KR20190121004A - Composition for anti-inflammatory treatment comprising nardosinone-based metabolites - Google Patents

Abstract

The present invention relates to an anti-inflammatory composition containing nardosinone-based metabolites. More specifically, the present invention relates to the anti-inflammatory composition containing nardosinone, isonardosinone, kanshone E, or kanshone B. A composition of the present invention exhibits an excellent anti-inflammatory effect, thereby being able to be usefully used as a pharmaceutical composition, a cosmetic composition, and a food composition.

Description

Composition for anti-inflammatory treatment comprising nardosinone metabolites {Composition for anti-inflammatory treatment comprising nardosinone-based metabolites}

The present invention relates to an anti-inflammatory composition containing a narcondanone-based metabolite, and more particularly, nardosinone, isonardosinone, which can be separated from the hexane fraction of the extract of persimmon fragrance. An anti-inflammatory pharmaceutical composition, cosmetic composition and food composition containing Kanshone E or Kanshone B.

Inflammatory disease refers to the pathological condition of an abscess formed by the invasion of bacteria. Typical inflammatory diseases include acute chronic inflammatory diseases such as osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, tendonitis, tendonitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, asthma, atopy, Crohn's disease, ulcerative colitis, etc. have. Inflammation is a manifestation of normal and protective in vivo defense mechanisms that are localized to tissue damage caused by physical trauma, harmful chemicals, microbial infections or irritants in metabolites in vivo.

Various biochemical phenomena are involved in the development of inflammation in the living body. Macrophage is a multi-functional cell that plays an important role in the inflammatory response by generating various cytokines and NOx by chemical stimulation. In particular, inducible nitric oxide synthase (iNOS) expressed by cytokine stimulation such as interferons-gamma (IFN-γ) in macrophages produces large amounts of nitric oxide (NO) for a long time. This oxidative stress is known to promote NF-κB activity, a transcription factor of the inflammatory response inhibited by IκB. Activated NF-κB is known to promote the expression of genes that induce inflammatory responses, such as iNOS, COX-2, and various cytokines such as IL-1β or TNF-α. Inflammatory responses are known to be inhibited (Baeuerle et al., Annu. Rev. Immunol., 12: 141-179, 1994).

NO, one of the inflammatory substances, is produced in endothelial cells or macrophages in a normal state and exhibits various physiological activities in addition to cell killing and bactericidal action. In particular, it plays a role in maintaining homeostasis of blood pressure in the relaxation of vascular endothelial cells It is known to do. Stimulation of lipopolysaccharide (LPS), pro-inflammatory factors, and irradiation, in particular, induces the expression of iNOS, an inducible nitric oxide synthase, continuously producing large amounts of NO for 4-6 hours. NO causes such inflammatory diseases.

The most common inflammatory disease prevention or treatment for treating such inflammatory diseases is divided into steroidal and nonsteroidal inflammatory disease prevention or treatment, and most of the synthetic inflammatory disease prevention or treatment has several side effects in addition to the main action. In many cases, excellent effects and development of drugs for preventing or treating inflammatory diseases with fewer side effects are urgently needed. In particular, in terms of efficacy and side effects, natural product formulations, which have a long history of clinical experience and excellent evaluation in terms of safety, are considered to be good candidates for the development of preventive and therapeutic agents for inflammatory diseases.

Nardostachys jatamansi is traditionally used for stomach pain, gastrointestinal spasms, chest pain, neurological gastrointestinal disorders, vomiting, headaches, and the like, and has been used extensively as a tonic, irritant and anticonvulsant in several Asian countries. It has also been used to treat pathological excitement, palpitations and spasms (Bagchi, A., et al., Planta Med., 57, 9697 (1991)).

At the root of the nectar is a variety of sesquiterpenes, lignans, and neolignans such as Jatamansic acid and Jatamansone (Chatterji, A, et al., National Institute of Science Communication, 5, pp 99-100 (1997); Arora, RB., Indian Council of Medical Research, vol. 51 (1965).

The rooted water of the fennel has been used for mental disorders, blood disorders and circulatory disorders, and the main therapeutic components of the sensation enhances neuronal activity and central nervous system effects (Li, p., Et al., Journal of Pharmacology Science, 93). , 122-125 (2003).

The inventors of the present invention, while studying a novel substance with excellent anti-inflammatory activity from a metabolite derived from natural products, by purely separating and purifying Nardondonon-based metabolite having excellent anti-inflammatory activity from the sweet scent and confirming its anti-inflammatory effect The invention has been completed.

It is an object of the present invention to provide an anti-inflammatory composition comprising a narcondanon-based metabolite.

In addition, the present invention is to provide a cosmetic composition and a food composition comprising the metabolite.

The present invention provides a novel narcionone family metabolite, a compound of Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof.

[Formula 3]

[Formula 4]

The compounds of Formulas 3 and 4 are called Kanshone E and Kanshone B, respectively.

The present invention also provides the following narcionone family metabolites, or pharmaceutically acceptable salts thereof:

[Formula 1]

 [Formula 2]

The compounds of Formula 1 and Formula 2 are referred to as Nardonsinone and Isonardosinone, respectively.

The present invention relates to compounds of the formulas 1 to 4, specifically Nardoneone, Isonardosinone, Kanshone E and Kanshone B, and their pharmaceutically acceptable It provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising at least one narcionone-based metabolite selected from the group consisting of salts as an active ingredient.

[Formula 1]

[Formula 2]

 [Formula 3]

[Formula 4]

In this case, the narcionone-based metabolite may be separated from the hexane fraction of the extract of methanol.

The compositions of the invention may also show anti-inflammatory effects by inhibiting the production of NO (Nitric oxide), or PGE ₂ (prostaglandin E _2).

In addition, the composition of the present invention can inhibit the expression of iNOS (inducible NO synthase) or COX-2 (Cyclooxygenase-2) protein.

In addition, the composition of the present invention can inhibit mRNA expression of IL-1β (Interleukin 1β), IL-6 (Interleukin 6) or TNF-α (Tumor Necrosis Factor α).

In addition, the composition of the present invention can inhibit the nuclear factor kappa-light-chain-enhancer of activated B (NF-kB) or miogen-activated protein kinase (MAPK) pathway.

At this time, the pharmaceutical composition is a powder, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, external preparations, external preparations, external preparations, ointments, creams, gels, warnings It may be formulated in the form of a dressing, a patch, a spray or an injection.

In another aspect, the present invention provides a cosmetic composition comprising the narcondanon-based metabolite as an active ingredient.

The cosmetic composition can be formulated in the form of solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations or sprays. .

In another aspect, the present invention provides a food composition containing the narcondanon-based metabolite as an active ingredient.

At this time, the food composition may be formulated in the form of tablets, granules, pills, capsules, solutions or powders.

Inflammatory diseases of the present invention may also be encephalitis, osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, tendonitis, tendonitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, asthma, atopy, Crohn's disease or ulcerative colitis , Preferably encephalitis.

An anti-inflammatory composition comprising the Nardocone family metabolite of the present invention as an active ingredient inhibits the production of NO or PGE ₂ , iNOS or COX-2 protein expression, and mRNA expression of IL-1β, IL-6 or TNF-α. Or by inhibiting nuclear factor kappa-light-chain-enhancer of activated B (NF-kB) or miogen-activated protein kinase (MAPK) pathways.

In particular, it exhibits an excellent anti-inflammatory effect in microglia, and has an excellent effect on the improvement, treatment and prevention of encephalitis.

Therefore, it is possible to develop environmentally friendly and human-friendly medicines, cosmetics, and foods using the anti-inflammatory composition comprising the narcondanon-based metabolite of the present invention as an active ingredient.

Figure 1 shows a method for separating the narcondanone-based metabolites from the hexane fraction of the extract of the Persimmon fragrance.
Figure 2 is a result of measuring the cytotoxicity of the narcondan family metabolites.
FIG. 3 shows the NO production inhibitory effect (FIG. 3A) and PGE ₂ production inhibitory effect (FIG. 3B) of the narcodonon series metabolites.
Figure 4 shows the suppression of iNOS and COX-2 protein expression levels of the Nardocone family metabolite, Nardocone (Fig. 4a), isonanardocone (Fig. 4b), Kanshon E (Fig. 4c), and Kanshon B (Fig. 4d) The effect is shown.
Figure 5 shows the mRNA expression inhibitory effect of the inflammatory cytokines IL-1β (Fig. 5a), IL-6 (Fig. 5b) and TNF-α (Fig. 5c) of the narcondan family metabolites.
FIG. 6 shows the effects of inhibiting IκB-α degradation and phosphorylation of nardocone (FIG. 6A), isonadrondonone (FIG. 6B), Kanshon E (FIG. 6C), and Kanshon B (FIG. 6D). It is shown.
FIG. 7 shows p65, an NF-κB dimer, in the nuclear fractions of the Nardocone family metabolites, Nardocone (FIG. 7A), Isonadocondonon (FIG. 7B), Kanshon E (FIG. 7C), and Kanshon B (FIG. 7D). And the inhibitory effect of p50 and the inhibitory effect of NF-κB's p65 binding activity (FIG. 7E).
FIG. 8 shows mitogen-activated protein kinase caused by the inflammatory response of the narcondan family metabolites, narcondonon (FIG. 8A), isonanardocone (FIG. 8B), Kanshon E (FIG. 8C), and Kanshon B (FIG. 8D). Inhibitory effect on the active pathway JNK.
FIG. 9 shows mitogen-activated protein kinase by the inflammatory response of the narcondan family metabolites, narcondanone (FIG. 9A), isonardoconeone (FIG. 9B), Kanshon E (FIG. 9C), and Kanshon B (FIG. 9D). Inhibitory effect on the active pathway ERK.
FIG. 10 shows mitogen-activated protein kinase by the inflammatory response of the narcondan family metabolites, narcondanone (FIG. 10A), isonanardocone (FIG. 10B), Kanshon E (FIG. 10C), and Kanshon B (FIG. 10D). Inhibitory effect on the active pathway p38.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are provided only for the purpose of illustration to help the understanding of the present invention, the scope of the present invention is not limited by the following examples.

Example 1

Preparation of Persimmon Hexane Fraction

5 kg of persimmon (Nardostachys jatamansi) was added to 24 L of methanol and sonicated for 2 hours to obtain 663 g of persimmon methanol extract.

The resulting methanol extract was dissolved in 8 L of water and 1 L of methanol, and partitioned in the order of hexane (18 L), chloroform (18 L), ethyl acetate (18 L), butanol (18 L), and the hexane fraction 307.6. g was obtained.

Example 2

Separation of Nardocone-Based Metabolites from Persimmon Hexane Fraction

As in the method described in Fig. 1, narcondanon, isonardoconeone, cannon Sean E and canson B were separated from the sensitized hexane fraction obtained in Example 1.

Stage 1

The hexane fraction obtained in Example 1 was subjected to silica gel column chromatography to obtain seven fractions using chloroform methanol mixture (chloroform: methanol = 50: 1, v / v) as an extraction solvent.

2 steps

The third fraction of the seven fractions of the first step was subjected to silica gel column chromatography, hexane ethyl acetate mixed solution (hexane: ethyl acetate = 20: 1, v / v) to obtain six fractions as an extraction solvent.

3 steps

Nardonone (7.7 g) using the hexane ethyl acetate mixed solution (hexane: ethyl acetate = 20: 1, v / v) as an extraction solvent using the silica gel column chromatography for the fifth fraction of the six fractions of the second step. And isonarondonon (3.0 g), and 11 fractions were obtained.

4 steps

Separation of Kanshon B and Kanshon E

The eleventh fraction of the eleven fractions of step 3 was subjected to reverse phase HPLC for 50 minutes under a solvent gradient of 40% to 100% MeOH in H ₂ O (0.1% formic acid) to obtain Kanshon B (3.6 mg) and Kanshon E ( 6.9 mg) was isolated.

Example 3

Confirmation of the structure of the narchodoid family of metabolites

Nardodone-based metabolites obtained in Example 2 were confirmed using ¹ H-NMR and ¹³ C-NMR, the results are shown in Table 1 below.

compound Chemical formula NMR Nardondonon
(Nardosinone)

1 H-NMR (400 MHz, CDCl 3) δ 7.04 (1H, m, H-1), 4.90 (1H, ddd, J = 1.9, 7.4, 9.3 Hz, H-7), 2.93 (1H, d, J = 9.3 Hz, H-6), 2.88 (1H, dd, J = 7.5, 18.8 Hz, H-8), 2.64 (1H, dd, J = 1.9, 18.8 Hz, H-8), 2,28 (2H, m, H-2, H-3), 1.93 (1H, m, H-4), 1.54 (2H, m, H-2, H-3), 1.38 (3H, s, H-13), 1.17 ( 3H, s, H-12), 1.12 (3H, s, H-14), 1.02 (3H, d, J = 6.8 Hz, H-15); 13 C-NMR (100 MHz, CDCl 3) δ 196.6 (C-9), 140.1 (C-10), 137.9 (C-1), 85.2 (C-11), 78.1 (C-7), 59.7 (C- 6), 40.0 (C-8), 38.6 (C-5), 33.1 (C-4), 26.9 (C-13), 25.6 (C-2, C-3), 23.9 (C-14), 22.2 (C-12), 16.2 (C-15). Isonardosinone

1 H-NMR (400 MHz, CDCl 3) δ7.00 (1H, m, H-1), 3.65 (1H, dd, J = 3.4, 6.5, Hz, H-7), 3.35 (1H, d, J = 3.4 Hz, H-8), 3.35 (1H, d, J = 3.4 Hz, H-8), 2.56 (1H, m, H-4), 2.20 (2H, m, H-2), 1.50 (1H, m , H-3), 1.48 (3H, s, H-12), 1.36 (3H, s, H-13), 1.27 (1H, m, H-3), 1.04 (3H, m, H-14), 0.97 (3H, doublet, J = 6.8 Hz, H-15); 13C-NMR (100 MHz, CDCl3) δ 194.3 (C-9), 140.7 (C-10), 139.7 (C-1), 75.4 (C-11), 57.0 (C-7), 53.5 (C- 8), 50.0 (C-6), 43.5 (C-5), 33.3 (C-4), 32.0 (C-12), 26.5 (C-3), 26.1 (C-2), 27.7 (C-13 ), 25.1 (C-14), 17.4 (C-15). Kanshone E

1 H-NMR (400 MHz, CDCl 3) δ6.68 (1H, s, H-1), 3.71 (1H, dd, J = 3.4, 6.3 Hz, H-7), 3.51 (1H, d, J = 3.4 Hz , H-8), 3.32 (1H, m, H-4), 2.47 (1H, d, J = 6.4 Hz, H-6), 2.31 (1H, dd, J = 5.1, 16.1 Hz, H-3) , 2.26 (1H, dd, J = 14.0, 16.0 HZ, H-3), 1.52 (3H, s, H-12), 1.32 (3H, s, H-13), 1.22 (3H, s, H-14 ), 1.09 (3H, d, J = 6.3 Hz, H-15); 13 C-NMR (100 MHz, CDCl 3) δ 199.3 (C-2), 193.8 (C-9), 153.6 (C-10), 130.2 (C-1), 75.4 (C-11), 56.8 (C- 7), 53.2 (C-8), 50.1 (C-6), 44.8 (C-5), 42.2 (C-3), 32.9 (C-12), 27.6 (C-13), 21.8 (C-14 ), 17.4 (C-15). Kanshone B

1 H-NMR (400 MHz, CDCl 3) δ6.90 (1H, d, J = 5.2 Hz, H-1), 4.91 (1H, ddd, J = 2.0, 7.3, 9.3), 4.36 (1H, m, H- 2), 2.95 (1H, d, J = 9.3 Hz, H-6), 2.90 (1H, dd, J = 7.3, 18.8 Hz, H-8), 2.71 (1H, dd, J = 2.0, 18.8 Hz, H-8), 2.32 (1H, m, H-4), 1.71 (2H, m, H-3), 1.40 (3H, s, H-13), 1.22 (3H, s, H-13), 1.10 (3H, s, H-14), 1.04 (3H, d, J = 6.8 Hz, H-15); 13C-NMR (100 MHz, CDCl3) δ 197.2 (C-9), 142.5 (C-10), 133.4 (C-1), 85.3 (C-11), 77.9 (C-7), 62.8 (C- 2), 59.5 (C-6), 40.2 (C-8), 39.2 (C-5), 34.5 (C-3), 27.6 (C-4), 27.0 (C-14), 22.8 (C-13 ), 21.9 (C-12), 15.8 (C-15).

Example 4

Culture and cytotoxicity of mouse-derived microglia BV2 cells

Mouse derived microglia BV2 cells (2 × 10 ⁵ cells / well) were treated with 10% heat-inactivated FBS, penicillin G (100 IU / ml, Gibco, 15240062) and streptomycin (100 μg / ml, Gibco, 15240062) were dispensed in DMEM medium and incubated for 24 hours at 37 ° C. in a 5% carbon dioxide incubator (Sanyo, MCO175). After incubation, the narcionone-based metabolites isolated in Example 2 were treated by concentration and incubated in a 5% CO ₂ incubator for 24 hours, and cell viability was measured using the MTT method.

In addition, all experimental values were expressed as the average of three times the cell survival rate for the control, the results are shown in FIG.

As can be seen in Figure 2, the cells do not die until the treatment of the narcondanone-based metabolite of the present invention at a concentration of 80 μM, the cell number appears to be slightly reduced by reaching a concentration of 160 μM, Non-line metabolites were found to have excellent cell viability.

Example 5

Inhibition of Inflammatory Mediator Expression by Nardocone Metabolites

To investigate the generation of nardogonone family metabolites, NO, PGE ₂ , which are inflammation mediators in BV2 cells, and inhibition of protein expression of iNOS and COX-2 (Kim et al., European Journal of Pharmacology, 721, pp. 267-276 (2013)).

The specific experimental method for performing western blot analysis is as follows.

Incubate BV2 cells at a concentration of 3 X 10 ⁶ cells / ml in a 60 mm dish for 12 hours, and perform pretreatment to incubate for 3 hours after treatment with narcionine-based metabolites at 20, 40, and 80 μM concentrations, and then lipo The polysaccharide (LPS) was treated with 1 μg / ml and incubated for 24 hours to induce an inflammatory response. After incubation, RIPA (89900, Thermo) buffer was added and the supernatant was separated by centrifugation for 25 minutes at 4 ° C. and 14,000 × g. Protein quantification in the isolated supernatant was performed using BSA protein experiment kit (Pierce Biotechnology).

Specifically, the supernatant was electrophoresed for 2 hours using 7.5% SDS-polyacrylamide gel, and then transferred from the polyacrylamide gel using a nitrocellulose membrane (NC membrane). It was. The transferred nitrocellulose membrane was quenched for 1 hour in a fresh blocking buffer containing 0.1% Tween 20 in Tris-buffered saline containing 5% nonfat milk. After stopping the reaction, the membrane was washed three times every 10 minutes with PBST (PBS, 0.1% Tween 20), and then iNOS (SC-650, Santacruz biotechnology, USA), COX-2 (SC-1745, Santacruz biotechnology, USA) (Ab) was diluted 1: 1000 and the reaction was performed for 3 hours. After the reaction, washed three times with PBST once every 10 minutes, the secondary antibody (Anti-rabbit IgG, AP132, Millipore, USA) was diluted 1: 1000 and the reaction was carried out for 1 hour.

After the reaction, washed three times with PBST once every 10 minutes, and then mixed ECL (Amersham Pharmacia Biotech) solution 1: 1 well, poured onto a nitrocellulose membrane (NC membrane) to emit light, X-ray in the dark room It developed after photosensitive to a film. Actin (SC-1616, Santacruz biotechnology, USA) using the same method to measure and quantify the content of Actin (Actin), the results are shown in Figures 3 and 4.

As shown in FIG. 3, it was found that the production amount of NO and PGE ₂ was suppressed as the concentration of the narcionone series metabolites increased.

In addition, as shown in Fig. 4, as the concentration of the narcionone-based metabolite increases, the protein expression of iNOS and COX-2 is significantly inhibited, and it was confirmed that the anti-inflammatory effect is excellent.

Example 6

Inhibition of Cytokine mRNA Expression by Nardocone Metabolites

To the BV2 cells, which are mouse-derived microglioblasts, the narcionone-based metabolites isolated in Example 2 were added at 20, 40 and 80 μM and pretreated for 3 hours, followed by lipopolysaccharide (LPS). The inflammatory response was then induced and incubated in a 5% carbon dioxide incubator for 6 hours.

After culture, the mRNA expression levels of IL-1β (FIG. 5A), IL-6 (FIG. 5B) and TNF-α (FIG. 5C) were measured by RT-PCR.

As shown in FIG. 5, mRNA expression of IL-1β (FIG. 5A), IL-6 (FIG. 5B) and TNF-α (FIG. 5C) was concentration-dependent when treated with the Nardocone family metabolites of the present invention. It was confirmed that it is suppressed.

Example 7

Inhibition of IκBα degradation, inhibition of IκBα phosphorylation, inhibition of NFκB (p65, p50) nuclear transcription and inhibition of NFκB p65 binding activity

To examine the anti-inflammatory effects of Nardokone-based metabolites on NF-κB-related pathways in BV2 cells, the effects of inhibition of IκB-α degradation, inhibition of IκB-α phosphorylation, inhibition of NF-κB p65 and p50 nuclear transcription, The effect of inhibiting NF-κB p65 binding capacity was determined using the method of Kim et al., European Journal of Pharmacology, 721, pp. 267-276 (2013) and the Western blot analysis of Example 5 above. Confirmed.

Add Nardionone family metabolites to BV2 cells at 20, 40 and 80 μM concentrations, pretreatment for 3 hours, induce inflammatory response pathways with lipopolysaccharide (LPS), and then in a 5% carbon dioxide incubator for 1 hour. Incubated at.

Inhibition of IκB-α (SC-371, Santacruz biotechnology, USA) degradation after culture, inhibition of IκB-α phosphorylation (p-IκBα, SC-8404, Santacruz biotechnology, USA), NF-κB p65 and p50 (SC-8008, SC) -7178, Santacruz biotechnology, USA) In order to confirm the degree of inhibition of nuclear transcription and inhibition of NF-κB p65 binding capacity, a nuclear separation experiment was conducted, and the results are shown in FIGS. 6 and 7.

As shown in Figures 6 and 7, the treatment of narcionone-based metabolites, concentration-dependent phosphorylation of IκB-α in the cytoplasm was reduced and the degree of degradation increased (Figs. 6a to 6d), the NF-κB Intranuclear transcription of p65 and p50 was reduced (FIGS. 7A-7D), and NF-κB p65 binding capacity was decreased (FIG. 7E), confirming the superior anti-inflammatory effect on NF-κB-related pathways of the narcionone family metabolites.

Example 8

Inhibition of the expression of mitogen-activated protein kinase by inflammatory reaction of the narcondan family metabolites

P-ERK, p-JNK, p-38, a type of mitogen activated protein kinase (MAPKs) for inflammatory responses induced by lipopolysaccharide (LPS) in mouse-derived microglia BV2 cells In order to confirm the expression inhibition pathway, the method of the literature (Kim et al., European Journal of Pharmacology, 721, pp. 267-276, 2013) and the Western blot analysis of Example 5 were tested.

After pretreatment with narcionine-based metabolites to BV2 cells for 3 hours at 20, 40, 80 μM, induce inflammatory reaction pathways with lipopolysaccharide, and incubate in 5% carbon dioxide incubator for 1 hour and then p-ERK, p- Expression of JNK and p-38 was confirmed.

As shown in FIGS. 8 to 10, p-JNK (FIG. 8), p-ERK (FIG. 9), and p-38 (FIG. 10) expressions increased when LPS was treated. It was confirmed that expression decreased with treatment.

Therefore, it was confirmed that the inhibition of nardonone-based metabolites was suppressed by the phosphorylation of p-JNK, p-ERK, and p-38 pathways, which are a type of mitogen activated protein kinase (MAPKs).

Claims (12)

A pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising as an active ingredient at least one narcionone-based metabolite selected from the group consisting of a compound of Formulas 1 to 4, and pharmaceutically acceptable salts thereof.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

The method of claim 1, wherein the inflammatory disease is encephalitis, osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, tendinitis, tendonitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, asthma, atopy, Crohn's disease or ulcerative colitis Pharmaceutical composition, characterized in that.
The pharmaceutical composition of claim 2, wherein the inflammatory disease is encephalitis.
The pharmaceutical composition for preventing or treating inflammatory disease according to claim 1, wherein the narcionone-based metabolite is separated from the hexane fraction of the extract of the Persimmon Fragrance.
According to claim 1, wherein the composition is a pharmaceutical composition for the prevention or treatment of inflammatory diseases, characterized in that the production of NO (Nitric oxide) or PGE ₂ (prostaglandin E2).
According to claim 1, wherein the composition is a pharmaceutical composition for the prevention or treatment of inflammatory diseases, characterized in that by inhibiting the expression of inducible NO synthase (iNOS) or COX-2 (Cyclooxygenase-2) protein.
According to claim 1, wherein the composition is for the prevention or treatment of inflammatory diseases, characterized in that the suppression of the expression of IL-1β (Interleukin 1β), IL-6 (Interleukin 6) or TNF-α (Tumor Necrosis Factor α) Pharmaceutical compositions.
According to claim 1, wherein the composition is for preventing or treating inflammatory diseases, characterized in that by inhibiting the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B) or MAPK (Mitogen-activated protein kinase) pathway Pharmaceutical compositions.
A food composition for preventing or ameliorating an inflammatory disease containing as an active ingredient at least one narcionone-based metabolite selected from the group consisting of a compound of Formulas 1 to 4, and pharmaceutically acceptable salts thereof.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

The food composition of claim 9, wherein the food composition may be formulated in the form of tablets, granules, pills, capsules, liquids or powders.
A cosmetic composition for preventing or ameliorating an inflammatory disease containing as an active ingredient at least one narcionone-based metabolite selected from the group consisting of a compound of Formulas 1 to 4, and pharmaceutically acceptable salts thereof.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

The composition of claim 11 wherein the cosmetic composition is in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation or spray. Cosmetic composition characterized in that it can be converted.

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