Inhibitors of cellular expression of ICAM-1 and ldlr

Abstract

To provide inhibitors of cellular expression of ICAM-1 and LDLR and inhibitors of pathogen infection.SOLUTION: The inventors searched for herbal medicines as candidates for agents capable of inhibiting cellular expression of ICAM-1 and LDLR. As a result, we found that Radix Puerariae inhibits the cell surface expression of ICAM-1 and LDLR induced by virus infection. In particular, it was found that cinnamon and Ephedrae Herba contained in the Radix Puerariae is an active ingredient. The present invention provides an inhibitor of ICAM-1 and LDLR cell surface expression comprising Radix Scutellariae.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to an inhibitor of cellular expression of ICAM-1 and LDLR, and also to an inhibitor of pathogen infection. [Background technology]

[0002] In living organisms, signal transduction occurs within cells via various receptors. Receptor-mediated signal transduction is used not only by cells themselves but also by infectious agents such as foreign viruses and parasites when they infect cells.

[0003] For example, receptor-mediated viral infection is one of the important mechanisms by which viruses enter host cells. This process is known to proceed through a series of steps, including receptor recognition and binding by the virus, followed by cell membrane fusion or endocytosis, viral replication, and the release of new virus particles.

[0004] When a virus or other pathogenic organism infects a host cell, it uses specific proteins, such as spike proteins, present on the cell surface to bind to specific receptors on the surface of the host cell. These receptors are usually molecules involved in the normal functioning of the cell. For example, rhinoviruses are known to bind to intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptor (LDLR).

[0005] Once the virus binds to the receptor, it either fuses with the cell membrane and the viral coat, or the cell takes in the virus through endocytosis, a process through which the virus enters the cell and releases its genetic material (RNA or DNA) into the cell.

[0006] Once the viral genetic material is released into the cell, it uses the host cell's machinery to begin replicating its proteins and genetic material, a process that leads to the virus replicating itself and producing new viral particles.

[0007] Once new virus particles are produced, they are released from the cell and can infect other cells via their receptors, thereby spreading the infection. This release can occur either by cell destruction or by secretion of virus particles from the cell (called "budding off").

[0008] Thus, viruses, parasites, and other pathogens invade living organisms via specific receptors. Therefore, understanding receptor-mediated viral infection is important for the development of prevention and treatment of viral infections. Vaccines and therapeutic drugs that target the binding of viruses to receptors are being developed.

[0009] In the above viral infection process, if we could reduce the amount of virus that enters cells, which is the beginning of viral infection, and the subsequent re-entry into cells, we could slow down the rate at which the virus spreads within the body, allowing the body's immune response to catch up with the rate of viral infection and preventing the condition from becoming severe.

[0010] In this study, we focused on the host virus receptors involved in virus entry, among the infection routes, and investigated receptors that may have some effect on receptor expression and inhibit virus entry into cells. Among the various receptors, we focused on ICAM-1 and LDLR and attempted to develop new drugs. We searched for substances that can inhibit the recognition and binding of infectious agents such as viruses to the receptors ICAM-1 and LDLR. In our search, rather than searching for substances that inhibit the binding of ICAM-1 and LDLR to viruses, we searched for substances that can inhibit the expression of ICAM-1 and LDLR on cells, and discovered new drugs.

[0011] There are many known diseases that involve signaling pathways mediated by the receptors ICAM-1 and LDLR. Many diseases are exacerbated by increased expression of ICAM-1 and LDLR. For example, the following are known infectious diseases that recognize LDLR and infect the body, and are exacerbated by increased LDLR:

[0012] Non-Patent Document 1 reports that hepatitis B virus (HBV) is associated with LDLR. This document discloses that a monoclonal antibody blocking LDLR potently inhibits HBV infection in HepG2 cells, a liver cell line, and primary human hepatocytes. It has also been shown that knockdown of LDLR expression via small interfering RNA (siRNA) and knockout of the LDLR gene using CRISPR / Cas9 significantly reduced HBV infection. Furthermore, human apolipoprotein E (apoE) binds to the HBV envelope, and recombinant LDLR protein inhibited heparin-mediated apoE retrieval, suggesting that LDLR acts as an HBV receptor through its binding to apoE. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress HBV infection and the onset and progression of hepatitis B associated with infection.

[0013] Non-Patent Documents 2 and 3 report that hepatitis C virus (HCV) is associated with LDLR. These documents demonstrate that recombinant LDLR protein, LDLR-blocking antibodies, and LDL inhibited intracellular viral RNA accumulation regardless of HCV genotype, viral load, or liver donor. Furthermore, they demonstrated that viral RNA accumulation increased in cells treated with squalestatin, which increases LDLR activity, before infection, whereas it decreased in cells treated with 25-hydroxycholesterol, which inhibits LDLR activity. Furthermore, they observed that small interfering RNA (siRNA) targeting LDLR in Huh-7 cells reduced HCV infectivity, and that blocking LDLR with an antibody reduced HCV RNA replication. Furthermore, soluble LDLR inhibited HCV entry into hepatocytes and HCV binding to LDLR expressed on CHO cells. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress HCV infection and the onset and progression of infection-associated hepatitis C.

[0014] Non-Patent Document 4 reports that vesicular stomatitis virus (VSV, VSVG) associates with LDLR. This document discloses that soluble LDLR binds to VSV-G, a VSV outer coat protein, that soluble LDLR inhibits VSV infection, and that VSV and LDL compete for binding to LDLR. It has also been reported that an inhibitory antibody against the ligand-binding domain of LDLR inhibits VSV internalization and infectivity, demonstrating that LDLR is the primary entry site for VSV. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress VSV infection and the onset and spread of vesicular stomatitis during lytic infection.

[0015] Non-Patent Document 5 reports that Chagas disease (T. cruzi parasite) is associated with LDLR. This document found that T. cruzi infection significantly increases LDLR in host cells, particularly in the host heart, while LDLR inhibition reduces T. cruzi infection in infected cells. It has also been shown that T. cruzi directly binds to recombinant LDLR, and that LDLR co-localizes with T. cruzi in infected hearts. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress the onset and spread of T. cruzi infection.

[0016] Non-Patent Document 6 reports that toxoplasmosis (Toxoplasma parasite) is associated with LDLR. Toxoplasma intracellular replication requires the uptake of cholesterol by the host cell LDLR, which is an important factor in atherosclerosis. In this paper, LDLR knockout mice (LDLr(- / -)) were infected with Toxoplasma and their proliferation levels and the development of atherosclerosis were evaluated. The results showed that LDLr(- / -) mice had fewer infectious cysts and atherosclerotic lesion area. These results indicate that Toxoplasma uses the host LDLR to acquire cholesterol and promote its proliferation. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress the onset and progression of Toxoplasma infection and associated atherosclerosis.

[0017] Non-Patent Document 7 reports that rhinoviruses associate with LDLR. This paper reports that the majority of human rhinoviruses (HRVs) use ICAM-1 as a binding receptor, while a minor group uses LDLR as a receptor. The β-propeller domain of LDLR is known to be involved in the dissociation of bound LDL through intramolecular competition at low pH. This paper also shows that intracellular viral transformation and de novo virus synthesis are delayed in cells expressing LDLR mutants lacking the β-propeller. It has also been suggested that the β-propeller of LDLR weakens the virus-stabilizing effect of LDLR binding, thereby promoting RNA release from endosomes and thereby enhancing infection. Therefore, removal or internalization of LDLR from the cell surface is thought to suppress the onset and progression of rhinovirus infection.

[0018] Non-Patent Document 8 reports that the novel coronavirus (SARS-CoV2) is associated with LDLR. Patients infected with SARS-CoV2 have reported ocular symptoms such as photophobia (photophobia, sensitivity to light, 18%), itchy eyes (17%), sore eyes (16%), watery eyes, foreign body sensation, and eye discharge. The literature also showed that treatment of the ocular cell line ARPE-19 with an inhibitor of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 viral receptor, did not prevent infection with SARS-CoV-2 spike-containing viruses, whereas an LDLR-inhibiting antibody blocked infection, and LDLR-specific siRNA also reduced infection. Therefore, it is highly likely that the SARS-CoV-2 viral receptor in the eye is the LDLR. Removal or internalization of LDLR from the cell surface may suppress the onset and progression of SARS-CoV-2 infection and associated symptoms, particularly ocular symptoms.

[0019] The following diseases are known to be involved in the ICAM-1 pathway and are exacerbated by increased ICAM-1:

[0020] Non-Patent Document 9 reports that allergic bronchial asthma is associated with ICAM-1. In this paper, the lung and airway characteristics of an ovalbumin (OA)-sensitized allergic asthma model rat were evaluated after antigen challenge, and the results showed that the model was worse than that of normal mice. However, administration of an inhibitory antibody against ICAM-1 and its receptor, LFA-1α, resulted in significant improvement. Therefore, removal or internalization of ICAM-1 from the cell surface may suppress the onset and progression of allergic asthma symptoms.

[0021] Non-Patent Document 10 reports that eosinophilic pneumonia is associated with ICAM-1. In this paper, ICAM-1-deficient mice were used to examine whether ICAM-1 is important for pulmonary eosinophil migration after allergen challenge. The results showed that eosinophil migration into lung tissue was significantly suppressed by 84% in ICAM-1-deficient mice 3 hours after allergen challenge. Furthermore, ICAM-1-deficient mice also showed significantly reduced bronchoalveolar lavage (BAL) eosinophil counts and significantly lower eosinophil peroxidase (EPO) levels. Therefore, removal or internalization of ICAM-1 from the cell surface may directly affect the onset and progression of allergic eosinophilic pneumonia.

[0022] Non-Patent Document 11 reports that acute respiratory distress syndrome (ADRS) is associated with ICAM-1. In this paper, a rat model of ARDS was performed using intratracheal administration of hydrochloric acid. The rats were then treated with either ICAM-1 or an antibody blocking LFA-1, an ICAM-1 receptor. The results showed significant increases in neutrophil counts and protein concentration in BAL fluid, as well as in the lung wet-to-dry weight ratio, suggesting neutrophil infiltration and pulmonary edema. In contrast, the ICAM-1 and LFA-1 inhibitor groups showed significantly milder gas exchange impairment, all physiological changes, neutrophil infiltration, and pulmonary edema. The increase in neutrophils in BAL fluid was also significantly suppressed, resulting in alleviation of ARDS symptoms. Therefore, removal or internalization of ICAM-1 from the cell surface may potentially inhibit the onset and progression of ADRS.

[0023] Non-patent document 12 reports that scleroderma and pulmonary fibrosis are associated with ICAM-1. In this paper, skin thickening was reduced by approximately 50% when tight skin (TSK) mice were deficient in ICAM-1, or when antisense oligonucleotides or ICAM-1-blocking antibodies were administered. Therefore, removal or internalization of ICAM-1 from the cell surface may suppress the onset and progression of scleroderma symptoms.

[0024] Non-Patent Document 13 reports that Parkinson's disease is associated with ICAM-1. In this paper, ICAM-1 was elevated in brain tissue in a mouse model of Parkinson's disease, and the ICAM-1 receptor, LFA1, was overexpressed in brain T cells. Furthermore, inhibition of ICAM-1 or LFA-1 improved behavioral characteristics indicative of the severity of Parkinson's disease in mice. Therefore, the interaction between ICAM-1 in brain tissue and LFA-1 on T cells is thought to be related to the severity of Parkinson's disease. Removal or internalization of ICAM-1 from the cell surface is thought to reduce the opportunity for interaction and thus suppress the progression of Parkinson's disease.

[0025] Non-Patent Document 14 reports that atherosclerosis is associated with ICAM-1. In this paper, the progression of atherosclerosis was evaluated using apolipoprotein E (APOE)-deficient mice, which develop atherosclerosis, and APOE and ICAM-1 double-deficient mice. The double-deficient mice showed significantly fewer lesions at 5 and 10 months compared with APOE-deficient mice. Therefore, removal or internalization of ICAM-1 from the cell surface may suppress the progression of atherosclerosis.

[0026] As described above, in infections and diseases involving signal transduction pathways mediated by ICAM-1 or LDLR, the onset of infection and disease can be suppressed by reducing the number of available receptors, for example, by inhibiting the expression of ICAM-1 or LDLR on the cell surface, inhibiting their expression, and promoting endocytosis of the expressed receptors. [Prior art documents] [Non-patent literature]

[0027] [Non-Patent Document 1] Yingying Li, et al., “Human low-density lipoprotein receptor plays an important role in hepatitis B virus infection”, PLoS Pathog., 2021, 17(7): e1009722. [Non-patent document 2] Sonia Molina et al., “The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus”, J Hepatol, 2007, vol. 46(3), p. 411-9. [Non-patent document 3] Anna Albecka et al., “Role of low-density lipoprotein receptor in the hepatitis C virus life cycle”, Hepatology, 2012, 55(4), p.998-1007 [Non-patent document 4] Danit Finkelshtein et al., “LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus”, Proc Natl Acad Sci USA, 2013, vol. 110(18), p.7306-11 [Non-Patent Document 5] Fnu Nagajyothi et al., “Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion”, PLoS Negl Trop Dis., 2011, 5(2): e953. [Non-patent document 6] Luciane R Portugal et al., “Influence of low-density lipoprotein (LDL) receptor on lipid composition, inflammation and parasitism during Toxoplasma gondii infection”, Microbes Infect., 2008, vol. 10(3), p. 276-84 [Non-Patent Document 7] Tuende Konecsni et al., “Low pH-Triggered Beta-Propeller Switch of the Low-Density Lipoprotein Receptor Assists Rhinovirus Infection”, Journal of virology, 2009, Volume 83, Issue 211, p.10922-10930

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Non-licensed literature 9

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[0028] An object of the present invention is to provide an inhibitor of cellular expression of ICAM-1 and LDLR, and an inhibitor of pathogen infection. [Means for solving the problem]

[0029] The present inventors searched for herbal medicines as candidates for drugs that can inhibit the cellular expression of ICAM-1 and LDLR. As a result, they found that Kakkonto inhibits the cellular expression of ICAM-1 and LDLR induced by viral infection. In particular, they found that the cinnamon bark and ephedra herb contained in Kakkonto are active ingredients.

[0030] The present invention provides an inhibitor of cell surface expression of ICAM-1 and LDLR, which contains Kakkonto.

[0031] The present invention also provides an inhibitor of cellular expression of ICAM-1 and LDLR, which comprises cinnamon.

[0032] The present invention also provides an inhibitor of cell surface expression of ICAM-1 and LDLR, which contains Ephedra herb.

[0033] The present invention also provides an inhibitor of pathogen infection via the ICAM-1 or LDLR pathway, which contains Kakkonto.

[0034] The present invention also provides an inhibitor of pathogen infection via the ICAM-1 or LDLR pathway, which comprises cinnamon.

[0035] The present invention also provides an inhibitor of pathogen infection via the ICAM-1 or LDLR pathway, which contains Ephedra Herb. [Effects of the Invention]

[0036] According to the present invention, an inhibitor of cellular expression of ICAM-1 and LDLR can be provided, and also an inhibitor of pathogen infection can be provided. [Brief explanation of the drawings]

[0037] [Figure 1] Graph showing the effect of Kakkonto on cellular expression of ICAM-1. [Figure 2] Graph showing the effect of Kakkonto on cellular expression of LDLR. [Figure 3] Graph showing the effects of Kakkonto and various herbal medicines on cellular expression of ICAM-1. [Figure 4] Graph showing the effects of Kakkonto and various herbal medicines on cellular expression of LDLR. [Figure 5] Graph showing the effect of Kakkonto on ICAM-1 expression. [Figure 6] Graph showing the effect of Kakkonto on LDLR expression. DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention provides inhibitors of cellular expression of ICAM-1 and LDLR. The present invention also provides inhibitors of pathogen infection mediated through the ICAM-1 or LDLR pathway.

[0039] Intercellular adhesion molecule-1 (ICAM-1) is a cell surface glycoprotein known to be expressed on vascular endothelial cells and immune system cells. ICAM-1 has binding sites for numerous immune-related ligands. For example, ICAM-1 binds to proteins commonly expressed on endothelial cells and leukocytes, promoting leukocyte passage through the vascular endothelium. Furthermore, ICAM-1, expressed on respiratory epithelial cells, can act as a receptor for pathogens such as rhinoviruses to penetrate the respiratory epithelium.

[0040] Diseases known to involve the ICAM-1 pathway and be exacerbated by increased ICAM-1 include allergic bronchial asthma, eosinophilic pneumonia, acute respiratory distress syndrome (ADRS), scleroderma / pulmonary fibrosis, Parkinson's disease, and ischemic brain and heart disease.

[0041] Rhinoviruses are RNA viruses that belong to the genus Enterovirus and family Picornaviridae, and are a common cause of upper respiratory tract infections (common colds). Rhinoviruses are known to infect cells by recognizing and binding to ICAM-1, which is expressed on the surface of the cell membrane in the upper respiratory tract, and then invading the cells.

[0042] The low-density lipoprotein receptor (LDLR) is a protein that binds to and transports ligands such as low-density lipoprotein (LDL) into cells. LDLR is also known to act as a receptor for numerous pathogens when they infect the body. Pathogens that recognize LDLR and infect the body include hepatitis B virus (HBV), hepatitis C virus (HCV), vesicular stomatitis virus (VSV, VSVG), the Trypanosoma cruzi parasite (which causes Chagas disease), the Toxoplasma parasite (which causes toxoplasmosis), and rhinovirus. For example, rhinoviruses recognize and bind to LDLR on the surface of upper respiratory tract cells, invading and infecting cells. Increased LDLR activity is known to exacerbate infections caused by these pathogens.

[0043] As used herein, the term "cell surface expression" means that a protein is expressed on the cell membrane and is in a state where it can bind to a ligand from outside the cell. Cell surface expression includes the transfer of a protein that was present intracellularly to the cell membrane surface, and further includes the synthesis of a new protein through gene expression.

[0044] In the present invention, "cell expression" of ICAM-1 and LDLR is not particularly limited, but refers to expression in epithelial cells, preferably in epithelial cells of the respiratory tract. The respiratory tract (airways) includes the upper and lower respiratory tracts. The upper respiratory tract includes the nose, nasal cavity, nasopharynx, pharynx, and larynx. The lower respiratory tract includes the trachea, bronchi, bronchioles, and lungs. "Cell expression" of ICAM-1 and LDLR is more preferably expression in epithelial cells of the upper respiratory tract, and particularly preferably expression in nasal epithelial cells.

[0045] As used herein, "inhibiting" cell surface expression means reducing the amount of protein expressed on the cell membrane. Inhibition of protein surface expression includes, but is not limited to, inhibition of cell surface expression by reducing the amount of protein expression and inhibition of cell surface expression by suppressing the migration of protein to the cell surface. "Inhibiting cell surface expression" in the present invention includes, for example, reducing the amount of cell-exposed protein by about 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more compared to before or without administration of the agent of the present invention. The reduction in the amount of protein expressed on the cell membrane can be measured using methods such as flow cytometry (e.g., FACS), fluorescence microscopy, affinity purification, and optical tweezers. Furthermore, "inhibition of cell expression" in the present invention also includes reducing the amount of protein expression by approximately 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more compared to when the agent of the present invention is not administered or before administration.

[0046] It has been shown that the amounts of ICAM-1 and LDLR expressed on cells increase upon infection with a pathogen such as a virus. In the present invention, the inhibition of ICAM-1 and LDLR expression on cells is not particularly limited, and may include suppression of the increase in ICAM-1 and LDLR expression on cells due to pathogen infection.

[0047] As used herein, "pathogen infection" means that a pathogen invades a host cell. As used herein, "pathogen infection via the ICAM-1 pathway" means that a pathogen recognizes and binds to ICAM-1 expressed on the cell surface of a host cell, thereby invading the cell. As used herein, "pathogen infection via the LDLR pathway" means that a pathogen recognizes and binds to LDLR expressed on the cell surface of a host cell, thereby invading the cell.

[0048] As used herein, "inhibiting" pathogen infection includes inhibiting, reducing, or suppressing the invasion of a pathogen into a cell, inhibiting, suppressing, or delaying the onset of an infectious disease caused by a pathogen, and inhibiting, slowing, or eliminating the progression of an infectious disease caused by a pathogen.

[0049] In the present invention, the term "pathogen" refers to any pathogen capable of recognizing ICAM-1 or LDLR and invading cells, and includes, but is not limited to, viruses and parasites. Examples of viruses include hepatitis B virus (HBV), hepatitis C virus (HCV), vesicular stomatitis virus (VSV, VSVG), and rhinovirus, with rhinovirus being preferred. Examples of parasites include Trypanosoma cruzi and Toxoplasma.

[0050] The inhibitor of the present invention contains Kakkonto as an active ingredient.

[0051] Kakkonto is a mixture of crude drug powders consisting of kudzu root, ephedra, jujube, cinnamon bark, peony, licorice, and ginger. The amounts of the crude drugs that make up Kakkonto can be those prescribed in the Japanese Pharmacopoeia, for example, the usual weight ratio can be 4-8 parts kudzu root, 3-4 parts ephedra, 3-4 parts jujube, 2-3 parts cinnamon bark, 2-3 parts peony, 2 parts licorice, and 1-2 parts ginger.

[0052] The inhibitors of the present invention also contain cinnamon as an active ingredient.

[0053] Cinnamon is a medicinal herb made from the bark or periderm of Chinese cinnamon (Cinnamomum cassia Blume) or other plants of the same genus (Lauraceae).

[0054] The inhibitor of the present invention also contains ephedra as an active ingredient.

[0055] Ephedra is a herbal medicine made from the aboveground stems of Ephedra sinica Stapf or other plants of the same genus (Ephedraceae).

[0056] The inhibitor of the present invention may be a herbal medicine preparation containing only cinnamon bark or ephedra as the active ingredient.

[0057] The herbal medicine used in the present invention may be an extract obtained from the plant material. The "extract" used in the present invention includes an extract obtained by adding a solvent to the plant material, a squeezed liquid obtained after compressing the raw material, an extract obtained by adding a solvent to the residue after compressing the raw material, a concentrate obtained by concentrating these, and an extract powder obtained by drying these.

[0058] The extract used in the present invention can be produced by known methods. For example, the extract used in the present invention can be produced by room temperature extraction or heated extraction using an extraction solvent. Extraction may be performed under reduced pressure or pressure, if necessary. The obtained extract may be used as is as the extract in the present invention, or may be subjected to any treatment before or after extraction before use as the extract in the present invention. For example, the extract may be used after concentration or after being dried by freeze-drying.

[0059] The extract may be subjected to hydrolysis after extraction with an extraction solvent. Hydrolysis can be carried out using any conventionally known method. Alternatively, the extract may be subjected to enzymatic hydrolysis before extraction with an extraction solvent. Enzymatic hydrolysis can be carried out using any conventionally known method.

[0060] The extract can be obtained by extracting with an extraction solvent and then removing solid matter by filtration, centrifugation, and / or decantation, etc. Filtration, centrifugation, and decantation can be carried out using any conventionally known method.

[0061] Examples of extracting solvents that can be used include water, physiological saline, alcohols (e.g., lower alcohols such as methanol, absolute ethanol, and ethanol, and polyhydric alcohols such as propylene glycol and 1,3-butylene glycol), ketones such as acetone, esters such as ethyl ether, dioxane, acetonitrile, and ethyl acetate, xylene, benzene, and chloroform. Among these, it is preferable to use water, alcohols such as methanol and ethanol, or mixed solvents of these as the extracting solvent. The above-mentioned extracting solvents may be used alone or in combination of two or more.

[0062] The extract can be pH adjusted as necessary and subjected to gel filtration and / or ultrafiltration to remove macromolecules without losing its activity. The extract or its fractions may be concentrated by methods such as vacuum concentration, ultrafiltration and / or freeze concentration. The extract may also be dried by methods such as freeze drying, spray drying and / or plate drying, resulting in a dried product, such as a powder.

[0063] The route of administration of the agent of the present invention is not particularly limited and may be either oral or parenteral. Parenteral administration includes administration via transdermal, nasal, and intravenous injection. The route of administration of the agent of the present invention is preferably oral administration. In this specification, "administration" can be rephrased as "ingestion."

[0064] The agent of the present invention can be a preparation in any form. For oral administration, the agent of the present invention can be, for example, tablets such as sugar-coated tablets, buccal tablets, coated tablets, and chewable tablets; troches; pills; powders; capsules including hard capsules and soft capsules; granules; and liquids such as suspensions, emulsions, syrups, and elixirs.

[0065] The agent of the present invention may be a parenteral administration preparation such as intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, enteral administration, oral administration, or transmucosal administration, etc. The agent of the present invention may be, for example, an injection, a transdermal absorption tape, an aerosol, or a suppository.

[0066] The agent of the present invention may be in a form suitable for consumption, such as a solid, liquid, granule, powder, capsule, cream, or paste.

[0067] The agent of the present invention may further contain any ingredient commonly used in pharmaceuticals, quasi-drugs, and foods, such as a pharmaceutically acceptable base, carrier, excipient, binder, disintegrant, lubricant, and colorant.

[0068] Examples of carriers and excipients used in the agent of the present invention include lactose, glucose, sucrose, mannitol, dextrin, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, and crystalline cellulose.

[0069] Examples of binders include starch, gelatin, syrup, tragacanth gum, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, and the like.

[0070] Examples of disintegrants include starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, sodium carboxymethylcellulose and calcium carboxymethylcellulose.

[0071] Examples of lubricants include magnesium stearate, hydrogenated vegetable oil, talc, macrogol, etc. As the coloring agent, any coloring agent permitted to be added to pharmaceuticals, quasi-drugs, and foods can be used.

[0072] Furthermore, the agent of the present invention may be coated with one or more layers of sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate, methacrylic acid polymers, or the like, if necessary.

[0073] Furthermore, the agent of the present invention may contain, as necessary, a pH adjuster, a buffer, a stabilizer, a preservative, an antiseptic, a diluent, a coating agent, a sweetener, a flavoring agent, a solubilizer, and the like.

[0074] The content of Kakkonto in the agent of the present invention may be any amount that can fully exert the effects of the present invention, and can be appropriately set depending on the subject, purpose, and administration method (intake method) to which it is applied. For example, when orally ingested by humans, the content of Kakkonto can be, for example, 0.0375 to 0.6 g / kg body weight, preferably 0.075 to 0.6 g / kg body weight, more preferably 0.15 to 0.3 g / kg body weight per day as Kakkonto extract (assuming an adult body weight of 50 kg).

[0075] The content of cinnamon in the agent of the present invention may be any amount that can fully exert the effects of the present invention, and can be appropriately set depending on the target, purpose, and administration method (ingestion method). For example, when orally ingested by humans, the content of cinnamon per day can be, for example, 0.02 to 0.32 g / kg body weight, preferably 0.04 to 0.32 g / kg body weight, more preferably 0.08 to 0.16 g / kg body weight (assuming an adult body weight of 50 kg).

[0076] The amount of ephedra contained in the agent of the present invention may be any amount that can fully exert the effects of the present invention, and can be appropriately set depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the amount of ephedra contained per day can be, for example, 0.015 to 0.24 g / kg body weight, preferably 0.03 to 0.24 g / kg body weight, and more preferably 0.06 to 0.12 g / kg body weight (assuming an adult body weight of 50 kg).

[0077] The timing of administration of the agent of the present invention is not particularly limited and may be before meals, between meals, simultaneously with meals, or after meals. "Before meals" means about 30 minutes to about 1 hour or more before a meal. "Between meals" means between meals, for example, about 2 hours after eating a meal. "Simultaneous with a meal" may be immediately before eating a meal, during eating a meal, or immediately after eating a meal, for example, within 1 hour before or after a meal, particularly within 30 minutes before or after a meal. "After meals" means about 30 minutes after eating a meal. Meals may be breakfast, lunch, dinner, or snacks. The number of times the agent of the present invention is administered per day is not particularly limited and may be once, twice, or three or more times.

[0078] The present invention also provides a composition for treating, ameliorating, and / or preventing infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR, which contains Kakkonto as an active ingredient. The composition of the present invention can be configured in the same manner as the above-mentioned agent. Kakkonto has the effect of inhibiting the cellular expression of ICAM-1 and LDLR, and is therefore useful for inhibiting the onset and spread of infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR.

[0079] The present invention also provides a composition for treating, ameliorating, and / or preventing infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR, which contains cinnamon as an active ingredient. The composition of the present invention can be configured in the same manner as the above-mentioned agent. Because cinnamon has the effect of inhibiting the cellular expression of ICAM-1 and LDLR, it is useful for inhibiting the onset and spread of infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR.

[0080] The present invention also provides a composition containing Ephedra herb as an active ingredient for treating, ameliorating, and / or preventing infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR. The composition of the present invention can be configured in the same manner as the above-mentioned agents. Ephedra herb has the effect of inhibiting the cellular expression of ICAM-1 and LDLR, and is therefore useful for inhibiting the onset and spread of infectious diseases caused by pathogens that transmit via ICAM-1 or LDLR.

[0081] In the present invention, the infectious disease can be, for example, an infectious disease caused by hepatitis B virus (HBV), hepatitis C virus (HCV), vesicular stomatitis virus (VSV, VSVG), Trypanosoma cruzi parasite (causing Chagas disease), Toxoplasma parasite (causing toxoplasmosis), and rhinovirus, etc. The infectious disease is preferably an infectious disease caused by rhinovirus.

[0082] The present invention also provides a composition containing Kakkonto as an active ingredient for treating, ameliorating, and / or preventing at least one disease selected from the group consisting of allergic bronchial asthma, eosinophilic pneumonia, acute respiratory distress syndrome (ADRS), scleroderma / pulmonary fibrosis, Parkinson's disease, and ischemic cerebral and cardiac diseases. The composition of the present invention can be configured in the same manner as the above-mentioned agent. Kakkonto has the effect of inhibiting cellular expression of ICAM-1, and is therefore useful for treating, ameliorating, and preventing the above-mentioned diseases, which are known to be mediated by the ICAM-1 pathway and exacerbated by increased ICAM-1.

[0083] The present invention also provides a composition containing cinnamon as an active ingredient for treating, ameliorating, and / or preventing at least one disease selected from the group consisting of allergic bronchial asthma, eosinophilic pneumonia, acute respiratory distress syndrome (ADRS), scleroderma / pulmonary fibrosis, Parkinson's disease, and ischemic cerebral and cardiac diseases. The composition of the present invention can be configured in the same manner as the above-described agent. Because cinnamon has the effect of inhibiting cellular expression of ICAM-1, it is useful for treating, ameliorating, and preventing the above-mentioned diseases, which are known to be mediated by the ICAM-1 pathway and exacerbated by increased ICAM-1.

[0084] The present invention also provides a composition containing ephedra as an active ingredient for treating, ameliorating, and / or preventing at least one disease selected from the group consisting of allergic bronchial asthma, eosinophilic pneumonia, acute respiratory distress syndrome (ADRS), scleroderma / pulmonary fibrosis, Parkinson's disease, and ischemic cerebral and cardiac diseases. The composition of the present invention can be configured in the same manner as the above-mentioned agent. Ephedra has the effect of inhibiting cellular expression of ICAM-1, and is therefore useful for treating, ameliorating, and preventing the above-mentioned diseases, which are known to be mediated by the ICAM-1 pathway and exacerbated by increased ICAM-1.

[0085] As used herein, the term "treatment" includes inhibiting, alleviating or alleviating a disease or symptom, inhibiting, suppressing, slowing or eliminating the progression of a disease or symptom, achieving remission, and achieving an improved prognosis.

[0086] As used herein, the term "amelioration" includes alleviating or alleviating a disease or symptom, as well as inhibiting, slowing or eliminating the progression of a disease or symptom.

[0087] As used herein, the term "prevention" includes inhibiting, suppressing or delaying the occurrence (development) of a disease or condition, and inhibiting, suppressing or delaying the recurrence of a disease or condition.

[0088] The present invention also provides a food composition containing Kakkonto as an active ingredient for inhibiting pathogen infection via the ICAM-1 or LDLR pathway. The present invention also provides a food composition containing Cinnamon Bark as an active ingredient for inhibiting pathogen infection via the ICAM-1 or LDLR pathway. The present invention also provides a food composition containing Ephedra Herb as an active ingredient for inhibiting pathogen infection via the ICAM-1 or LDLR pathway. The food composition of the present invention can be constructed in the same manner as the agents and compositions described above.

[0089] As used herein, "food compositions" include not only general foods and beverages, but also foods for the sick, health foods, functional foods, foods for specified health uses, nutritional supplements, and supplements. General foods and beverages include, for example, various beverages, various foods, confectioneries, seasonings, liquid foods (such as soups), nutritional drinks, and processed foods. Supplements include, for example, tablet-type supplements.

[0090] As used herein, the term "processed food" refers to natural ingredients (such as animals and plants) that have been processed or cooked, and includes, for example, processed meat products, processed vegetables, processed fruit products, frozen foods, retort foods, canned foods, bottled foods, and instant foods.

[0091] The food composition of the present invention may be a food product labeled as inhibiting pathogen infection via the ICAM-1 or LDLR pathway. The food composition of the present invention may also be provided in a sealed form, such as a bag or container. The bag or container used in the present invention may be any bag or container commonly used for food.

[0092] The food composition may contain any of the following ingredients, if necessary, as long as the object of the present invention is not impaired: for example, carbohydrate sweeteners (monosaccharides such as fructose, glucose, tagatose, and arabinose, oligosaccharides such as lactose, oligosaccharides, maltose, and trehalose, powdered starch syrup, dextrin, and sugar alcohols), high-intensity sweeteners (sucralose, acesulfame K, and stevia), polysaccharides such as starch, oils and fats, dairy products, stabilizers, emulsifiers, flavors (vanillin, linalool, and natural flavors), pigments, coloring agents, acidulants, flavoring ingredients (eggs, coffee, tea, cocoa, fruit juice and pulp, yogurt, and alcoholic beverages), flavorings (raspberry flavor, apple flavor, and the like), and the like. flavors and coffee flavors, etc.), anti-humectants, electrolytes, preservatives, humectants, proteins, amino acids, peptides, dietary fiber, organic acids (citric acid, malic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, lactic acid, etc.), vitamins (L-ascorbic acid, dl-α-tocopherol, vitamin B1, vitamin B2, niacin, pantothenic acid, vitamin B6, vitamin B12, folic acid, biotin, inositol, etc.), gold, silver, platinum, minerals (zinc, iron, calcium, magnesium, chromium, selenium, potassium, sodium, etc.). ), marine collagen, hydrolyzed collagen, hyaluronic acid, fermented yeast extract, glucosamine, yeast, eggshell membrane, lycopene, astaxanthin, other carotenoids, silk, chondroitin, ceramide, placenta extract, shark fin extract, deep sea shark extract, squalene, gamma-aminobutyric acid, casein dodecapeptide, raw chestnut skin extract, chestnut leaf extract, chestnut bur extract, chestnut pulp extract, chestnut bark extract, fermented cabbage extract, rose petal extract, grape leaf extract, grape seed extract, apple polyphenols, chamomile extract, lychee seed Extract, gotu kola extract, shell ginger leaf extract, lotus germ extract, star fruit leaf extract, mulberry leaf extract, guava tea extract, red wine, green tea, black tea, oolong tea, coffee, cocoa, chocolate, black sesame, beans, soy milk, nuts, mushrooms, green and yellow vegetables, egg-derived ingredients such as iodine eggs, catechins, other polyphenols, raspberry ketone, low molecular weight alginic acid, psyllium seed coat, ginkgo leaf extract, pine bark extract, nattokinase, plant sterols, diacylglycerol, chitosan, hyaluronic acid, methylsulfonylmethane,These include kojic acid, ellagic acid, arbutin, rucinol, magnolignan, magnesium L-ascorbate phosphate, CoQ10, and α-lipoic acid.

[0093] The present invention also provides a method for inhibiting the cellular expression of ICAM-1 and LDLR in a subject, comprising administering Kakkonto to the subject. The present invention also provides a method for inhibiting the cellular expression of ICAM-1 and LDLR in a subject, comprising administering Cinnamon Cortex to the subject. The present invention also provides a method for inhibiting the cellular expression of ICAM-1 and LDLR in a subject, comprising administering Ephedra Herb to the subject.

[0094] The present invention also provides a method for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway in a subject, comprising administering Kakkonto to the subject. The present invention also provides a method for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway in a subject, comprising administering Cinnamon Bark to the subject. The present invention also provides a method for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway in a subject, comprising administering Ephedra Herb to the subject.

[0095] In the method of the present invention, Kakkonto, Cinnamon or Maoh can be administered in the form of the agent or composition described above.

[0096] In the method of the present invention, the dosage of Kakkonto may be any amount that can exert its effect, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when administered orally to humans, the daily intake of Kakkonto extract can be, for example, 0.0375 to 0.6 g / kg body weight, preferably 0.075 to 0.6 g / kg body weight, and more preferably 0.15 to 0.3 g / kg body weight (assuming an adult body weight of 50 kg).

[0097] In the method of the present invention, the dosage of cinnamon bark may be any amount that can exert its effect, and can be appropriately determined depending on the subject, purpose, and administration method (ingestion method). For example, when orally ingested by humans, the daily intake can be, for example, 0.02 to 0.32 g / kg body weight, preferably 0.04 to 0.32 g / kg body weight, more preferably 0.08 to 0.16 g / kg body weight (assuming an adult body weight of 50 kg).

[0098] In the method of the present invention, the dosage of ephedra may be any amount sufficient to exert its effects, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the daily intake can be, for example, 0.015 to 0.12 g / kg body weight, preferably 0.03 to 0.24 g / kg body weight, and more preferably 0.06 to 0.24 g / kg body weight (assuming an adult body weight of 50 kg).

[0099] The present invention can be applied to humans and non-human mammals, including, for example, mice, rats, rabbits, cats, dogs, cows, horses, and monkeys.

[0100] The subjects to which the present invention can be applied are not particularly limited, and can be subjects in need of inhibition of cellular expression of ICAM-1 and LDLR, such as those in particular need of prevention of pathogen infection via the ICAM-1 or LDLR pathway.

[0101] The present invention also provides Kakkonto for use in inhibiting cellular expression of ICAM-1 and LDLR. The present invention also provides Cinnamon Bark for use in inhibiting cellular expression of ICAM-1 and LDLR. The present invention also provides Ephedra Herb for use in inhibiting cellular expression of ICAM-1 and LDLR.

[0102] The present invention also provides Kakkonto for use in inhibiting pathogen infection via the ICAM-1 or LDLR pathway.The present invention also provides Cinnamon Bark for use in inhibiting pathogen infection via the ICAM-1 or LDLR pathway.The present invention also provides Ephedra Herb for use in inhibiting pathogen infection via the ICAM-1 or LDLR pathway.

[0103] The present invention also provides the use of Kakkonto for inhibiting cellular expression of ICAM-1 and LDLR.The present invention also provides the use of Cinnamon Bark for inhibiting cellular expression of ICAM-1 and LDLR.The present invention also provides the use of Ephedra Herb for inhibiting cellular expression of ICAM-1 and LDLR.

[0104] The present invention also provides the use of Kakkonto for inhibiting pathogen infection via the ICAM-1 or LDLR pathway.The present invention also provides the use of Cinnamon Bark for inhibiting pathogen infection via the ICAM-1 or LDLR pathway.The present invention also provides the use of Ephedra Herb for inhibiting pathogen infection via the ICAM-1 or LDLR pathway.

[0105] The present invention also provides use of Kakkonto for producing an inhibitor of cellular expression of ICAM-1 and LDLR, a composition for inhibiting cellular expression of ICAM-1 and LDLR, and a food composition for inhibiting cellular expression of ICAM-1 and LDLR.The present invention also provides use of Kakkonto for producing an inhibitor of pathogen infection mediated by the ICAM-1 or LDLR pathway, a composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway, and a food composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway.

[0106] The present invention also provides use of cinnamon bark for producing an inhibitor of cellular expression of ICAM-1 and LDLR, a composition for inhibiting cellular expression of ICAM-1 and LDLR, and a food composition for inhibiting cellular expression of ICAM-1 and LDLR.The present invention also provides use of cinnamon bark for producing an inhibitor of pathogen infection mediated by the ICAM-1 or LDLR pathway, a composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway, and a food composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway.

[0107] The present invention also provides use of Ephedra herb for producing an inhibitor of cellular expression of ICAM-1 and LDLR, a composition for inhibiting cellular expression of ICAM-1 and LDLR, and a food composition for inhibiting cellular expression of ICAM-1 and LDLR.The present invention also provides use of Ephedra herb for producing an inhibitor of pathogen infection mediated by the ICAM-1 or LDLR pathway, a composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway, and a food composition for inhibiting pathogen infection mediated by the ICAM-1 or LDLR pathway. [Example]

[0108] When viruses infect and replicate in cells, dsRNA, a component of the virus that accumulates in the cytoplasm, is known to activate immune cells. A molecule combining synthetic dsRNA poly(I:C) and cationic lipids (CL) (poly(I:C)+CL) has the same immunostimulatory activity as viral dsRNA and can mimic viral infection of cells.

[0109] To mimic viral infection in vitro, we transfected nasal epithelial cells (HNEpC) with poly(I:C) + CL (Non-Patent Documents 15, 16) to create a viral infection model. Using this model, we assessed the expression and membrane surface expression of host viral receptors (ICAM-1 and LDLR) using FACS.

[0110] We found that transfection of poly(I:C)+CL increased the expression of host virus receptors, which was suppressed by Kakkonto. Furthermore, we found that the cinnamon bark and ephedra herb contained in Kakkonto are active ingredients.

[0111] Example 1: Kakkonto Extract Kakkonto extract was prepared by dissolving Kakkonto extract bulk powder (Kracie Co., Ltd.) in 10% DMSO, sonicating (25°C, 30 minutes), centrifuging (12,500 x g, 25°C, 10 minutes), and recovering the supernatant.

[0112] (Test 1) Nasal epithelial cells HNEpC (Promocell) were seeded onto a 12-well plate (1.0 × 10 5 The cells were transfected into HNEpCs (100 ng / well) and cultured for 48 hours under culture conditions (37°C, 5% CO2). After 48 hours, the culture supernatant was removed and replaced with a culture medium containing a transfection reagent (QIAGEN) and poly(I:C)+CL (100 ng / well) (Invitrogen), followed by 24 hours of culture. The resulting HNEpCs transfected with poly(I:C)+CL were used as a viral infection model for nasal epithelial cells. After 24 hours, the transfection reagent was removed, and the cells were cultured for an additional 24 hours in the presence of the Kakkonto extract (0.03-0.1 mg / mL) from Example 1.

[0113] The expression and membrane surface expression of viral receptors (ICAM-1 and LDLR) were then assessed using FACS (CytoFLEX flow cytometer). In FACS analysis, ICAM-1 was stained with PE anti-human CD54 antibody (Biolegend) and LDLR was stained with FITC anti-human LDLR antibody (Invitrogen), and cells expressing ICAM-1 or LDLR were detected by detecting the stained cells. Then, cells expressing ICAM-1 (ICAM-1 + ) to the viable cells (%) and the cells expressing LDLR (LDLR + ) relative to viable cells (%) was calculated.

[0114] Figure 1 is a graph showing the effect of Kakkonto on ICAM-1 cellular expression. Figure 2 is a graph showing the effect of Kakkonto on LDLR cellular expression. Data are shown as mean ± standard error (n = 3). Statistical analysis was performed using t-test (*, **: p < 0.05, 0.01 vs. non-treatment (nontreat); #, ##: p < 0.05, 0.01 vs. control).

[0115] Table 1 shows the cells expressing ICAM-1 in each group (ICAM-1 + ) and the percentage of cells expressing LDLR (LDLR + ) percentage.

[0116] [Table 1]

[0117] When human nasal epithelial cells (HNEpC) were transfected with poly(I:C)+CL, the expression of ICAM-1 and LDLR on the cell surface was significantly increased (control). Treatment with Kakkonto (0.03-0.1 mg / mL) inhibited the expression of ICAM-1 and LDLR on the cell surface in a concentration-dependent manner.

[0118] We also investigated the effect of Kakkonto on ICAM-1 and LDLR expression. Specifically, total RNA was extracted from nasal epithelial cells, and cDNA was synthesized using one cycle of 37°C for 15 minutes, 50°C for 5 minutes, and 98°C for 5 minutes. qPCR was then performed to detect ICAM-1 and LDLR mRNA levels. The target gene was amplified using three steps: (1) one cycle of 95°C for 30 seconds, (2) 40 cycles of 95°C for 5 seconds and 60°C for 30 seconds, and (3) one cycle of 95°C for 15 seconds, 60°C for 1 minute, and 95°C for 15 seconds. Figure 5 shows the effect of Kakkonto on ICAM-1 expression. Figure 6 shows the effect of Kakkonto on LDLR expression. In the Kakkonto-treated group, ICAM-1 and LDLR mRNA levels were significantly reduced compared to the control group. Therefore, it was suggested that Kakkonto also reduces the expression levels of ICAM-1 and LDLR present in cells.

[0119] These results suggest that Kakkonto is effective against pathogen infections mediated by the ICAM-1 or LDLR pathway, and that Kakkonto is particularly effective against infections caused by viruses that infect the upper respiratory tract, such as rhinovirus.

[0120] (Test 2) Nasal epithelial cells HNEpC (Promocell) were seeded onto a 12-well plate (1.0 × 10 5The cells were transfected into HNEpCs (100 ng / well) and cultured for 48 hours under culture conditions (37°C, 5% CO2). After 48 hours, the culture supernatant was removed and replaced with a medium containing transfection reagent (QIAGEN) and poly(I:C)+CL (100 ng / well) (Invitrogen), followed by 24 hours of culture. The resulting poly(I:C)+CL-transfected HNEpCs were used as a viral infection model for nasal epithelial cells. After 24 hours, the transfection reagent was removed, and the cells were cultured for another 24 hours in the presence of Kakkonto extract (0.1 mg / mL) from Example 1, Kudzu root (0.032 mg / mL; Kracie Inc.), Ephedra (0.016 mg / mL; Kracie Inc.), Jujube root (0.016 mg / mL; Kracie Inc.), Peony root (0.012 mg / mL; Kracie Inc.), Cinnamon bark (0.012 mg / mL; Kracie Inc.), Licorice root (0.008 mg / mL; Kracie Inc.), or Ginger (0.004 mg / mL; Kracie Inc.).

[0121] Subsequently, the expression and membrane surface expression of viral receptors (ICAM-1 and LDLR) were evaluated using FACS (CytoFLEX flow cytometer) in the same manner as in Experiment 1. Figure 3 is a graph showing the effects of Kakkonto and each herbal medicine on the cellular expression of ICAM-1. Figure 4 is a graph showing the effects of Kakkonto and each herbal medicine on the cellular expression of LDLR. Data are shown as mean ± standard error (n = 3).

[0122] Table 2 shows the cells expressing ICAM-1 in each group (ICAM-1 + ) and the percentage of cells expressing LDLR (LDLR + ) percentage.

[0123] [Table 2]

[0124] When human nasal epithelial cells (HNEpC) were transfected with poly(I:C)+CL, the expression of ICAM-1 and LDLR on the cell surface was significantly increased (control). Treatment with Kakkonto extract suppressed the expression of ICAM-1 and LDLR on the cell surface. Furthermore, treatment with Ephedra or Cinnamon bark also suppressed the expression of ICAM-1 and LDLR on the cell surface.

[0125] These results suggest that the inhibition of ICAM-1 and LDLR expression on the cell surface by Kakkonto is due to the action of Ephedra and Cinnamon Bark contained in Kakkonto. [Industrial Applicability]

[0126] The present invention can inhibit the cellular expression of ICAM-1 and LDLR, and is therefore suitable for use in pharmaceuticals, foods, and the like for pathogen infections and diseases related to the ICAM-1 or LDLR pathway.

Claims

1. Contains Kakkonto, an inhibitor of cell surface expression of ICAM-1 and LDLR.

2. Cinnamon-containing inhibitor of cell surface expression of ICAM-1 and LDLR.

3. Contains Ephedra, an inhibitor of cellular expression of ICAM-1 and LDLR.

4. Contains Kakkonto, an inhibitor of pathogen infection via the ICAM-1 or LDLR pathway.

5. Cinnamon-containing inhibitor of pathogen infection via ICAM-1 or LDLR pathway.

6. Contains Ephedra, an inhibitor of pathogen infection via the ICAM-1 or LDLR pathway.

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