KR101146234B1 - Extracts of Lagerstroemia indica for allergy treating and pharmaceutical compositions for allergy comprising the extracts - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for anti-atopic dermatitis as an active ingredient, more specifically Lagerstroemia indica ) extract and allergy preventing or improving pharmaceutical composition containing the same as an active ingredient, the pharmaceutical composition according to the present invention is harmless to the human body and does not irritate the skin at all, secretion of inflammatory cytokines and chemokines (chemokine) It acts as a regulator, inhibits the synthesis of immunoglobulin IgE, and has effects such as erythema reduction, itching quenching, antibacterial action, immune suppression and regulatory action, and can be usefully applied to atopic dermatitis and / or asthma or treatment. .

Description

Extracts of Lagerstroemia indica for allergy treating and pharmaceutical compositions for allergy comprising the extracts}

The present invention relates to a pharmaceutical composition for anti-atopic dermatitis as an active ingredient, and more particularly to a barberry extract and a pharmaceutical composition for preventing or improving allergy containing the same as an active ingredient.

Atopy (atopy) is a skin disease that has been used since Coca in 1925 described atopic dermatitis, asthma and fever as a result of allergic reactions to food and inhalable substances. In addition to atopic dermatitis, there are asthma, allergic rhinitis, and allergic conjunctivitis.

The exact pathophysiology of the atopic dermatitis is not yet fully understood, but it has been reported that immunological and non-immunological mechanisms are involved with genetic predisposition. Exogenous atopic dermatitis, which accounts for the majority of atopic dermatitis, is caused by immune mechanisms associated with immunoglobulin IgE, and there are reports of primary immune responses caused by T-cell abnormalities rather than secondary immune responses to certain allergens. As cell-mediated immune dysfunction has been shown to be associated with an increase in immunoglobulin IgE in patients, in addition to secondary immune responses, there are also reports that primary immune responses are involved in the pathogenesis of atopic dermatitis. , Seoul, 2001, pp 23-52).

Another characteristic of atopic dermatitis is the incidence of atopic dermatitis due to the deficiency of gamma-linolenic acid and the secretion of chemokine in lipids forming cell membranes of skin cells.

In view of the etiology, mechanisms, and symptoms of atopic dermatitis as described above, a therapeutic agent for atopic dermatitis has been developed. As a result, a number of natural or synthetic immunosuppressive agents, antihistamines, steroid preparations, and the like have been developed. For example, immunosuppressants include Cyclosporin A, FK506 (Tacrolimus, Tacrolimus; Wasik et al., Immunopharmacology 20: 57-61, 1990) and SDZ ASM981 (Pimecrolimus, Pimecrolimus; Grassberger et al., Br. J. Dermatology 141: 264-273, 1999). On the other hand, steroids and antihistamines, which are used as treatments for atopic dermatitis, have the effect of temporarily relieving symptoms, but skin thinning and osteoporosis in long-term use of external or oral steroid hormones. It is clinically problematic due to local and systemic side effects such as induction and growth inhibition in children. Therefore, there is a need to develop a therapeutic agent having no such side effects and excellent efficacy.

The inventors of the present invention, while researching a natural product that can treat allergic diseases such as atopic dermatitis and asthma, EoL-1 cells, THP-1 cells, which are cell lines of immune cells, the extract of Lagerstroemia majorly works in allergic diseases And the Jurkat cells confirmed the inhibitory effect of the production of inflammatory cytokines and cytotoxicity for each cell and completed the present invention.

An object of the present invention is to provide a pharmaceutical composition for preventing or improving allergies containing an extract of Lagerstroemia indica as an active ingredient, which is harmless to the human body as an extract derived from natural products and has no irritation to the skin.

The present invention Lagerstroemia ( Lagerstroemia) to achieve the above object indica ) alcohol extracts; Lagerstroemia obtained from at least one solvent fraction selected from water, hexane, ethyl acetate and butanol of the alcohol extract indica ) provides an extract.

The present invention the Lagerstroemia ( Lagerstroemia) It provides a pharmaceutical composition for preventing or improving allergy containing the extract of indica ) as an active ingredient.

Hereinafter, the present invention will be described in detail.

Lagerstroemia according to the present invention is a deciduous shrub belonging to the genus Botanical plant Sangnok Leaf Plant River Plating Co. indica (Li), native to southern China and distributed mainly in Korea, Japan, and Australia. The tree is about 5 m high and its leaves are facing each other in the shape of long oval. In July to September, pink or white flowers bloom at the ends of the branches. The flowers are called crape myrtle. It is also called paoyangsu or tickle because it looks like it tickles as it shakes with a tree. Lagerstroemia has been known to be effective for hemostasis, fracture, detoxification, and has been used for various bleeding, fracture, cirrhosis, etc., but the effect on allergic disease has not been reported yet.

Accordingly, the present invention is derived from natural products, harmless to the human body and no irritation to the skin ( Lagerstroemia) indica ) provides a pharmaceutical composition for preventing or improving allergy containing the extract as an active ingredient.

The allergy is atopic dermatitis or asthma, Lagerstroemia indica extract used in the present invention is a lower alcohol extract having 1 to 4 carbon atoms of the barberry; At least one solvent fraction selected from water, hexane, ethyl acetate and butanol of the alcohol extract; Or a mixture thereof; more preferably, it is an ethanol extract of Lagerstroemia , the Lagerstroemia indica ) is characterized in that the leaves, stems, roots or mixtures thereof.

Lagerstroemia indica ) extract refers to a liquid portion obtained by dipping and solid-liquid separation of dried barberry tree outpost using a lower alcohol having 1 to 4 carbon atoms according to a conventional extraction method, and the lower alcohol having 1 to 4 carbon atoms used above. The concentration and amount of immersion temperature and immersion time, the number of repetition of immersion extraction, the degree of filtration and concentration of the immersion extract can be easily changed according to the intended use.

In addition, the alcohol extract of the barberry may be further fractionated into hexane fraction, ethyl acetate fraction, butanol fraction and water fraction, the preparation of each fraction of the barberry according to the invention is used hexane, ethyl acetate, butanol The concentration and amount of, the number of times of shaking and separation and the degree of concentration can be easily changed depending on the intended use.

As a specific example, the dried larvae starch is added to ethanol (80% concentration) in an amount in the range of 500 to 1,500 ml with respect to 100 g of larvae starch powder, and ethanol immersion extraction is allowed to stand at room temperature for 20 to 30 hours. After repeatedly collecting the immersion extracts, and filtered to remove impurities, and concentrated to a volume of 1/2 to 1/4 of the total amount of immersion extract to obtain the ethanol extract of the barberry tree according to the present invention.

Lagerstroemia according to the present invention indica ) extracts are characterized by inhibiting the synthesis of pro-inflammatory cytokines, chemokines and immunoglobulins IgE.

More specifically, Lagerstroemia according to the present invention ( Lagerstroemia indica ) extracts (1) the toxic effects on the cells of Lagerstroemia extract, (2) EoL-1 cells (human eosinophilic leukemic cells), THP-1 cells (human monocytic cells), Jurkat cells (human T cell lymphoblast-like) The inhibitory effect of barberry extract on inflammatory cytokines in cells) and (3) the effects of barberry extract on asthma-induced mice were identified and can be effectively used for the prevention or improvement of atopy and / or asthma. It could be confirmed.

As a specific example, the Lagerstroemia As a result of confirming the cytotoxicity against the cell lines of immune cells, which acts mainly in the allergic disease of the indica extract, it was confirmed that the cell viability did not decrease when the barberry extract was treated, compared with the control group. It was confirmed that the extract did not show toxicity for each cell. See FIG. 2.

Lagerstroemia according to the present invention indica ) extracts showed inhibitory effects on various inflammatory cytokines in EoL-1 cells, THP-1 cells, and Jurkat cells, resulting in interleukin (IL) -2, interleukin (IL) -4, and interleukin (IL). Inhibition of the production of interleukin, IL) -5, interleukin (IL) -6, interleukin (IL) -13, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) It was. See FIGS. 3 and 4.

In addition, Lagerstroemia for asthma-induced mice The anti-allergic effects of indica ) extracts showed that the total cell number and eosinophils in the lung washing solution of the barberry extract treatment group decreased concentration-dependently with treatment concentration, and the number of cells in the infiltrated lung tissue also decreased. The morphology of was maintained similar to normal, and the amount of albumin-specific immunoglobulin IgE was clearly reduced, confirming the surprising anti-allergic effect.

The present invention Lagerstroemia It provides a pharmaceutical composition for preventing or improving allergy containing the extract of indica ) as an active ingredient.

The extract of Lagerstroemia indica may further include a pharmaceutically usable carrier or dispersing agent, suspending agent, stabilizer, etc., raw materials of cosmetics, bath products, soap, pharmaceutical ointments, animal medicines or pack products Can be used as

The pharmaceutical composition may be parenterally administered during clinical administration, and may be used in the form of a general pharmaceutical formulation. That is, it may be prepared as a solution, suspension, spray, patch, pad, cream, ointment, gel, tablets or pills.

In addition to the active compounds, the solution may be prepared by conventional excipients such as solvents, solubilizers and emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, camellia oil, aloe vera, glycerin, jade oil, olive oil, castor oil, almond oil and sesame oil, glycerol, glycerol form alcohol, tetrahydrofurfuryl alcohol, polyethylene glycol And fatty acid esters of sorbitan, or mixtures of these materials, and may include methyl- or propyl-p-hydroxybenzoate or sorbic acid as a preservative.

The suspending agents, in addition to the active compounds, include conventional excipients such as liquid diluents such as water, ethanol and propylene glycol, polyethylene glycol, and suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters. , Cellulose derivatives and hydrogenated edible oils), microcrystalline cellulose, aluminum methoxide, bentonite, agar and injectable esters such as tragacanth, ethyloleate or mixtures of these materials.

The ointments, creams and gels may be prepared in addition to the active compounds by conventional excipients such as animal and vegetable fats, wax paraffins, starches, targacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide or these It may contain a mixture of substances.

In addition, the method of administration may generally be applied to the affected area, it is possible to select the preferred method of administration according to the type. Daily dosage of the composition of the present invention may be determined depending on the administration target, administration method, symptoms. The number of administration is preferably two or more times a day, but the number of administration may also be adjusted according to the degree of symptoms. That is, the method of administration, dosage and frequency of administration may be changed in particular taking into account the constitution specificity and weight of the subject to be treated, the type and depth of the disease, the nature of the formulation, the nature of the drug administration, and the duration or interval of administration.

In order to effectively improve atopy, it is important to select a suitable external formulation. In order to improve atopy, the barberry extract may be appropriately diluted and applied directly to the skin, and the present invention provides an ointment that can effectively apply the pharmaceutical composition for preventing or improving atopy. The ointment of the present invention is prepared by combining the pharmaceutical composition for preventing or improving atopy with an inorganic substance, and then coating it with a fat-soluble base. The inorganic material is preferably used a material having excellent antibacterial, anti-inflammatory effect, epidermal regeneration effect, and specific examples thereof include zinc oxide, zinc carbonate, iron oxide.

In addition, it is preferable to further use a ceramic carrier that can safely impregnate the pharmaceutical composition for preventing or improving atopy of the present invention, which is a water-soluble substance. As the ceramic carrier, zeolite, talc, gypsum, seed powder and mixtures thereof are preferably used. Such a ceramic carrier is excellent in the impregnation of the water-soluble component can facilitate the supply of the water-soluble component to the skin.

The pharmaceutical composition according to the present invention is an extract derived from natural products of Lagerstroemia indica , which is harmless to the human body, has no irritation to the skin, controls the secretion of inflammatory cytokines and chemokines, and inhibits the synthesis of immunoglobulin IgE. It can be usefully applied to the improvement of atopy or asthma by showing effects such as erythema reduction, itching quenching action, antibacterial action, immune suppression and regulating action.

Before describing the present invention in detail, it is to be understood that the invention is not limited by the specific embodiments of the invention described below, as variations of specific embodiments may be made but are included within the scope of the appended claims. do. Also, it is to be understood that the terminology used is for the purpose of describing particular embodiments only and is not intended to be limiting. Instead, the scope of the invention will be established by the appended claims.

It should be understood that the singular forms used in the specification and the appended claims also include the plural forms unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[ Manufacturing example ] Preparation of Lagerstroemia Extract

(1) Preparation of Ethanol Extract of Barberry Tree

The ethanol extract of the Barberry tree was prepared using the dried Barberry tree outpost.

Dried Lagerstroemia indica ) ethanol immersion extraction was added to ethanol (80% concentration) in an amount in the range of 1,000 ml with respect to 100 g of the powder of the outpost (including the entire leaf, stem and root), and allowed to stand at room temperature for 24 hours. The immersion extracts were collected, filtered to remove impurities, and concentrated to a volume of 1/3 of the total amount of immersion extract, thereby preparing an ethanol extract of barberry tree according to the present invention.

(2) of Lagerstroemia Hexane Fraction  Produce

Hexane fraction of barberry tree is suspended in ethanol extract of barberry tree in water, shaken with addition of the same amount of n-hexane, and left to separate only the upper layer when separated into the upper layer of hexane and the lower water layer. The separation process was repeated three times, and the fractions were collected, and then concentrated to a volume of 1/3 of the total amount of the fractions to prepare a hexane fraction of barberry tree according to the present invention.

(3) ethyl acetate of barberry Fraction  Produce

Ethyl acetate fraction of the barberry tree is obtained from the ethanol extract of the barberry tree as described above, and then the same amount of ethyl acetate is added using ethyl acetate instead of hexane using the remaining aqueous layers, followed by shaking. After separation, the mixture is separated into an upper layer composed of ethyl acetate and an aqueous layer below. The separation process of separating only the upper layer is repeated three times. After collecting the fractions, the volume is 1/3 of the total amount of the fractions. By concentration, ethyl acetate fraction of Barberry was prepared according to the present invention.

(4) of Lagerstroemia Butanol Fraction  Produce

The butanol fraction of the barberry is obtained from the ethanol extract of the barberry as described above, and the ethyl acetate fraction is obtained as described above, followed by adding the same amount of butanol using butanol instead of ethyl acetate using the remaining aqueous layers, followed by shaking. Thereafter, the mixture is separated into an upper layer consisting of butanol and an aqueous layer below it, and the separation process of separating only the upper layer is repeated three times. After collecting the fractions, the fractions are concentrated to a volume of 1/3 of the total amount of the fractions. By to prepare a butanol fraction of barberry according to the present invention.

(5) water of Lagerstroemia Fraction  Produce

The water fraction of Barberry tree is obtained by obtaining butanol fraction as described above from the ethanol extract of Barberry tree, collecting the remaining aqueous layers, and concentrating to a volume of 1/3 of the total amount of the aqueous layers. To prepare a water fraction of the barberry according to.

[ Experimental Example  1] Cytotoxicity of Lagerstroemia Extract

In order to confirm the cytotoxicity of the barberry extract according to the present invention, EoL-1 cells (human eosinophilic leukemic cells), THP-1 cells (human monocytic cells) and Jurkat cells (human T cell lymphoblast-like cells) 5 After treatment with 10 ㎍ / ㎖ ethanol extract prepared in the above preparation to × 10 ⁵ cells / ㎖, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl after 24 hours -2H-tetrazolium bromide) analysis was performed, and the results are shown in FIG. 2.

As a result, as shown in Figure 2, when the barberry extract was treated to EoL-1 cells, THP-1 cells and Jurkat cells, it was confirmed that the cell viability did not decrease compared to the control group, which is not treated. The results confirm that the concentration does not show toxicity for each cell.

[ Experimental Example  2] Inhibitory Effect of Barberry Extract on Inflammatory Cytokines in Various Cells

The inhibitory effect of the barberry extract according to the present invention on various intracellular inflammatory cytokines was confirmed.

Human eosinophils, monocytes, and T lymphocytes produce various cytokines in acute inflammatory reactions such as asthma, which increase the inflammatory response and exacerbate the disease. Cells, T lymphocytes were confirmed in vitro (in vitro) experiments using Jurkat cells.

House dust mite (mite) after pretreatment of 0.1 g / ml and 1.0 μg / ml of Barberry ethanol extract prepared in Preparation Example to 1 × 10 ⁶ cells / ml of EoL-1 cells, THP-1 cells and Jurkat cells for 1 hour. 24 hours after treatment with 1 μg / ml, the amount of inflammatory cytokines in the supernatant was measured by ELISA.

As a result, as shown in Figure 3, it was confirmed that the interleukin (IL) -6 increased by house dust mite is concentration-dependently inhibited by the barberry extract in EoL-1 cells and THP-1 cells.

In addition, as shown in Figure 4, Jurkat cells, interleukin (IL) -2, interleukin (IL) -4, interleukin (IL) -5, interleukin (IL) increased by house dust mite It was confirmed that various inflammatory cytokines of -13, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were inhibited in concentration-dependent manner by the extract of Lagerstroemia. In Jurkat cells, the secretion of various inflammatory substances caused by Lagerstrophyllum can be confirmed.

It is believed that cytokines such as IL-2, IL-4, IL-5, IL-6, IL-13, TNF-α and IFN-γ are secreted from various cells to induce the migration of inflammatory cells and are involved in activity and inflammation Based on the report that plays an important role in the regulation of immune cells activity in the response and various inflammatory reactions, barberry extract according to the present invention was found to inhibit the secretion of cytokines involved in the inflammatory response, which is an allergic disease The results confirm that it is effective for treatment.

[ Experimental Example  3] of Lagerstroemia Extract in Asthma-induced Mice Anti-allergy  effect

Asthma-induced mice induced by Ovalbumin were used to observe the anti-allergic effect of Barberry extract in in vivo experiments.

In order to confirm the effect of the extract of Lagerstroemia by inducing asthma disease, intraperitoneal injections were repeated twice intraperitoneally with 10 μg of egg albumin per two weeks to 10 asthma-induced mice in each group. After 1 week of intraperitoneal injection, 5% egg albumin solution was inhaled for 1 hour daily for 1 week, and the following tests were performed 4 weeks after the start of the experiment.

Asthma non-induced mouse group (normal) was not treated with egg albumin for asthma-induced asthma, and did not receive barberry extract, and asthma-induced asthamp-untreated group (control group) Asthma was induced, but no drug treatment was performed, including barberry extract.

Asthma-induced mouse groups were further divided into barberry extract administration groups and dexamethasone oral administration group (Dex) administered dexamethasone 3 mg / kg.

Lager tree extract administration group was administered the ethanol extract 50 mg / kg of barberry ethanol extract prepared in the above preparation daily (Li 50), the group administered the 250 mg / kg of daily Lagerstroemia extract (Li 250) and daily Lagerstroemia extract Subdivided into groups administered 500 mg / kg (Li 500).

(One) In waste washing liquid Total cell count  And effects on eosinophils

As a result of investigating changes in total cell number and eosinophils in pulmonary lavage fluid against barberry extract in in vivo experiments using the ovalbumin-induced asthma-inducing mice, shown in FIG. As described above, the total number of cells in the asthma-induced group was increased by 40 times compared to the normal group, but the barberry extract treatment group was gradually decreased according to the dosage of the extract.

In addition, as a result of measuring eosinophils, a cell mainly acting on asthma among leukocytes, as shown in B of FIG. 5, eosinophils increased in the asthma-induced group by the gingko biloba extract. Many decreases were found.

(2) Lung tissue  Impact

Lungs close to trachea in each group of mice to investigate the effect on lung tissue on Barberry extract in in vivo experiments using the ovalbumin-induced asthma-induced mice Tissues were extracted and fixed with 10% neutral formalin to prepare paraffin tissue blocks. Thereafter, tissue sections were made using a microtome, and then subjected to H & E staining (hematoxylin & eosin stain), and observed under a microscope. The results are shown in FIG. 6A.

As shown in FIG. 6A, the number of cells infiltrated into the bronchus was increased in the asthma-induced group compared to the normal group, and the alveoli were narrowed as a whole. The alveolar morphology remained normal to normal.

Periodic acid-schiff staining was performed on the tissue sections as in the H & E staining and observed under a microscope. The results are shown in B of FIG. 6. As shown in FIG. 6B, in the asthma-induced group, mucus secretion to the bronchus was increased and the bronchus was narrowed due to the asthma-induced group, compared to the asthma-induced group. Depending on the concentration of the extract, the secretion of mucus decreased, and the narrowed lung tissue was similar to normal.

(3) serum immunoglobulins IgE Impact on

The effect of Barberry extract on total immunoglobulin IgE and albumin specific immunoglobulin IgE antibodies in the serum of asthma induced mice induced by Ovalbumin was measured using the ELISA method.

As a result, as shown in FIG. 9, the total immunoglobulin IgE and albumin-specific immunoglobulin IgE increased sharply in the asthma-induced group, but the total immunoglobulin IgE did not change significantly by the barberry extract. The amount of albumin-specific immunoglobulin IgE was found to be reduced when 500 mg / kg of barberry extract was administered.

(4) Waste washing liquid  Immunoglobulins IgE  Level impact

The effect of Barberry extract on total immunoglobulin IgE and albumin specific immunoglobulin IgE antibodies in the lung wash solution of the asthma induced mice induced by Ovalbumin was measured using the ELISA method. Shown in

As a result, as shown in FIG. 8, the asthma-induced group was increased compared to the normal group, and the amount of total immunoglobulin E was slightly decreased by the barberry extract, but the amount of albumin-specific immunoglobulin IgE was significantly decreased. Could confirm.

(5) Reactive oxygen species  Impact on Removal

In order to confirm whether barberry extract is effective in removing reactive oxygen species in experiments using asthma-induced mice, the amount of reactive oxygen species produced in the cells isolated from the lung washing solution was measured. 9 is shown.

Reactive oxygen species are important for alleviating diseases because reactive oxygen species are oxygen molecules in the state of oxygen or metastable states of oxygen, which have strong power to oxidize other substances and cause massive damage to body tissues when they are produced in large quantities in the body. It is recognized. As shown in FIG. 9, the amount of reactive oxygen species increased rapidly in the asthma-induced group, compared to the normal group, but the amount of reactive oxygen species was significantly reduced in the mice administered the 50 mg / kg barberry extract.

As a result, as can be seen from the results of Experimental Example 3, it was confirmed that the extract of the gingko tree according to the present invention can be usefully used for atopic diseases and asthma diseases.

1 is a view schematically illustrating a process of causing atopic dermatitis and tissue lesions of asthma,

2 is a result confirming the cytotoxicity of the barberry extract according to the present invention,

3 is a result of confirming the inhibitory effect on the interleukin-6 of the barberry extract according to the present invention in EoL-1 cells and THP-1 cells,

(A: EoL-1 cells, B: THP-1 cells)

Figure 4 is a result confirming the inhibitory effect on various inflammatory cytokines of barberry extract according to the present invention in Jurkat cells,

(A: IL-2, B: IL-4, C: IL-5, D: IL-6, E: TNF-α, F: IFN-γ)

5 is a result of confirming the change in the total cell number and eosinophils in the lung washing liquid according to the extract of barberry tree of the present invention,

(A: total cell number, B: eosinophils)

6 is a result confirming the effect on the lung tissue of the barberry extract according to the present invention,

(A: H & E dyeing, B: periodo-acid dye)

Figure 7 is the result confirming the effect on the serum immunoglobulin IgE of the barberry extract according to the present invention,

(A: total immunoglobulin IgE, B: albumin specific immunoglobulin IgE)

8 is a result confirming the effect on the immunoglobulin IgE in pulmonary lavage fluid of the Lagerstroemia extract according to the present invention,

(A: total immunoglobulin IgE, B: albumin specific immunoglobulin IgE)

Figure 9 is a result confirming the effect on the active oxygen species of barberry extract according to the present invention.

Claims (5)

A pharmaceutical composition for inhibiting or preventing allergic reactions through the inhibition of the synthesis of pro-inflammatory cytokines, chemokines and immunoglobulins IgE, Lagerstroemia indica containing a mixture of leaves, stems and roots as an active ingredient Pharmaceutical composition containing a lower alcohol extract having 1 to 4 carbon atoms). delete delete delete delete

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