WO2016028092A2 - Pharmaceutical composition, comprising gold compound, for preventing or treating liver fibrosis or liver cirrhosis - Google Patents

Description

Pharmaceutical composition for preventing or treating liver fibrosis or cirrhosis, including a contraindication

The present invention relates to a pharmaceutical composition for preventing or treating liver fibrosis or cirrhosis, and more particularly to a pharmaceutical composition for preventing or treating liver fibrosis or cirrhosis, including a prophylactic agent.

The liver plays a pivotal role in metabolism in the body and in the body, and is a living organ that continuously undergoes enzyme reactions and energy metabolism. Currently, hepatitis, cirrhosis and liver cancer account for the highest proportion of chronic diseases in Korea, along with circulatory diseases, and account for a large proportion of the causes of death due to diseases. In particular, as the drinking population is relatively high and the causes of liver damage caused by binge drinking are higher than those in developed countries, interest in them is also enormous. Persistent damage to liver tissue caused by viral infections or drinking is characterized by diseases that lead to cirrhosis or liver cancer. Considering the physiological characteristics and importance of liver tissues, the treatment and prevention of liver disease is very important and the development of therapeutic and prophylactic pharmaceutical compositions that can reduce liver tissue damage and ultimately be applied to treatment are required.

In particular, liver fibrosis refers to a condition in which damaged liver tissue is transformed into fibrous tissue such as collagen, rather than being restored to normal hepatocytes, as part of a bioadaptation reaction involving chronic liver disease such as hepatitis. Hepatic fibrosis is a bioadaptive reaction that occurs during the repair of tissue damage, but the liver is inevitably deteriorated in that the liver is replaced by a fibrous tissue that cannot perform the intrinsic functions of the liver such as metabolism and bile secretion. The development of appropriate therapeutics has been an important task in the development of medicines in that liver fibrosis develops repeatedly and leads to liver cirrhosis and death. However, until now, the mechanism of liver fibrosis itself has not been clearly revealed, and therefore, a suitable therapeutic drug has not been developed.

Recently, transforming growth factor-beta (TGF-beta), a cytokine released from macrophages and astrocytes in liver tissues, has been found to be an important mediator of liver fibrosis. In addition, it has been reported that liver fibrosis is significantly inhibited when TGF-beta is blocked by TGF-beta antibody, antisense RNA, and cellular TGF-beta receptor modification. However, these studies have only been carried out experimentally, and there are no clinically used drugs to date.

As described above, the development of an effective therapeutic agent for liver fibrosis or cirrhosis has been a major problem, and research has been made (Korea Patent No. 10-0949417), but it is still inadequate.

The present invention has been made to solve the above problems in the prior art, the present invention is to provide a pharmaceutical composition for the prevention or treatment of liver fibrosis or liver cirrhosis comprising a gold (gold) agent as an active ingredient The purpose.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention provides a pharmaceutical composition for preventing or treating liver fibrosis or cirrhosis, comprising a gold agent as an active ingredient.

In one embodiment of the present invention, the braze agent is auranofin (auranofin), sodium aurothiomalate, gold thioglucose (aurothioglucose), sodium aurothiosulfate (sodium aurothiosulfate) and gold thiomamal acid (isoiso) aurothiomalate) may be any one or more selected from the group consisting of.

In another embodiment of the invention, the composition may promote transformation to M2-type macrophages.

In another embodiment of the present invention, the composition may increase the expression of triggering receptor expressed on myeloid cells 2 (TREM-2).

In addition, the present invention provides a health functional food composition for preventing or improving liver fibrosis or liver hardening, comprising a gold preparation as an active ingredient.

In one embodiment of the present invention, the braze agent is auranofin (auranofin), sodium aurothiomalate, gold thioglucose (aurothioglucose), sodium aurothiosulfate (sodium aurothiosulfate) and gold thiomamal acid (isoiso) aurothiomalate) may be any one or more selected from the group consisting of.

Moreover, the present invention provides a method for treating liver fibrosis or cirrhosis, comprising administering a gold agent to a subject.

In addition, the present invention provides the use of a gold formulation to produce a medicament for preventing or treating liver fibrosis or cirrhosis.

The pharmaceutical composition of the present invention contains gold as an active ingredient, and not only promotes M2 transformation of macrophages, but also inhibits activation of astrocytes by increasing TREM-2 expression, thereby preventing liver fibrosis or liver hardening. It is expected to be usefully used as a pharmaceutical composition, food composition, and the like for preventing, treating or improving.

In addition, gold preparations, especially orranofin and similar sodium aurothiomalate or aurothioglucose, have already been used for other purposes (rheumatic arthritis), so drugs There is also an advantage that the possibility of side effects is low, and in addition, it is expected to be effective in other diseases in which fibrosis is a problem, for example, renal fibrosis.

1 schematically shows M1 / M2 transformation characteristics and induced cytokines of macrophages.

Figure 2 shows the structural formula of the various inhibitors.

Figure 3a shows the results of confirming the increase or decrease of the expression of the macrophage M2 marker TREM-2 in liver tissue isolated from human liver fibrosis patients and carbon tetrachloride-induced liver fibrosis mouse model.

Figure 3b shows the result of confirming the α-SMA and collagen-1a1 increase and decrease by treating the medium obtained from the macrophage cells overexpressed TREM-2 to MEF cells.

Figure 4 shows the result of treating oranopin (auranofin) under the conditions of differentiating M1 type macrophages by treating LPS / IFN-γ to RAW264.7 cells, and confirmed the iNOS and TREM-2 expression.

Figure 5 shows the result of treating oranofin (auranofin) to RAW264.7 cells, then treating the medium to MEF cells, the increase and decrease of α-SMA expression.

FIG. 6 shows the results of quantifying α-SMA and Collagen-1a1 by pulverizing liver tissues by H & E staining after auranofin treatment in a carbon tetrachloride-derived mouse liver fibrosis model.

Figure 7a is treated with sodium aurothiomalate and goldthioglucose (aurothioglucose), respectively, and treated with LPS / IFN-γ to differentiate to M1 type macrophages RAW264.7 cells, and confirmed the increase and decrease of iNOS expression The results are shown.

Figure 7b is treated with sodium aurothiomalate and gold thioglucose (aurothioglucose), respectively, under conditions in which differentiation of M2 type macrophages by IL-4 treatment to RAW264.7 cells, and confirmed the increase and decrease of arginase-1 expression The results are shown.

In the process of liver fibrosis, many researchers noticed the action of astrocytes to repair liver cells and repair them through collagen production such as collagen. However, in the present invention, attention was paid to the action of Cooper cells that function as macrophages in liver tissue and bone marrow-derived macrophages penetrating through the bloodstream.

Macrophages are classified into two types according to differentiation process. M1-type macrophages are mainly formed by stimulating lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), bacterial endotoxins, which are tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). , inducible nitric oxide synthase (iNOS) induces phagocytosis, a macrophage-specific phagocytosis, and subsequent amplification of inflammatory responses. M2-type macrophages are secreted by interleukin-4 (IL-4) and TGF-beta. It is known to form anti-cytokine and arginase induction, such as IL-10, which is known to be involved in tissue repair and other reactions (see Figure 1).

Recent studies have shown that M1 / M2 transformation affects fibrosis signals. Inflammatory progression of M1 macrophages has been reported to exacerbate fibrosis, and M2 macrophages have been reported to inhibit Th2 inflammatory response and renal fibrosis through arginase-1 expression. Thus, it may be possible to use drugs that properly modulate M1 / M2 transformation for the purpose of preventing and treating liver fibrosis and cirrhosis.

Therefore, the present inventors have conducted research on the development of a drug that appropriately regulates M1 / M2 transformation, and as a result, the gold preparation used for other uses is transformed into M2 of macrophages and triggering receptor expressed on TREM-2. For the first time, it was newly confirmed that inhibiting liver fibrosis by causing an increase in the expression of a receptor called myeloid cells 2), thereby completing the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating liver fibrosis or cirrhosis, comprising a gold agent as an active ingredient.

As used herein, the term "prevention" means any action that inhibits or delays the onset of liver fibrosis or cirrhosis by administration of the pharmaceutical composition according to the invention.

As used herein, the term "treatment" refers to any action in which symptoms caused by liver fibrosis or cirrhosis are improved or beneficially altered by administration of the pharmaceutical composition according to the present invention.

"Inhibitor" included in the pharmaceutical composition of the present invention as an active ingredient means a compound composed of a certain ratio of gold (gold) and other elements (components), that is, a gold compound (gold compound), which includes gold ( I) It can include both compound and gold (III) compound. Examples of the forbidden agent used in the present invention include, but are not limited to, auranofin (2, 3, 4, 6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S- [triethylphosphine] gold, sodium aurothiomalate, aurothioglucose, sodium aurothiosulfate, and isodium aurothiomalate (see FIG. 2), and are preferred. Preferably, aranoffin, sodium aurothiomalate or aurothioglucose may be used, and most preferably, auranofin may be used.

The pharmaceutical composition of the present invention contains a forbidden agent as an active ingredient, and not only promotes M2 transformation of macrophages, but also inhibits activation of astrocytes by increasing TREM-2 expression, thereby preventing and treating liver fibrosis or liver cirrhosis. Or improve.

In one embodiment of the present invention, as a result of confirming whether the gold agent causes transformation into M2 type macrophages, the gold agent treatment inhibits the expression of α-SMA and iNOS, and results in TREM- 2 expression and arginase-1 expression was increased, resulting in inhibition of M1-type macrophages and at the same time promoting transformation to M2-type macrophages (see Examples 3, 4 and 6). .

In another embodiment of the present invention, as a result of confirming inhibition of liver fibrosis by administration of a gold preparation, the expression of a-sMA and collagen 1a1, which are indicators of astrocytic activation, was significantly lowered when the gold preparation was treated. Hepatic fibrosis was also found to significantly decrease at 10 mg / kg (see Example 5).

On the other hand, the pharmaceutical composition of the present invention may further contain one or more known active ingredients having a liver fibrosis or liver cirrhosis therapeutic effect together with the gold agent.

The composition of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. It may also be used in the form of oral dosage forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions in accordance with conventional methods, preferably oral administration It can be formulated into a dosage unit formulation suitable for use.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose , Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. In formulating the composition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like may be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general It can be administered in an amount of 0.01 mg / kg / day to about 100 mg / kg / day, preferably 0.1 mg / kg / day to 30 mg / kg / day, once or several times a day You may.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections. The pharmaceutical composition of the present invention is determined according to the type of drug that is the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient and the severity of the disease.

In another aspect of the invention, the invention provides a method for treating liver fibrosis or cirrhosis, comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses and cattle, etc. Mean mammal.

Furthermore, as another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving liver fibrosis or liver cirrhosis comprising a gold agent as an active ingredient.

As used herein, the term "improvement" refers to any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms. In this case, the functional food composition may be used simultaneously or separately with a medicament for treatment before or after the onset of the disease in order to prevent or improve liver fibrosis or cirrhosis.

There is no particular limitation on the kind of food. Examples of foods to which the active ingredient may be added include drink, meat, sausage, bread, biscuit, rice cake, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups , Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, etc., and includes all the health functional foods in the conventional sense.

In the nutraceutical composition of the present invention, the active ingredient may be added to the food as it is, or may be used together with other foods or food ingredients, and may be appropriately used according to conventional methods. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, in the manufacture of food or beverages the compositions of the invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials. However, in the case of prolonged intake for health and hygiene purposes or health control purposes, the amount may be below the above range.

The health functional food composition of the present invention contains the active ingredient as an essential ingredient in the indicated ratio, and there are no special limitations to other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.

In addition to the above, the health functional food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents such as natural flavoring agents, colorants and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. These components can be used independently or in combination. The proportion of such additives may also be appropriately selected by those skilled in the art.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

EXAMPLE

Example 1 Experiment Preparation and Method

1-1. Experiment preparation

end. Liver Tissue Preparation of Patients with Human Liver Fibrosis

Human normal and liver fibrotic tissues were used in 36 cases of liver cancer tissue after clinical trial approval (CHOSUN 2013-04-005) at Chosun University College of Medicine.

I. Preparation of Carbon Tetrachloride-induced Liver Fibrosis Mouse Model

Carbon tetrachloride-induced mouse liver fibrosis model was prepared by repeated intraperitoneal administration of 0.5 ml / kg of carbon tetrachloride twice a week for 3 weeks in C57BL / 6J mice.

1-2. Experiment method

end. Western blot

Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed using a gel electrophoresis device (Mighty Small SE 250, Hoefer Scientific Instruments, San Francisco) according to Lamley's method. Cell lysis fractions were diluted in sample dilution buffer [63 mM Tris (pH.6.8), 10% glycerol, 2% SDS, 0.0013% bromophenol blue, 5% β-mercaptoethanol] and then 8%, 10 Electrophoresis was performed in electrode buffer (containing 15 g of Tris, 72 g of glycerin, 5 g of SDS) in an electrode buffer. The electrophoresis gel was subjected to nitrocellulose membrane for 3 hours at 40 mAmps in a transfer buffer solution (25 mM Tris, 192 mM glycerin, 20% v / v methanol (pH.8.3)] using a transfer electrophoresis device. The protein was transferred to anti-TREM-2, anti-Arginase-1, anti-iNOS, anti-α-SMA, and anti-collagen-1a1, respectively, as a primary antibody, followed by reaction with the nitrocellulose membrane. Secondary antibody was used for horseradish peroxidase-conjugated goat anti-rabbit IgG (horseradish peroxidase-conjugated goat anti-rabbit IgG) and horseradish peroxidase-conjugated goat anti-mouse IgG for 1 hour. And developed using an ECL detection system (ECL chemiluminecence system, Amersham, Gaithersberg, MA.) The homogeneity of the protein content in the sample was determined by anti-β-actin antibody, anti-LaminA / C. Changes in the amount of protein expression were determined by densitometry of the color intensity in the blot. W were obtained, the concentration meter was scanned using an image scanning and analysis system (Image Scan and Analysis System, Alpha-Innotech Co.). Each lane using AlphaEase ^TM version 5.5 software was first calculates the strength of the background.

In the case of liver tissue, a certain amount of liver tissue was homogenized in a mortar and pestle with liquid nitrogen and cell lysis buffer, and then the tissue solution was transferred to a new tube and vortexed. After centrifugation at 14,000 rpm and 4 ° C. for 20 minutes, the middle layer was taken and protein was quantified by the Bradford method. After 30 μg of protein was subjected to electrophoresis on SDS polyacrylamide gel, the expression change of α-SMA protein was measured using Western blot.

I. Fibrous Numerical Evaluation

The fibrosis was performed by a pathologist with a double-blind examination of at least 10 parts of each tissue sample. The criteria are as follows. Stage 0: none; Stage 1: Enlarged, fibrotic portal areas; Stage 2: Periportal or portal-portal septa but intact architecture; Stage 3: Fibrosis with architectural distortion but no obvious cirrhosis; Stage 4: Probable or definite cirrhosis.

Example 2 Confirmation of Hepatic Fibrosis Inhibition of TREM-2, a Macrophage M2 Marker

2-1. Decreased expression of TREM-2 in liver fibrotic tissue

Example 1-1 confirmed the increase or decrease of expression of the macrophage M2 marker TREM-2 in liver tissues isolated from human liver fibrotic patients and carbon tetrachloride-induced liver fibrotic mice by Western blot. Indicated.

As shown in FIG. 3A, the expression of TREM-2, an M2 marker, was significantly increased in liver tissues isolated from human liver fibrosis patients and carbon tetrachloride-induced liver fibrosis mice.

2-2. Confirmation of TREM-2 Inhibition of Liver Fibrosis

The release of collagen, a causative agent of liver fibrosis, and transforming growth factor-β (TGF-β), a key factor for fibrosis, is due to the activation of stellate cells in the liver.

Thus, the media obtained from macrophage cells overexpressed with TREM-2 were treated with mouse embryonic fibroblasts (MEFs) of active astrocytic similarity, indicating that alpha-smooth muscle is widely used as an indicator of astrocytic activation. Actin (α-SMA, astrocyte-specific protein differentiated into fibroblast type) and collagen-1a1 expression, a representative fibrin collagen, were confirmed by Western blot, and the results are shown in FIG. 3B.

As shown in FIG. 3B, it was confirmed that α-SMA and collagen-1a1 expression was suppressed when the medium obtained from macrophages overexpressed with TREM-2 was treated. From the above results, it can be seen that the TREM-2 receptor, an M2 marker, effectively inhibits liver fibrosis.

Example  3: Gold  Macrophage M2 by treatment Antifibrotic Factor TREM Increase in -2 expression

To determine whether gold preparations cause transformation into M2-type macrophages, RAW14.7 cells, a mouse macrophage, were treated with lipopolysaccharide (LPS) / interferon-gamma (IFN-γ) to treat M1 type macrophage. Oranopine (auranofin) was treated under the conditions of differentiation into macrophages, iNOS and TREM-2 expression was increased or decreased by Western blot, the results are shown in FIG.

As shown in FIG. 4, it was confirmed that iNOS expression was suppressed and TREM-2 expression was increased during oranofin treatment. From the above results, it was found that the gold preparation, particularly orranofin, inhibits the transformation into M1 type macrophages and promotes the transformation into M2 type macrophages.

Example  4 : Gold  Pretreatment of macrophage medium Astrocytes  By exposure Astrocytes  Confirm suppression of activation

After treating aoranofin to RAW264.7 cells, which are mouse macrophage lines, the medium was treated with MEF cells of active astrocytic similarity, and the increase in α-SMA expression, an astrocytic activation index, was confirmed by Western blot. The results are shown in FIG.

As shown in FIG. 5, it was confirmed that α-SMA expression was suppressed during oranofin treatment. From the above results, it was found that the gold preparation, particularly orranofin, inhibits the activation of astrocytes by promoting M2 transformation of macrophages and increasing TREM-2 expression.

Example 5 Confirmation of Inhibition of Liver Fibrosis by Administration of Gold

Oral administration (auranofin) to the carbon tetrachloride-induced mouse liver fibrosis model prepared in Example 1-1 based on the dose known to be effective for existing arthritis 1, 3, 10 mg / kg oral administration three times a week It was. After the end of the administration, liver tissues were evaluated for fibrosis by H & E staining, and some tissues were ground to quantify collagen-1a1 as an astrocytic activation index and collagen accumulation index, and the results are shown in FIG. 6.

As shown in FIG. 6, the oranopine treatment significantly lowered the expression of astrocyte activation markers α-SMA and Collagen 1a1 and significantly reduced the actual hepatic fibrosis at 10 mg / kg. .

Example  6. Gold  Inhibition of M1 Transformation and M2 Transformation Promoting Effect of Macrophages by Treatment

In addition to orranopine (auranofin), the effect of inhibiting M1 transformation and M2 transformation of macrophages by treatment with other inhibitors was further confirmed.

First, sodium aurothiomalate, similar to orranopine, was treated with lipopolysaccharide (LPS) / interferon-gamma (IFN-gamma) in mouse macrophage line RAW264.7 cells to differentiate into M1 type macrophages. ) And gold thioglucose (aurothioglucose), respectively, and iNOS expression increase and decrease was confirmed by Western blot.

As a result, as shown in FIG. 7A, it was confirmed that iNOS expression was suppressed during the treatment of sodium aurothiomalate and aurothioglucose.

In addition, sodium aurothiomalate and aurothioglucose, similar to auranofin, were respectively treated with IL-4 treatment in mouse macrophage RAW264.7 cells to differentiate into M2-type macrophages. Treatment was performed, and the increase and decrease in arginase-1 expression was confirmed by Western blot.

As a result, as shown in Figure 7b, it was confirmed that the expression of arginase-1 is increased during the treatment of sodium aurothiomalate and gold thioglucose (aurothioglucose).

From the above results, it was found that the gold preparation inhibits the transformation into M1-type macrophages and promotes the transformation into M2-type macrophages.

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

The composition according to the present invention not only promotes M2 transformation of macrophages, but may also inhibit activation of astrocytes by increasing TREM-2 expression, and thus prevents, treats or improves liver fibrosis or liver hardening, It is expected that it may be usefully used as a food composition.

Claims (4)

1. A method of treating liver fibrosis or cirrhosis, comprising administering a gold agent to a subject.
2. The method of claim 1,

   The braze agent is selected from the group consisting of auranofin, sodium aurothiomalate, aothioglucose, sodium aurothiosulfate, and isodium aurothiomalate. The treatment method, characterized in that any one or more.
3. The method of claim 1,

   The composition is characterized in that to promote the transformation into M2-type macrophages, the method of treatment.
4. The method of claim 1,

   The composition is characterized in that to increase the expression of triggering receptor expressed on myeloid cells 2 (TREM-2).

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