CN110922337A - Monomer compound, pharmaceutical composition for treating chronic kidney disease and application thereof - Google Patents

Monomer compound, pharmaceutical composition for treating chronic kidney disease and application thereof Download PDF

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CN110922337A
CN110922337A CN201911055511.2A CN201911055511A CN110922337A CN 110922337 A CN110922337 A CN 110922337A CN 201911055511 A CN201911055511 A CN 201911055511A CN 110922337 A CN110922337 A CN 110922337A
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pharmaceutical composition
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kidney disease
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刘志刚
刘杰
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Abstract

The invention provides a monomer compound or pharmaceutically acceptable salt thereof, the structural formula of the monomer compound is shown as a formula I,
Figure DDA0002256444600000011
the monomeric compound has the effect of relieving glomerular cell injury caused by inflammation and the like, and is helpful for relieving morphological and functional injury of cells such as glomeruli and the like. The invention also provides a pharmaceutical composition for treating chronic kidney disease and application thereof.

Description

Monomer compound, pharmaceutical composition for treating chronic kidney disease and application thereof
Technical Field
The invention relates to the field of biomedicine, and in particular relates to a monomer compound, a pharmaceutical composition for treating chronic nephropathy and application thereof.
Background
Chronic Kidney Disease (CKD) is a generic term for heterogeneous diseases that affect kidney structure and function. Statistically, more than 10.8% of people in china have kidney disease, and the mortality rate of end-stage renal disease in the united states is more than 20%. In recent years, chronic kidney diseases have been increasing year by year in global morbidity, and have poor prognosis and high cost, thus becoming a public health problem seriously harming human health worldwide.
Disclosure of Invention
In order to solve the above problems, the present invention provides a monomeric compound, a pharmaceutical composition for treating chronic kidney disease and use thereof; the monomeric compound has the effect of relieving glomerular cell injury caused by inflammation and the like, and is helpful for relieving morphological and functional injury of cells such as glomeruli and the like. The invention also provides a pharmaceutical composition for treating chronic kidney disease and application thereof.
In a first aspect, the invention provides a monomeric compound or a pharmaceutically acceptable salt thereof, wherein the monomeric compound has a structural formula shown in formula I,
Figure BDA0002256444580000011
alternatively, the pharmaceutically acceptable salt of the monomeric compound is selected from the group consisting of sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridine salt, picoline salt, 2, 6-dimethylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, purine salt, piperazine salt, piperidine salt, N-ethylpiperidine salt, polyamine resin salt, phentermine penicillin salt, hydrochloride salt, hydrobromide salt, sulfate salt, nitrate salt, phosphate salt, formate salt, acetate salt, glycolate salt, propionate salt, 2-hydroxypropionate salt, malonate salt, trifluoroacetate salt, methanesulfonate salt, ethanesulfonate salt, glycine salt, penicillin salt, and the like, Trifluoromethanesulfonate, vinylsulfonate, benzenesulfonate, p-toluenesulfonate, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malate, oxalate, salicylate, glucuronate, galacturonate, citrate, aspartate, glutamate, cinnamate, or a combination thereof.
The monomeric compound or the pharmaceutically acceptable salt thereof provided by the first aspect of the invention has the efficacy of relieving glomerular cell injury caused by inflammation and the like, is beneficial to relieving morphological and functional injury of cells such as glomeruli and the like, and can be widely used in medicines for treating chronic nephropathy or in the field of foods or health care products for assisting in nourishing the stomach. The monomeric compound or the pharmaceutically acceptable salt thereof can be prepared by probiotic fermentation of natural plants, and is safe and reliable.
In a second aspect, the present invention provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable excipient; the active component comprises a monomer compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002256444580000021
optionally, the pharmaceutical composition comprises a fermentation broth obtained by fermenting a Chinese herbal medicine compound extract of barbary wolfberry fruit, dogwood, radix rehmanniae, Chinese yam, medicinal cyathula root, mulberry, epimedium herb and medicinal indianmulberry root with probiotics, wherein the probiotics comprise lactic acid bacteria and bifidobacteria.
Optionally, the Chinese herbal medicine compound extract comprises the following raw material components in parts by weight: 1-20 parts of wolfberry fruit, 1-25 parts of dogwood, 1-15 parts of radix rehmanniae recen, 5-20 parts of Chinese yam, 3-18 parts of medicinal cyathula root, 1-15 parts of mulberry, 2-16 parts of epimedium and 1-10 parts of morinda officinalis.
Further, optionally, the Chinese herbal medicine compound extract comprises the following raw material components in parts by weight: 3-20 parts of wolfberry fruit, 5-25 parts of dogwood, 3-15 parts of radix rehmanniae recen, 5-10 parts of Chinese yam, 6-15 parts of medicinal cyathula root, 5-10 parts of mulberry, 2-5 parts of epimedium and 2-8 parts of morinda officinalis.
Optionally, the lactic acid bacteria is lactobacillus paracasei and the bifidobacteria is bifidobacterium infantis. Optionally, the mass ratio of lactic acid bacteria to bifidobacteria is 1: (0.1-10).
Further, the mass ratio of the lactic acid bacteria to the bifidobacteria is 1: (0.5-3).
Optionally, the preparation method of the fermentation broth comprises:
weighing the components according to the weight percentage, putting the components into a container, adding water for soaking, decocting and sterilizing to obtain a Chinese herbal medicine compound extracting solution;
and inoculating a bacterium solution containing the probiotics into the Chinese herbal medicine compound extracting solution for fermentation at the fermentation temperature of 23-30 ℃ for 16-48 hours, and after the fermentation is finished, filtering and concentrating to obtain the fermentation liquor.
Optionally, the pH during the fermentation is 5.0-6.0.
Further, optionally, the pH during the fermentation is 5.5-6.0.
For example, the pH during the fermentation is 5.0, or 5.5, or 5.8, or 6.0.
In the embodiment of the invention, the fermentation liquor prepared by probiotic fermentation of the Chinese herbal medicine compound extract of barbary wolfberry fruit, common macrocarpium fruit, raw rehmannia root, common yam rhizome, medicinal cyathula root, mulberry fruit, epimedium herb and medicinal indianmulberry root contains the monomer compound. The monomeric compound can be obtained by subjecting the fermentation broth to vacuum low-temperature lyophilization, chromatographic separation and High Performance Liquid Chromatography (HPLC).
In one embodiment, the method for isolating the monomeric compound from the fermentation broth comprises:
centrifuging 7000-10000r/min to obtain supernatant, and collecting the supernatant by chromatography and HPLC to obtain the monomer compound. The preparation process is simple, the operation is convenient, and the purity of the obtained monomer compound is high.
In one embodiment of the invention, the pharmaceutical composition is the fermentation liquid prepared by probiotic fermentation of a Chinese herbal medicine compound extract of medlar, dogwood, radix rehmanniae, Chinese yam, medicinal cyathula root, mulberry, epimedium and morinda officinalis; wherein the monomeric compound contained in the fermentation broth serves as at least one active component in the pharmaceutical composition.
Optionally, in the pharmaceutical composition, the mass percentage of the monomer compound or the pharmaceutically acceptable salt thereof is 0.01-90%. Wherein, the mass percentage of the monomer compound in the pharmaceutical composition can be adjusted by adding an additional monomer compound.
For example, in the pharmaceutical composition, the mass percentage of the monomeric compound or the pharmaceutically acceptable salt thereof is 0.01-50%, or 10-50%, or 20-50%, or 0.1-10%.
In another embodiment of the present invention, the pharmaceutical composition is composed of the fermentation broth and pharmaceutically acceptable excipients; the fermentation liquor is prepared by probiotic fermentation of a Chinese herbal medicine compound extract of barbary wolfberry fruit, dogwood, radix rehmanniae, Chinese yam, medicinal cyathula root, mulberry, epimedium and morinda officinalis.
In a third embodiment of the present invention, the pharmaceutical composition comprises an active ingredient of the monomeric compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant; wherein, the monomeric compound or the pharmaceutically acceptable salt thereof is obtained by separation by a fermentation method and/or synthesis by an artificial synthesis method. The fermentation method comprises the following steps: the preparation method comprises the steps of fermenting Chinese herbal medicine compound extracting solutions of barbary wolfberry fruit, common macrocarpium fruit, raw rehmannia root, common yam rhizome, medicinal cyathula root, mulberry, epimedium herb and medicinal indianmulberry root with probiotics to obtain fermentation liquor, and then separating and extracting the monomeric compound or pharmaceutically acceptable salt thereof from the fermentation liquor. The artificial synthesis method may be, but is not limited to, a method by Boc solid phase synthesis or Fmoc solid phase synthesis.
Optionally, the pharmaceutical composition further comprises other active ingredients including at least one of vitamin C, vitamin E, coenzyme Q, glutathione, carotene, and betaine.
In one embodiment, the other active ingredient may be vitamin C, vitamin E, coenzyme Q, glutathione, carotene, or betaine. In another embodiment, the other active ingredient may be at least two of vitamin C, vitamin E, coenzyme Q, glutathione, carotene, and betaine.
Alternatively, other active ingredients in the pharmaceutical composition may be adjusted according to the specific use of the pharmaceutical composition. For example, the other active ingredients also have certain efficacy against chronic kidney disease, or the other active ingredients have certain efficacy as auxiliary anti-inflammatory, and the like.
Optionally, in the pharmaceutical composition, the mass percentage of the other active components may be, but is not limited to, 1% to 70%.
Optionally, the dosage form of the pharmaceutical composition comprises one of a capsule, a microcapsule, a suppository, a powder, a granule, an oral liquid, an aerosol, a jelly and a granule.
In an embodiment of the present invention, the dosage form of the pharmaceutical composition may be formed by adding pharmaceutically acceptable excipients.
Optionally, the pharmaceutically acceptable excipient may include, but is not limited to, a carrier or excipient. Optionally, the carrier comprises at least one of a solvent, a polymer, a liposome, and a diluent. Wherein, the solvent may include, but is not limited to, water, physiological saline, or other non-aqueous solvents. The polymer may include, but is not limited to, at least one of polylysine, polyethyleneimine and modifications thereof, chitosan, polylactic acid, and gelatin. Optionally, the liposome may include, but is not limited to, at least one of cholesterol, soy lecithin, and egg yolk lecithin. Optionally, the diluent comprises one or more of starches, sugars, celluloses, and inorganic salts. Optionally, the excipient comprises at least one of a binder in a tablet, a filler, a lubricant, a base portion in a semisolid formulation ointment, a cream, a preservative, an antioxidant, a flavoring agent, an aromatic, a cosolvent, an emulsifier, and a colorant.
In a second aspect, the present invention provides a pharmaceutical compound for use in the treatment of chronic kidney disease, said pharmaceutical composition comprising at least the active ingredient of the monomeric compound of the first aspect of the invention; the pharmaceutical composition has the effects of relieving glomerular cell injury caused by inflammation and the like, and is helpful for relieving morphological and functional injuries of cells such as glomeruli and the like. Specifically, the pharmaceutical composition can remarkably reduce the accumulation of Reactive Oxygen Species (ROS), the reduction of superoxide dismutase (SOD) activity and the secretion of inflammatory factors caused by high sugar, and is helpful for reducing the damage of the oxidative factors and the inflammatory factors to cells. Meanwhile, the pharmaceutical composition can play a role in protecting cells by regulating a TLR 4/NF-kB/NLRP 3 inflammatory signal pathway axis.
The pharmaceutical compound for treating chronic kidney disease provided by the second aspect of the invention can be prepared by fermenting the Chinese herbal medicine compound extract of medlar, dogwood, radix rehmanniae, yam, medicinal cyathula root, mulberry, epimedium herb and morinda root with probiotics, wherein the Chinese herbal medicine compound extract is extracted from natural Chinese herbal medicines, has the characteristic of good pharmacological activity, and can avoid the huge side effects of medicines brought by the traditional medicines. Meanwhile, the probiotics used in the preparation of the pharmaceutical composition comprising the fermentation broth of the present invention are active microorganisms that colonize the human body and are beneficial to the host. The probiotics play an important role in regulating the immune function of a host and keeping the intestinal health; has important functions in the aspects of resisting inflammation, preventing tumor, reducing blood fat, preventing food allergy and the like. The preparation process is simple, and the prepared medicine components have quick effect and obvious effect and can achieve the effect of treating both symptoms and root causes.
The Chinese herbal medicine compound extract liquid consisting of the medlar, the dogwood, the radix rehmanniae recen, the yam, the medicinal cyathula root, the mulberry, the epimedium herb and the morinda officinalis has good pharmacological activity on chronic kidney diseases; meanwhile, the probiotics have good functions of reducing toxicity and increasing the curative effect of the medicine, so that the medicine composition comprising the fermentation liquor has smaller side effect and higher curative effect.
In a third aspect, the present invention also provides a use of the pharmaceutical composition according to the second aspect of the present invention in the preparation of a medicament or health product for preventing or treating chronic kidney disease.
Optionally, the chronic kidney disease includes diabetic nephropathy, renal arteriosclerotic disease, primary and secondary glomerulonephritis, tubulointerstitial lesions, renal vascular lesions and hereditary nephropathy. For example, IgA nephropathy or IgG nephropathy.
In one embodiment, the present invention provides the use of a pharmaceutical composition according to the second aspect of the present invention in the manufacture of a medicament for the prevention or treatment of chronic kidney disease. In another embodiment, the present invention provides a use of the pharmaceutical composition according to the second aspect of the present invention for the preparation of a health product for preventing or treating chronic kidney disease. The pharmaceutical composition can be applied to food besides the application in medicines or health products. For example, in the embodiment of the present invention, the pharmaceutical composition is added to food, even health food, as a food additive as an effective ingredient for preventing or treating chronic kidney disease.
Optionally, the physical form of the health product may include, but is not limited to, gel or aqueous form. Optionally, the health product further comprises an additive, wherein the additive can include but is not limited to at least one of monosaccharide, oligosaccharide, polysaccharide, amino acid, antioxidant and pH regulator.
Optionally, the drug is at least one of a chemical drug and a biological drug. Further optionally, the biological drug comprises one or more of a polypeptide drug, a protein drug and a gene drug.
The pharmaceutical composition of the third aspect of the present invention has the effects of reducing the damage of glomerular cells caused by inflammation and the like, and helping to reduce the morphological and functional damages of the cells such as glomerulus, and can be widely applied to foods, medicines and health products.
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In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a mass spectrometric detection profile of a monomeric compound provided in an embodiment of the present invention;
FIG. 2 is a mass spectrometric detection profile of a monomeric compound provided in another embodiment of the present invention;
FIG. 3 is a high performance liquid chromatography detection profile of a monomeric compound provided in an embodiment of the present invention;
FIG. 4 is a graph of data on HG-induced cell proliferation of HBZY-1 induced by pharmaceutical compositions and monomeric compounds according to an embodiment of the present invention;
FIG. 5 is a graph of data of cellular inflammatory responses of an embodiment of the present invention to inhibit HG inhibition of HBZY-1;
FIG. 6 shows that the pharmaceutical composition and the monomeric compound provided by one embodiment of the invention inhibit HG-induced oxidative stress of HBZY-1 cells;
FIG. 7 is a data graph of the data of the pharmaceutical compositions and monomeric compounds of the present invention inhibiting TLR4 NF-kB/NLRP 3 inflammatory pathway;
FIG. 8 is a data graph of data of a pharmaceutical composition and monomeric compound of the present invention inhibiting TLR4/NF- κ B pathway and NLRP3 inflammatory response;
FIG. 9 is a data graph of the inhibitory effect of the TLR 4/NF-kB/NLRP 3 inflammatory axis on HBZY-1 cells under HG conditions for a pharmaceutical composition and a monomeric compound provided by an embodiment of the invention.
Detailed Description
While the following is a description of the preferred embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the raw materials and other chemicals used in the examples of the present invention are commercially available.
Example one
A pharmaceutical composition preparation comprising:
taking 30g of powder of 3 parts of medlar, 5 parts of dogwood, 5 parts of radix rehmanniae recen, 5 parts of Chinese yam, 8 parts of medicinal cyathula root, 10 parts of mulberry, 3 parts of epimedium herb and 2 parts of morinda officinalis extract according to the proportion; soaking in water, decocting, and sterilizing to obtain Chinese herbal compound extractive solution; selecting 10g of probiotic dry powder containing lactobacillus and bifidobacterium, wherein the lactobacillus is lactobacillus paracasei, and the bifidobacterium comprises bifidobacterium infantis; thus obtaining the mixture. Fermenting at 25 deg.C and pH of 5.5 for 24 hr to obtain fermentation liquid.
Centrifuging the fermentation liquid at 9000r/min for 30min, removing precipitate, retaining supernatant, and freeze drying the supernatant to obtain the pharmaceutical composition.
Effects of the embodiment
In order to evaluate the effects of the pharmaceutical composition for treating chronic kidney disease prepared by the above-described method of the present invention, the following effect test examples were conducted.
Separation and detection of monomeric Compound
60g of the pharmaceutical composition prepared in example 1 is subjected to vacuum low-temperature freeze-drying and is prepared by various chromatographs and HPLC to obtain a probiotic fermented monomer compound of the traditional Chinese medicine for resisting chronic kidney disease, and mass spectrum and high performance liquid chromatography are utilized to measure the probiotic fermented monomer compound, wherein the mass spectrum measurement conditions comprise ESI positive ion mode capillary voltage of 3kV, cone hole voltage of 50V, extraction voltage of 5V, desolvation temperature of 350 ℃ and atomized airflow of 350L/h; the conditions for the measurement by high performance liquid chromatography were a liquid Boston liquid chromatography column (Boston GreenODS-AQ column (250 × 4.6mm)), using a 0.1% aqueous trifluoroacetic acid solution as a mobile phase a, a 0.1% acetonitrile solution of trifluoroacetic acid as a mobile phase a, and a mobile phase a: the flow rate of the mobile phase B is 75:25, the flow rate is 1mL/min, the detection wavelength is 220nm, and the sample injection amount is 10 mu L.
The results are shown in FIGS. 1-3, wherein FIGS. 1 and 2 are mass spectrometry spectra of the monomeric compound under [ M-H ] -and [ M + H ] +, respectively, FIG. 3 is a high performance liquid chromatography spectrum of the monomeric compound, from which the chemical structure of the monomeric compound can be analyzed as shown in formula I,
Figure BDA0002256444580000081
(II) effects of pharmaceutical compositions and monomeric compounds on chronic kidney disease.
Animal model test design: a number of male Sprague-Dawley (SD) rats (180- & lt220 g) were housed in a 22 + -2 ℃ chamber at 55 + -5% relative humidity, light-dark-cycled (12-12 hours), allowed to acclimate for 1 week or tested. Rats were randomly divided into control group and high fructose feeding group; wherein the control group is administered with standard feed and drinking water, and the high fructose feeding group is administered with standard feed and drinking water containing 10% fructose, and the drinking water is changed every day for 10 weeks. During this period, 4 weeks later, the rats in the high fructose feeding group were further divided into 3 subgroups (n ═ 8), and gavaged with purified water (1mL/kg), monomeric compound (2mg/kg) and pharmaceutical composition (2mg/kg), respectively, for 6 weeks.
(1) And (3) testing the blood sugar content: for the last week of feeding, rats were weighed and fasted for 14 hours, followed by oral administration of glucose (1.5 g/kg). Collecting tail vein blood samples at different time of 0-120 min, centrifuging at 4 deg.C for 10min (4000g centrifugal force), and measuring blood sugar content with blood sugar measuring kit.
(2) Urine albumin analysis: at the end of the above experiment (1), rats were placed in metabolism cages for 24 hours, urine samples were collected and the volume was recorded. Centrifugation at 2000g for 10min removed particulate contaminants and the supernatant was used for urine albumin analysis.
(3) Histological analysis and immunoblot assay analysis: after the above oral glucose tolerance test, rats recovered for 3 days; the rats were then sacrificed after 16h of fasting. Kidney tissue was rapidly dissected on ice. One portion was immediately fixed for histological analysis and the other portion was kept in liquid nitrogen for immunoblot analysis (Western blotting). Collecting blood sample, centrifuging at 4 deg.C (3000g) for 10min, freezing and storing at-80 deg.C, and detecting uric acid, creatinine, blood urea nitrogen, insulin, triglyceride, total cholesterol and low density lipoprotein with enzyme linked immunosorbent assay (Elisa) kit.
Wherein, the distribution was such that HBZY-1 cells were cultured under normal glucose (NG, 5.5mM D-glucose), mannitol + glucose (M + G, 24.5mM mannitol and 5.5mM D-glucose) or high sugar (HG, 30mM D-glucose). Under each culture condition, a common non-addition group, a drug composition addition group, a monomer compound addition group and a blank control group (cells are cultured by using buffer only) are respectively arranged; then detecting the cell proliferation level by an MTT method (a tetramethylazoazolate trace enzyme reaction colorimetric method).
The results are shown in FIG. 4, in which (a) in FIG. 4 is a graph showing the relative activity of cells of each group under NG culture conditions; FIG. 4 (b) is a graph showing the relative activities of cells in each group under M + G culture conditions; FIG. 4 (c) is a graph showing the relative activities of the cells of each group under HG culture conditions. From the results of FIG. 4, it can be shown that HG induced HBZY-1 cell proliferation (p <0.05), while NG and M + G had no effect on HBZY-1 cell proliferation (p > 0.05). The pharmaceutical composition can inhibit HG-induced HBZY-1 cell proliferation.
Since inflammatory cytokines play an important role in chronic kidney disease, the levels of HBZY-1 cellular inflammatory cytokines, including IL-6, IL-1 β and TNF- α, were measured by the fluorescent real-time quantitative PCR (Q-RT-PCR) technique, as shown in FIG. 5, in which (a) and (b) in FIG. 5 are graphs of data on the relative expression amount of mRNA and the relative level of IL-6 for each group of IL-6 under HG culture conditions, (c) and (d) in FIG. 5 are graphs of data on the relative expression amount of mRNA and the relative level of IL-1 β for each group of IL-1 β under HG culture conditions, and (e) and (f) in FIG. 5 are graphs of data on the relative expression amount of mRNA and the relative level of TNF- α for each group of TNF- α under HG culture conditions;
the results show that HG stimulation significantly increases the mRNA- α levels of IL-6, IL-1 β and TNF (p <0.05), while the pharmaceutical composition significantly decreases the expression (p < 0.05). Elisa method measures the content of inflammatory cytokines in supernatant of HBZY-1 cells, and the results show that HG stimulation of cells significantly induces the secretion of inflammatory cytokines (p <0.05), while the pharmaceutical composition inhibits HG-induced inflammatory cytokine production (p <0.05)
Oxidative stress is an important cause of HG-induced cell damage, and was found by measuring the levels of Reactive Oxygen Species (ROS), Malondialdehyde (MDA), and superoxide dismutase (SOD) activity of HBZY-1 cells, as shown in fig. 6, wherein (a) in fig. 6 is a graph of data on the relative levels of ROS for each group under HG culture conditions; FIG. 6 (b) is a graph of data showing the relative levels of MDA in each group under HG culture conditions; FIG. 6 (c) is a graph showing the relative levels of SOD in each group under HG culture conditions. HG increased HBZY-1 cell ROS and MDA levels, decreasing SOD activity (p <0.05) compared to the blank control. The medicinal composition remarkably inhibits the secretion of ROS and MDA (p is less than 0.05). In addition, the pharmaceutical composition also remarkably weakens the inhibitory effect of HG on the SOD activity of HBZY-1 cells (p < 0.05).
High sugar (HG) exposure reportedly promotes accumulation of extracellular matrix proteins (ECM proteins) in chronic kidney disease, and thus, the effect of pharmaceutical compositions on ECM protein expression, including laminin, type IV collagen, fibronectin, was further investigated. Referring to FIG. 7, Q-RT-PCR results show that, referring to FIG. HG, induced an increase in the expression level of cellular ECM mRNA (p <0.05), whereas the pharmaceutical composition reduced the expression of mRNA (p < 0.05; FIG. 7 (a)). Furthermore, Elisa results showed that HG induced the expression of laminin, collagen type IV, fibronectin (p <0.05), and that the pharmaceutical composition inhibited its induction (p < 0.05; FIG. 7 (b)).
Referring to FIG. 8, in order to further discuss the relevant mechanism of the pharmaceutical composition for inhibiting HG-induced HBZY-1 cell damage, the expression levels of TLR4, MYD88, NF-kappa B p65, NF-kappa B p-p65 and NLRP3 were detected by Western blotting. As shown in fig. 8 (a), HG stimulation increased the expression of TLR4 and MYD88 (p <0.05), whereas pharmaceutical composition inhibition inhibited the expression of TLR4 and MYD88 (p < 0.05). HG also induced expression of NF-. kappa. B p-p65 (p <0.05), whereas pharmaceutical compositions inhibited HG from inducing expression of NF-. kappa. B p-p65 (p < 0.05; FIG. 8 (a)). Furthermore, HG-induced upregulation of NLRP3 expression was attenuated by the pharmaceutical composition inhibition (p < 0.05; FIG. 8 (b)). The result shows that the pharmaceutical composition plays a role in protecting HBZY-1 cells by regulating the expression of TLR4/MYD88, NF-kappa B, NLRP3 and the like.
In order to further discuss the damage effect of the pharmaceutical composition on HBZY-1 cells by HG resistance through regulating the expression of TLR4, MYD88, NF-kappa B p65 and NLRP3 proteins, TLR4 and NF-kappa B inhibitors are respectively used for acting on HBZY-1 cells. Results referring to figure 9, the TLR4 inhibitor TAK-242 inhibited HG-induced expression of NF- κ B p-p65 and NLRP3 (p < 0.05). Furthermore, the NF-. kappa.B inhibitor PDTC (1-pyrrolidinedithiocarboxylic acid ammonium salt) blocked HG-induced expression of NLRP3 in HNZY-1 cells (p < 0.05; FIG. 9 (B)). The results indicate that the TLR4, NF- κ B and NLRP3 inflammasome pathways form a signaling axis through which the pharmaceutical composition attenuates HG damage to HBZY-1 cells.
To demonstrate the effect of the TLR 4/NF-. kappa.B/NLRP 3 axis in HG-induced HBZY-1 cells, cell viability, inflammatory cytokines, oxidative stress and ECM expression were determined by treating cells with 30. mu. M D-glucose with or without the addition of inhibitors TAK-242(TLR4 inhibitor) or PDTC for 24 hours in FIG. 9 (a) shows that TAK-242 and PDTC inhibit HG-induced cell proliferation (p < 0.05). HG significantly induces production of IL-6, IL-1 β and TNF- α (p <0.05), TAK-242 or PDTC inhibits its production (p < 0.05; FIG. 9 (B)) HG stimulation also significantly increases ROS and MDA levels (p <0.05) and reduces SOD activity (p < 0.05; FIG. 9 (c)) after the effect of TAK-242 or PDTC, the effect of HG on oxidative stress is <0.05 (p <0.05), and increases in fibronectin levels <0.05 (p <0.05), fibronectin < 9 (a) and fibronectin <0.05) were detected by the opposite (a) and laminin <0.05) in the fibronectin (a) levels of fibronectin < 9, respectively).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A monomer compound or pharmaceutically acceptable salt thereof is characterized in that the structural formula of the monomer compound is shown as a formula I,
Figure FDA0002256444570000011
2. a pharmaceutical composition for treating chronic kidney disease, which is characterized by comprising an active component and pharmaceutically acceptable auxiliary materials; the active component comprises a monomer compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002256444570000012
3. the pharmaceutical composition of claim 2, comprising a fermentation broth obtained by fermenting a herbal compound extract of fructus Lycii, fructus Corni, radix rehmanniae, rhizoma Dioscoreae, radix Cyathulae, fructus Mori, herba Epimedii, and radix Morindae officinalis with probiotics including lactic acid bacteria and Bacillus bifidus.
4. The pharmaceutical composition of claim 3, wherein the Chinese herbal medicine compound extract comprises the following raw material components in parts by weight: 1-20 parts of wolfberry fruit, 1-25 parts of dogwood, 1-15 parts of radix rehmanniae recen, 5-20 parts of Chinese yam, 3-18 parts of medicinal cyathula root, 1-15 parts of mulberry, 2-16 parts of epimedium and 1-10 parts of morinda officinalis.
5. The pharmaceutical composition of claim 3, wherein the lactic acid bacteria is Lactobacillus paracasei, and the Bifidobacterium is Bifidobacterium infantis; the mass ratio of the lactic acid bacteria to the bifidobacteria is 1: (0.1-10).
6. The pharmaceutical composition of claim 2, further comprising an additional active ingredient comprising at least one of vitamin C, vitamin E, coenzyme Q, glutathione, carotene, and betaine.
7. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in a dosage form comprising one of a capsule, a microcapsule, a suppository, a powder, a granule, an oral liquid, an aerosol, a jelly, and a granule.
8. The pharmaceutical composition of claim 4, wherein the fermentation broth is prepared by a process comprising:
weighing the components according to the weight percentage, putting the components into a container, adding water for soaking, decocting and sterilizing to obtain a Chinese herbal medicine compound extracting solution;
and inoculating a bacterium solution containing the probiotics into the Chinese herbal medicine compound extracting solution for fermentation at the fermentation temperature of 23-30 ℃ for 16-48 hours, and after the fermentation is finished, filtering and concentrating to obtain the fermentation liquor.
9. Use of the pharmaceutical composition according to any one of claims 2 to 8 for the preparation of a medicament or health product for the prevention or treatment of chronic kidney disease.
10. The use of claim 9, wherein the chronic kidney disease comprises diabetic nephropathy, renal arteriolosclerosis, primary and secondary glomerulonephritis, tubulointerstitial lesions, renal vascular lesions and hereditary nephropathy.
CN201911055511.2A 2019-10-31 2019-10-31 Monomer compound, pharmaceutical composition for treating chronic kidney disease and application thereof Pending CN110922337A (en)

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