberine hydrochloride can relieve the side effect of the glucocorticoid on muscle decomposition. Specific values are shown in Table 3.
TABLE 3 ratio of mouse right hind limb soleus muscle weight to tibial length (g/mm)
(mouse Glucose, Glu), total Cholesterol (CHO), Triglyceride (TG), High-density lipoprotein cholesterol (HDL-c), Low-density lipoprotein cholesterol (LDL-c) for blood Glucose and blood lipid index comparison).
5. Berberine hydrochloride is used for prognosis of changes of blood sugar and blood fat related factors of various groups of C57 mice
Fig. 8 shows the comparison of blood sugar and blood fat related factors of C57 mice in each group after berberine hydrochloride drying, n is 6,
representation in comparison with model control group P<0.05, P in comparison with the model control group<0.01, P is compared with model control group<0.001. As can be seen from FIG. 8, the levels of triglyceride, cholesterol, low-density lipoprotein and blood glucose in the blood of the mice in the model group showed an increasing trend, while the level of high-density lipoprotein showed a decreasing trend, and after intragastric administration of berberine hydrochloride, the levels of triglyceride, cholesterol, low-density lipoprotein and blood glucose were decreased, and the level of high-density lipoprotein cholesterol was increased. The result shows that the berberine hydrochloride can regulate the abnormal blood sugar and blood fat metabolism caused by dexamethasone. Specific values are shown in Table 4.
TABLE 4 concentration (mmol/L) of glycolipid-related factor in mouse plasma
Fifth, mechanism discussion
We examined mRNA and protein level expression of important regulatory factors involved in energy metabolism in induced differentiated preadipocytes and mouse adipose tissues, mainly the peroxisome proliferator-activated receptor gamma (PPAR γ), adenosine-5' -monophosphate (AMP) -dependent kinase (AMPK).
PPAR γ is one of the subtypes of peroxisome proliferator-activated receptors (PPARs), belongs to ligand-activated receptors in nuclear hormone receptor family, is mainly present in adipose tissue, can regulate the gene expression of adipocyte differentiation, lipogenesis and glucose metabolism, and has close relationship with type 2 diabetes, amyotrophic lateral sclerosis, atherosclerosis, obesity and other metabolic diseases[13-15]. AMPK is a key molecule in the process of regulating energy metabolism, is closely related to metabolic diseases, participates in various biological processes such as fatty acid oxidation and insulin resistance, and the expression of the AMPK is mainly influenced by the change of the AMP/ATP ratio in vivo, and when the AMP level is increased or the ATP content is reduced, the AMPK can stimulate the expression of AMPK, thereby increasing the synthesis of ATP and promoting the catabolism[16]. AMPK activation can reduce the production of fatty acid and cholesterol and promote the oxidation of fatty acid, and simultaneously plays a role in regulating downstream pathways of lipid metabolism, thus being a research hotspot of obesity-related metabolic diseases.
1. Results of RT-PCR in adipocytes
FIG. 9 is a comparison of the mRNA expression levels of the action mechanism factor in each group of adipocytes after the completion of the intervention,
ratio of target gene to reference gene, P in comparison with model control group<0.01, P is compared with model control group<0.001; as can be seen from the figure, the blank control group and the solvent control group have no significant difference in the target gene expression level, and compared with the model group, each berberine dose group has reduced PPAR γ expression in fat cells and increased mRNA expression level of AMPK, and has significant difference. Therefore, in vitro experiments, berberine can improve blood lipid and blood glucose levels by regulating mRNA level of energy metabolism related gene. The relevant data are shown in Table 5.
Table 5 relative expression amounts of AMPK α and PPAR γ mrnas in cells (x ± s, n ═ 3)
2. Western blot results in adipocytes
FIG. 10 is a comparison result of the expression levels of the action mechanism factor protein in each group of adipocytes after intervention is completed, which indicates that berberine can increase AMPK and inhibit the expression of PPAR γ dose-dependently.
C57 mouse adipose tissue RT-PCR results
FIG. 11 is a graph showing the comparison of the expression level of mRNA, a mechanism of action factor, in adipose tissues of C57 mice in each group after the completion of the intervention, n-6,
ratio of target gene to reference gene, P in comparison with model control group<0.01, P is compared with model control group<0.001; as can be seen from the figure, compared with the model group, the berberine hydrochloride intragastric administration group has the advantages that the PPAR gamma expression of the adipose tissue is reduced, the mRNA expression level of AMPK is increased, and the significant difference is achieved. Therefore, in an in vivo test, berberine hydrochloride can improve the blood fat and blood sugar levels by regulating the mRNA level of the energy metabolism related gene. The data are shown in Table 6.
TABLE 6 relative expression levels of AMPK alpha and PPAR gamma mRNA in mouse adipose tissue
Western blot results of C57 mouse adipose tissues
FIG. 12 is a comparison of the expression levels of the action mechanism factor protein in each group of adipose tissues after termination of intervention. The result shows that the berberine hydrochloride can increase AMPK and inhibit the expression of PPAR gamma.
Reference to the literature
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[2]Raalte DHV,Ouwens DM,Diamant M.Novel insights into glucocorticoid-mediated diabetogenic effects:towards expansion of therapeutic options.Eur J Clin Invest,2009,39(2):81-93.
[3]Androulakis II,Kaltsas GA,Kollias GE.Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.J Clin Endocrinol Metab,2014,99(8):2754-2762.
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[7] Jiang T, Jia YH, Li YS.research progress of berberine lipid-lowering mechanism. drugs & Clinic (modern medicine and Clinic), 2016,31(5): 727-.
[8]Liu Y,Zhao Y,Guo Dl,et al.Synergistic antimicrobial activity of berberine hydrochloride,baicalein and borneol against candida albicans.Chinese Herbal Medicines,2017,9(4):353-357.
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[10]Liu SJ,Yin CX,Ding MC,et al.Berberine inhibits tumor necrosis factor-α-induced expression of inflammatory molecules and activation of nuclear factor-κB via the activation of AMPK in vascular endothelial cells.Molecular Medicine Reports,2015,12(4):5580-5586.
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Claims (10)
1. Application of berberine or its pharmaceutically acceptable salt in preventing and/or treating metabolism disorder caused by glucocorticoid.
2. Use according to claim 1, characterized in that berberine is chemically named 5, 6-dihydro-9, 10-dimethoxybenzo [ g ] -1, 3-benzodioxolane [5,6- α ] quinolizine.
3. The use according to claim 1, characterized in that said pharmaceutically acceptable salt is selected from the salts of berberine with organic or inorganic acids.
4. Use according to claim 3, characterized in that the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid and the organic acid is selected from oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, phthalic acid or p-toluenesulfonic acid-.
5. Use according to claim 3, characterized in that said pharmaceutically acceptable salt is selected from berberine hydrochloride.
6. Use according to claim 1, characterized in that the glucocorticoid is dexamethasone or a pharmaceutically acceptable salt thereof, the chemical name of dexamethasone being (11 β, 16 α) -9-fluoro-11, 17, 21-trihydroxy-16-methylpregnene-1, 4-diene-3, 20-dione.
7. Use according to claim 6, characterized in that said pharmaceutically acceptable salt is selected from dexamethasone acetate or dexamethasone sodium phosphate.
8. Use according to claim 1, characterized in that the metabolic disorders are mainly blood sugar, lipid metabolism disorders and visceral fat accumulation.
9. Use according to claim 8, characterized in that the disorder of the blood lipid metabolism is high low density lipoprotein-cholesterol, high total cholesterol, high low density lipoprotein-cholesterol, hypertriglyceridemia or low high density lipoprotein-cholesterol.
10. Use according to claim 8, characterized in that the disorder of blood glucose metabolism is hyperglycemia.
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