KR20140096222A - Pharmaceutical composition for treating and preventing inflammatory bowel disease comprising metformin - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating and preventing inflammatory bowel diseases comprising metformin as an active ingredient. Since the metformin inhibits the activity of NF-κB in an intestinal epithelial cell, the present invention can be effectively used for treating and preventing inflammatory bowel diseases such as Colitis and Crohn`s disease.

Description

[0001] The present invention relates to a pharmaceutical composition for treating and preventing inflammatory bowel disease comprising metformin as an active ingredient,

The present invention relates to a pharmaceutical composition for the treatment and prevention of inflammatory bowel disease containing metformin as an active ingredient.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic recurrent digestive tract inflammation caused by an impaired control of the immune response in the mucosal immune system. Up to now, the pathogenesis of IBD and biologic therapy There has been much progress in understanding IBD, but the healing of IBD without recurrence is still a problem. In addition, long-term IBD increases the risk of colitis-associated colon cancer (CAC), so it is in desperate need to develop more efficient and safe treatments for IBD patients.

As a mucosal barrier, it provides protection against isolates from hostile luminal antigens presented by vast microorganisms. In addition to the physical barrier function, intestinal epithelial cells (IECs) have been implicated in several proinflammatory cytokines including TNF-alpha, tumor-necrosis factor-alpha and interleukin (IL) It activates complex and highly integrated sequential reactions that induce proinflammatory gene transcription when exposed to bacterial surface molecules such as lipopolysaccharide (LPS). Activation of the nuclear factor-kappaB (NF-kB), a transcription factor in this complex continuous reaction, involves TNF-α, IL-2, IL-6, IL-8 and intracellular adhesion molecule-1 (ICAM-1) And regulates various genes involved in the early inflammatory reaction. In addition, NF-κB activation plays a key role in upregulating the epithelial permeability. Thus, existing evidence supports the role of NF-κB signaling in IBD, suggesting that modulation of NF-κB activity in IECs may be a therapeutic target for IBD.

Metformin (1,1-dimethylbiguanide hydrochloride, 1,1-dimethylbiguanide hydrochloride) is a biguanide derivative and has been prescribed for diabetics for more than 30 years. Metformin, in addition to its antidiabetic effect, provides metabolic benefits by improving lipid profile and insulin sensitivity. Metformin has recently been shown to provide anti-inflammatory effects in atherosclerosis through inhibition of NF-κB signaling in vivo and in vitro endothelial cells. Interestingly, metformin reduces the risk of colorectal cancer in type 2 diabetics and inhibits the azoxymethane-induced colorectal aberrant crypt foci in mouse models.

However, such studies suggest that metformin has anti-inflammatory or anti-tumor properties, but the exact mechanism of the metformin effect on intestinal inflammation has not yet been defined.

Therefore, the present inventors first confirmed that metformin inhibits the NF-κB pathway in IEC and can ameliorate intestinal inflammation and colon tumor formation. Specifically, the present inventors confirmed that metformin for NF-κB signaling in IEC And the effect of metformin on dextran sulfate sodium (DSS) -induced acute colitis. In addition, the antitumor effect of metformin was confirmed in azoxymethane and DSS-induced CAC mouse models.

[Prior Art Literature]

[Non-Patent Document]

(Non-Patent Document 1) Li SN, Wang X, Zeng QT, et al. Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein levels in experimental atherogenesis of rabbits. HeartVessels . 2009; 24: 446-453.

(Non-Patent Document 2) Huang NL, Chiang SH, Hsueh CH, et al. Metformin inhibits TNF-alpha-induced Ikappa B kinase phosphorylation, Ikappa B-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. IntJCardiol . 2009; 134: 169-175.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of inflammatory bowel disease.

The present invention provides a pharmaceutical composition for treating or preventing an inflammatory bowel disease comprising metformin as an active ingredient.

The metformin is a compound represented by the following formula 1, which is widely used at present for the treatment of diabetes, particularly for the treatment of type 2 diabetes, and its safety is sufficiently ensured. The present inventors have found that metformin It was first discovered that IBD (inflammatory bowel disease) can be effectively prevented and treated.

[Chemical Formula 1]

The present inventors have experimentally confirmed that metformin significantly inhibits interleukin (IL) -8 induction in tumor necrosis factor-alpha (TNF-α) -induced COLO 205 cells, and pretreatment with metformin inhibits TNF- Induced IκBα phosphorylation and NF-κB DNA binding activity. In an acute murine colitis model study, metformin administration significantly reduced the severity of dextran sulfate sodium (DSS) -induced colitis when assessed by disease activity index, colon length and histology. Also, DSS-induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin also weakened the incidence of colorectal cancer in mice inoculated with azoxymethane and DSS.

According to one embodiment of the present invention, the metformin may inhibit the activity of NF-κB (nuclear factor-κB) in the intestinal epithelial cells. That is, the composition according to the present invention may be used as an inhibitor of NF-kB activity in enterocytes.

In addition, inhibition of the activity of NF-κB may be attenuated by weakening IκBα phosphorylation and NF-κB DNA binding activity.

In addition, the inhibition of NF-κB activity may inhibit the expression of interleukin-8 (IL-8) gene. That is, the composition according to the present invention may also be used as a regulator of IL-8 gene expression.

The term "inflammatory bowel disease" includes all intestinal diseases mediated by inflammation, and may specifically be enterocolitis, Crohn's disease, Celiac disease, intestinal Behcet's disease, or ischemic enteritis.

The term "active ingredient" alone means an ingredient which exhibits the desired activity or can exhibit activity together with a carrier which is itself inactive.

The term " prevent "refers to all actions of inhibiting the onset or delaying the onset of inflammatory bowel disease by a composition comprising metformin according to the present invention as an active ingredient, and" Inflammatory bowel disease " refers to any action that improves or alleviates inflammatory bowel disease by the composition comprising it.

The composition for preventing or treating inflammatory bowel disease containing metformin according to the present invention may contain any amount (effective amount) of the effective ingredient as long as it can exhibit the improving activity of inflammatory bowel disease according to the purpose of use, formulation, , A typical effective amount will be determined within the range of from 0.001% to 15% by weight based on the total weight of the composition. The term "effective amount" as used herein refers to the amount of the active ingredient capable of inducing the prevention and treatment of inflammatory bowel disease or inhibiting the onset and delay of the onset of such pathological conditions. Such effective amounts can be determined experimentally within the ordinary skill of those skilled in the art.

The composition for the prevention or treatment of inflammatory bowel disease containing metformin according to the present invention can be used as a pharmaceutical composition in a specific embodiment, and the object to be prescribed and applied is preferably a mammal and a human, particularly a human.

The pharmaceutical composition of the present invention may be formulated into oral formulations such as tablets, suspensions, granules, emulsions, capsules, syrups and the like, including pharmaceutically acceptable carriers, excipients and the like, Parenteral formulations such as injectable or oily suspensions, or localized formulations such as solutions, creams, ointments, gels, lotions, patches, and the like.

The expression " pharmaceutically acceptable "as used herein means that the active ingredient does not inhibit the activity, and that the subject to be prescribed or applied does not have the above-mentioned toxicity (sufficiently low toxicity).

Examples of pharmaceutically acceptable carriers include starches such as lactose, glucose, sucrose, corn starch and potato starch, sodium carboxymethyl cellulose or derivatives thereof such as sodium carboxymethylcellulose, malt, gelatin, talc, stearic acid, magnesium stearate Solid lubricant of vegetable oil, vegetable oil such as calcium sulfate, peanut oil, cottonseed oil, sesame oil and olive oil, polyol such as propylene glycol and glycerin, alginic acid, TWEENS, sodium lauryl sulfate, coloring agent, flavor, stabilizer, antioxidant, Water, saline solution, and phosphate buffer solution. These carriers may be selected from one or more suitable ones according to the formulation of the pharmaceutical composition of the present invention.

The excipient may be selected from those suitable for the formulation of the pharmaceutical composition of the present invention. For example, when the pharmaceutical composition of the present invention is prepared with an aqueous suspension, suitable excipients include sodium carboxymethylcellulose, methylcellulose, Propyl methylcellulose, sodium alginate, and polyvinylpyrrolidone. Examples of suitable excipients when they are prepared by injection solutions include Ringer's solution, isotonic sodium chloride, and the like.

The pharmaceutical composition of the present invention may be administered orally or parenterally.

The daily dose of the pharmaceutical composition of the present invention is usually in the range of 0.001-150 mg / kg body weight, and may be administered once or several times in divided doses. However, since the dosage of the pharmaceutical composition of the present invention is determined in view of various related factors such as route of administration, age, sex, weight, and patient's severity of the patient, the dose is limited in any aspect to the scope of the present invention Should not be understood to be.

The pharmaceutical composition containing metformin according to the present invention can effectively prevent or treat inflammatory bowel disease, particularly ulcerative colitis, Crohn's disease, and the like.

Figure 1 shows the effect of metformin on IL-8 expression in TNF-alpha stimulated COLO 205,
As shown in Figure 1A, COLO 205 cells were transfected with pIL-8-luciferase transcription reporter. After 24 hours, the transfected cells were pretreated with metformin at the indicated concentrations for 18 hours and then combined with TNF-α (20 ng / mL) for 6 hours. Data are expressed as mean induction multiples of luciferase activity +/- SEM for non-stimulated controls (n = 5). The mean induction multiple of the [beta] -actin reporter gene activity for unstimulated controls remained relatively constant throughout the experiment. (B) COLO 205 cells were pretreated with metformin at the indicated concentrations for 18 hours and stimulated with TNF-α (20 ng / mL) for 8 hours. IL-8 mRNA expression was measured by real-time RT-PCR. The levels are normalized for [beta] -actin. Data are expressed as a multiple of change in mRNA transcript level for the non-stimulus control (mean ± SEM, n = 5). (C) COLO 205 cells were pretreated with metformin for 18 hours and stimulated with TNF-α (20 ng / mL) for 24 hours. Secretion of IL-8 was measured by ELISA (mean ± SEM, n = 5).
* P < 0.05, compared with TNF-alpha alone
Met: Metformin
Figure 2 shows the effect of metformin on NF-κB DNA binding activity in TNF-α-stimulated COLO 205 cells,
(A) COLO 205 cells were pretreated with metformin at the indicated concentrations for 18 hours and stimulated with TNF-α (20 ng / mL) for 1 hour. NF-κB DNA binding activity in nuclear extracts was assessed by EMSA. Data represent more than three independent experiments. (B) COLO 205 cells were transfected with 2 x pNF-KB-luciferase transcriptional reporter. After 24 hours, the transfected cells were pretreated with metformin at the indicated concentrations for 18 hours and then combined with TNF-α (20 ng / mL) for 1 hour. Data are presented as mean induction multiples of luciferase activity in unstimulated controls ± SEM (n = 5). The mean induction multiple of the [beta] -actin reporter gene activity for unstimulated controls remained relatively constant throughout the experiment.
* P <0.05 compared with TNF-a alone
Met: Metformin
Figure 3 shows the inhibition of IκBα phosphorylation by metformin in TNF-α-stimulated cells,
(A) COLO 205 cells were pretreated with metformin at the indicated concentrations for 18 hours and stimulated with TNF-α (20 ng / mL) for 1 hour. Immunoblot analysis was performed on phospho-IκBα, IκBα and actin. Data represent more than three independent experiments. (B) The level of phospho-I [kappa] B [alpha] was measured using a commercial I [kappa] B alpha ELISA as it was difficult to detect phospho-I kappa B alpha due to the short half-life of phospho-I kappa B alpha. Data are presented as mean induction multiples ± SEM for untreated controls (n = 5).
* P <0.05, compared with single
Met, Metformin
FIG. 4 shows the histological evaluation results of (A) near-intestinal colon and (B) circular intestine in DSS-induced acute murine colitis,
Mice were divided into four groups: control, sodium dextran sulfate (DSS) and vehicle, or DSS and metformin (100 or 500 mg / kg / day). The total number of histologic scores was derived from the severity and extent of total inflammation and depression damage (mean ± SD). The colon of DSS-treated mice exhibited complete destruction of the epithelium structure, loss of depression and epithelial integrity, submucosal edema, and intensive inflammatory cell infiltration in all layers. Metformin treatment weakened these morphological injuries. Results indicate at least three individual tested sites (magnification x 100).
DSS: Sodium dextran sulfate
PBS: phosphate buffered saline
Met 100: Metformin 100 mg / kg / day
Met 500: metformin 500 mg / kg / day
* P < 0.05, compared with vehicle-treated mice
FIG. 5 shows immunohistochemical staining results for in vitro IκB kinase (IKK) in (A) near-side intestinal epithelium and (B) round site colonic epithelium in DSS-induced murine colitis,
Tissue samples were immunohistochemically stained with anti-phospho-IKK-alpha / beta. Immunoreactivity index, DSS exposure to phospho-IKK-alpha / beta resulted in a significant increase (arrow) in the phospho-phospho-IKK-alpha / beta stain score compared to control mice. However, the administration of metformin (500 mg / kg / day) significantly reduced the degree of phospho-IKK-alpha / beta staining in colon samples (mean +/- SD).
DSS: Sodium dextran sulfate
PBS: phosphate buffered saline
Met 500: metformin 500 mg / kg / day
* P <0.05, compared with DSS + vehicle
Figure 6 shows the effect of metformin in a colitis-associated colorectal mouse model,
(A) the number of tumor occurrences in the colon sample (mean +/- SD) and (B) the case of metformin treated and untreated in a CAC model. Metformin administration significantly reduced tumorigenicity in the AOM / DSS model.
* P <0.05 compared with AOM + DSS
AOM: Aoshima Methane
DSS: Sodium dextran sulfate
Met 500: metformin 500 mg / kg / day

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. It will be clear to those who have knowledge.

<Examples>

Experimental Example: The experimental material and experimental method according to the present invention are as follows.

(1) Cell culture and treatment

Human colon cancer cell line COLO 205 [10222; Korean Cell Line Bank (KCLB), Seoul, Korea], and cells were grown.

Metformin was dissolved in phosphate-buffered saline (PBS). Cells were treated with various concentrations of metformin (0-500 mM) (Sigma, St. Louis, Mo.) or PBS and stimulated with TNF-α (10 ng / mL).

(2) Transfection and reporter analysis

Cells were transfected with 1.5 [mu] g plasmid DNA using luciferase plus reagent (Invitrogen, Carlsbad, Calif.). After transfection, cells were grown in a 5% CO2 incubator at 37 &lt; 0 &gt; C for 24 hours and then harvested and total cell extracts were prepared. Luciferase activity was measured according to a defined protocol (Tropix, Bedford, Mass.) And luciferase activity was normalized for beta -galactosidase expression.

(3) Real-time RT-PCR and ELISA

Real-time polymerase chain reaction (PCR) was performed. One μg of total cellular RNA was isolated from COLO 205 using Trizol (GIBCO, Gaithersburg, Md.) And reverse transcribed using SYBR Green PCR Master Mix and ABI Prism 7000 sequencing system (Applied Biosystems, Foster City, CA) did. Specific primers for human IL-8 and beta -actin were used. Amplification was performed three times in duplicate and the data normalized to the beta -actin level. The amount of human IL-8 and phospho-I kappa B alpha was measured using a commercial ELISA kit (R & D Systems, Minneapolis, MN).

(4) electrophoretic mobility analysis

COLO 205 cells were harvested and nuclear extracts were isolated. Protein concentrations in extracts were determined using Bradford assay (Bio-Rad, Hercules, Calif., USA). Electrophoretic mobility shift assay (EMSA) was performed with a commercially available kit (Promega, Madison, Wis.).

5 [mu] g of the nuclear extract was incubated at room temperature for 30 minutes with a [gamma] ³² P-labeled oligonucleotide probe (5'-AGTTGAGGGGACTTTCCCAGGC-3 ') corresponding to the consensus NF-KB binding site. The bound DNA and free DNA were separated on a 5% unmodified polyacrylamide gel.

(5) Immunoblot analysis

COLO 205 cells were washed with ice-cold PBS and lysed in 0.5 mL cell lysis buffer (150 mM NaCl, 20 mM Tris, pH 7.5, 0.1 Triton X-100, 1 mM PMSF, and 10 ug / mL aprotinin) . The protein concentration in the lysate was determined by Bradford assay (Bio-Rad). 20 [mu] g of lane glycoprotein was sized on a 10% polyacrylamide minicell and transferred to a microcellulose membrane. NF-κB signaling was performed using anti-IκBα (Santa Cruz Biotechnology, Santa Cruz, CA), phospho-IκBα (Cell Signaling, Beverly, Mass.) And anti-β-actin (Santa Cruz Biotechnology) The specific protein involved was detected. Peroxidase-conjugated anti-mouse IgG was used as the secondary antibody. Bound antibody was visualized using an enhanced chemiluminescence system (Amersham Life Science, Buckinghamshire, England) and then exposed to Kodak X-OMAT film.

(6) Induction of DSS-induced acute murine colitis and treatment with metformin

Specific pathogen free mice (C57BL / 6NCrljBgi male mice, 6-7 weeks) were purchased from Orient (Sungnam, Korea). The mice were free to access water and standard rodent feed until they reached the desired age (7-8 weeks) and body weight (20-22 g). All animal procedures were conducted at the Seoul National University Hospital .

DSS (MP biochemical, Irvine, Calif.) Was used to induce acute colitis. After weighing the mice, 5 mice were randomly assigned to each group. Mice assigned to the negative control provided only filtered water. DSS was dissolved in drinking water for 5 days. Metformin (ie, 100 mg / kg / day and 500 mg / kg / day) was dissolved in PBS, started 2 days before DSS administration and once daily by oral gavage. To assess the disease activity index (DAI), the inventors evaluated daily the presence of body weight, feces concentration, and blood or perineal blood, and also recorded the consumption of water and food.

(7) Visual and histological analysis

Visual and histological analyzes were performed. On day 8, mice were euthanized by inhalation of isoflurane, and after the mouse died, the entire colon was extracted from the large intestine to the anus and then opened longitudinally, and the colon length and overall appearance were evaluated. The removed tissue was fixed in paraffin-embedded 10% buffered formalin and stained with hematoxylin-eosin. Quantitative evaluation of histology was performed with no knowledge of group assignment.

(8) Colitis in mice - induction of ductal colorectal cancer

CAC induction was performed. 7-8 week old male mice were used and 5 mice were randomly assigned to each group according to body weight. On day 0, mice received one intraperitoneal injection of AOM (12 mg / kg), 7 days later, 2% DSS was administered via drinking water for 5 days and then water was freely consumed for 16 days. This cycle was repeated three times. Treatment with vehicle or metformin (500 mg / kg per day) was started on day 8 and once daily by oral gavage. The mice were euthanized 10 days after the last 2% DSS administration.

(9) Immunohistochemical staining

Immunohistochemical analysis was performed. The slides were immersed in Tris / EDTA buffer (pH 9.0) into a chamber where the cloaking was removed, heated at 125 ° C for 3 minutes, and then cooled for 10-20 minutes. After 3% hydrogen peroxide was added, the cells were incubated for 10 minutes. After washing with Tris-buffered saline (TBS) Tween-20 (pH 7.6), slides were stained with rabbit polyclonal anti-mouse IgG for 1 hour in an automated immunostaining system (Autostainer 2D, Lab Vision Co., Fremont, CA, USA) And stained with a phospho-IKK-alpha / beta antibody (Cell signaling Technology). The stained slide was washed 3 times with TBS Tween-20 and incubated with the secondary antibody for 30 minutes. The slides were reacted with streptavidin for 20 minutes, then the reaction was visualized by 3,3'-diaminobenzidine tetrahydrochloride for 5 minutes, and the slides were counterstained with Meyer's hematoxylin. Each slide was evaluated for immunoreactivity on a scale of 0 to 4+ for phospho-IKK-alpha / beta immunohistochemistry.

(10) Statistical analysis

Bonferroni-corrected variance analysis was used to analyze differences between groups. A P value of less than 0.05 was considered statistically significant.

Experiment result

(1) inhibition of TNF-α-induced IL-8 expression in metformin COLO 205 cells

First, the effect of metformin on expression of TNF-α-induced IL-8 gene was evaluated. As shown in FIG. 1A, TNF-α-induced IL-8 luciferase activity is attenuated by metformin pretreatment in a dose-dependent manner. Real-time PCR showed a significant reduction in IL-8 expression in response to metformin (FIG. 1B). IL-8 release was also significantly inhibited by metformin (Fig. 1C).

(2) inhibition of NF-kB transcriptional activity in TNF-a-stimulated COLO 205 cells of metformin

Since transcription factor NF-κB predominantly regulates IL-8 gene expression in IEC, electrophoretic mobility shift assay (EMSA) was performed to assess whether metformin inhibits TNF-α-induced NF-κB activity. As shown in Figure 2A, metformin pretreatment reduced NF-kB DNA binding activity in a dose-dependent manner. In addition, the results of the reporter gene analysis showed that TNF-α-induced NF-B luciferase activity was significantly reduced by metformin pretreatment (FIG. 2B).

(3) inhibition of NF-κB signaling in COLO 205 cells of metformin

Immunoblot analysis was performed to evaluate the effect of metformin on NF-κB signaling in IECs, and as shown in Figure 3A below, metformin pretreatment inhibited TNF-α-induced IκBα phosphorylation / degradation in a dose-dependent manner . To confirm this result, the phospho-IκBα release was also evaluated by a commercial IκBα ELISA kit, whereby the phospho-IκBα release was significantly inhibited by metformin (FIG. 3B).

(4) Mitigation of the severity of colitis induced by DSS in metformin

To evaluate the in vivo antiinflammatory activity of metformin, an evaluation was conducted on a DSS-induced murine colitis model. As shown in Table 1 below, DSS was administered for 5 days to induce severe colitis, whereas oral administration of metformin significantly reduced the severity of colitis when evaluated by weight loss, DAI and colon length.

division Weight change
(% For day 0) Colon length
(cm) Disease activity index Control group 99.0 + - 2.5 ± - DSS + PBS 87.0 ± 7.7 ^* 6.8 ± 1.0 ^* 2.9 ± 1.1 ^* DSS + Met (100 qd) 92.0 ± 2.8 7.8 ± 0.2 ⁺ 1.3 ± 0.3 ⁺ DSS + Met (500 qd) 97.5 ± 5.7 ⁺ 7.9 ± 0.1 ⁺ 0.6 ± 0.5 ⁺

Table 1 above is the clinical indices for DSS-induced acute murine colitis when treated with metformin and untreated, with percentages indicating weight change on day 7 compared to day zero. Data are mean SD of 5 mice.

DSS: Sodium dextran sulfate

PBS: phosphate buffered saline

Met 100 qd: Metformin 100 mg / kg / day

Met 500 qd: Metformin 500 mg / kg / day

^* : P <0.05 compared with the control group

⁺ : P < 0.05 compared to DSS + PBS group

In addition, histopathology was performed to evaluate the severity of colitis in the intestinal and intestinal colon. DSS administration to the PBS control group resulted in significant histologic changes such as inflammatory cell infiltration, depression damage, and mucosal ulceration. However, metformin treatment significantly reduced the histological damage to the linear structures and infiltration of inflammatory cells. Statistically significant differences were achieved in the round site colon (Fig. 4).

(5) Weakening of IκB kinase activity in mouse colon epithelium of metformin

In vivo, metformin was shown to inhibit NF-κB signaling and thus exhibited anti-inflammatory effects. To confirm the in vitro results of the DSS colitis model, the effect of metformin on IκB kinase (IKK) activity was investigated Respectively. To test IKK activity, immunohistochemistry was performed on mouse colon tissues. As shown in FIGS. 5A and 5B, there was DSS-induced expression of IKK activity in the colon epithelium, and metformin treatment significantly weakened IKK activity in the large intestine mucosa.

(6) In a murine model of metformin, colitis - inhibiting the formation of ductal colorectal tumors

In the results of the acute murine colitis model, in vivo experiments were carried out on the CAC murine model induced by repeated administration of AOM and DSS, with the determination that metformin could inhibit tumor formation through antiinflammatory activity. Tumor formation was confirmed in all mice treated with AOM / DSS, and these tumors were histologically confirmed as adenomas or adenocarcinomas, and the tumors predominated in the large intestine. The number of tumors was significantly reduced in the group treated with metformin compared to the untreated control (Fig. 6).

As described above, metformin contained as an active ingredient in the composition of the present invention inhibits NF-κB activity in enterocytes, and alleviates DSS-induced acute murine colitis and colitis-associated tumor formation in an animal (mouse) , The pharmaceutical composition containing metformin according to the present invention can be an effective therapeutic agent for inflammatory bowel disease.

Claims (5)

A pharmaceutical composition for treating or preventing an inflammatory bowel disease containing metformin as an active ingredient. The method according to claim 1,
Wherein the metformin inhibits the activity of NF-κB (nuclear factor-κB) in the intestinal epithelial cells. 3. The method of claim 2,
Wherein the inhibition of NF-κB activity is attenuated by weakening IκBα phosphorylation and NF-κB DNA binding activity. 3. The method of claim 2,
(IL-8) gene is inhibited by the inhibition of NF-κB activity. The present invention also provides a pharmaceutical composition for the treatment or prevention of inflammatory bowel disease. The method according to claim 1,
Wherein said inflammatory bowel disease is ulcerative colitis, Crohn's disease, Celiac disease, intestinal Behcet's disease or ischemic enteritis.

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