KR101808718B1 - Ethyl acetate extracts from Phellinus linteus fruiting bodies having neuroprotective effect and pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the same - Google Patents
Ethyl acetate extracts from Phellinus linteus fruiting bodies having neuroprotective effect and pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the same Download PDFInfo
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- KR101808718B1 KR101808718B1 KR1020150144969A KR20150144969A KR101808718B1 KR 101808718 B1 KR101808718 B1 KR 101808718B1 KR 1020150144969 A KR1020150144969 A KR 1020150144969A KR 20150144969 A KR20150144969 A KR 20150144969A KR 101808718 B1 KR101808718 B1 KR 101808718B1
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- ethyl acetate
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- fruiting body
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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Abstract
The present invention relates to a mushroom having a nerve cell protecting effect ( Phellinus The present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, which comprises as an active ingredient an extract of ethyl acetate derived from linteus , and more particularly, to a pharmaceutical composition for preventing or treating neuronal cell death induced by oxidative stress, And a pharmaceutical composition for preventing or treating degenerative brain diseases comprising the extract of ethyl acetate derived from mushroom fruiting body and an effective ingredient thereof.
Description
The present invention relates to a mushroom having a nerve cell protecting effect ( Phellinus The present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, which comprises as an active ingredient an extract of ethyl acetate derived from linteus , and more particularly, to a pharmaceutical composition for preventing or treating neuronal cell death induced by oxidative stress, And a pharmaceutical composition for preventing or treating degenerative brain diseases comprising the extract of ethyl acetate derived from mushroom fruiting body and an effective ingredient thereof.
It is known that the onset of degenerative brain diseases such as Alzheimer ' s disease and Parkinson ' s disease is closely related to the death of nerve cells due to oxidative stress. Recent studies have shown that free radicals and reactive oxygen species (ROS) in neurons are rapidly produced, resulting in the death of neurons and ultimately the development of degenerative brain diseases (Jensen K. Oxidative stress and free radicals. J Mol Struct 2003; 666: 387-92 .; Benz CC, Yau C. Aging, oxidative stress and cancer: paradigms in parallax Nat Rev Cancer 2008; 8 (11): 875-9).
Accordingly, it has been reported that inhibition or reduction of the radical production of free radicals and reactive oxygen species that cause oxidative stress in nerve cells can inhibit damage to nerve cells due to oxidative stress and prevent or treat such degenerative brain diseases Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Current Neuropharmacology 2009; 7: 65-74). (Kelsey NA, Wilkins HM, Linseman DA, Nutraceutical antioxidants as novel neuroprotective agents, Molecules 2010; 15: 7792-814), which can inhibit neuronal cell death induced by oxidative stress.
The intracellular antioxidant defense system is largely classified into a defense system by antioxidant enzymes and a defense system by antioxidants. Enzyme-based defense systems metabolize free radicals and reactive oxygen species produced intracellularly by antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), peroxidase-eliminating enzyme (SOD), and hemoxigenase (HO) (Miao L, Clair DKS. Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med 2009; 47: 344-56). Among these antioxidant enzymes, hemeoxygenase-1 (HO-1) is known to be activated by various oxidative stress inducers and exhibit antioxidative action against them (Keyse SM, Tyrrell RM, Heme oxygenase is the major 32- kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 1989; 86: 99-103 / Taketani S, Kohno H, Yoshinaga T, Tokunaga R. Induction of heme oxygenase in rat hepatoma cells by exposure to heavy metals and hyperthermia. Biochem Int. 1988; 17 (4): 665-72). In addition, HO-1 has been reported to play an important role in the neuroprotection of neuronal cell death due to oxidative stress (Kaizaki A, Tanaka S, Ishige K, Numazawa S, Yoshida T. The neuroprotective effect of heme oxygenase (HO) on oxidative stress in HO-1 siRNA-transfected HT22 cells. Brain Res 2006; 1108: 39-44).
Mitogen-activated protein kinases (MAPKs) are signaling mechanisms that regulate a variety of cellular responses and functions, including cell survival, proliferation, differentiation and death. It has been reported that the MAPK signaling pathway in neurons is activated by the production of free radicals and oxidative stress by reactive oxygen species (Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation Physiol Rev 2001; 81 (2): 807-69). In addition, activation of MAPK activates caspase-3, a major enzyme involved in apoptosis, and activated caspase-3 activates the lower signaling pathway, poly (ADP-ribose) polymerase (PARP) It is known that apoptosis proceeds by degradation of proteins, membranes and DNA in cells (Lu Z, Xu S. ERK1 / 2 MAP kinases in cell survival and apoptosis. IUBMB life 2006; 58: 621-31. ; Mandal C, Dutta A, Mallicka, Chandra S, Misra L, Sangwan RS, Mandal C. Withaferin induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. 2008; 13 (12): 1450-64).
As the aging population in the world increases rapidly, the trend of the degenerative brain nervous system disease is increasing every year. The preventive method and the treatment method are not yet clear, so that no effective medicines for treating these diseases have been found It is true. In addition, the therapeutic agents and therapies used in these diseases often exhibit side effects and toxicity due to long-term use, and they are effective in reducing the side effects and toxicity since they slow the progress of the symptoms rather than the complete disease treatment or only temporarily alleviate the symptoms. And it is urgent to find and develop materials with definite therapeutic effects.
On the other hand, it is well known that it is one of the medicinal mushrooms which are traditionally used for the treatment of various diseases such as stomach related diseases, cancer and diabetes in Northeast Asia such as Korea, China and Japan. These mushrooms contain polysaccharides, glycoproteins, furan derivatives, yellow pepper derivatives or various polyphenolic compounds (Huang GJ, Deng JS, Chiu CS, Liao JC, Hsieh WT, Sheu MJ, Wu CH. Hispolon COX-2, and MMP-9. Evidence-Based Complementary and Alternative Medicine, 2012, Article ID 480714, 12 / Hsieh PW, Wu JB, Wu Y. Chemistry and biology of Phellinus linteus ., BioMedicine 2013; 3: 106-13).
The mushroom has been used for various diseases for a long time and is relatively stable, has no side effects, and has a high possibility of being developed as a natural medicine-derived pharmaceutical material. Although various extracts such as antioxidant, antiinflammatory, anticancer and antiallergic extracts from various mushroom extracts have been reported, neuroprotective activities of ethyl acetate extract from mushroom fruiting bodies and the Research on the mechanism has not been reported. There has been no development of a composition for the prevention or treatment of neurodegenerative diseases caused by suppression of neuronal cell death by reducing oxidative stress induced by H 2 O 2 .
Accordingly, the present inventors have tried to evaluate and develop new physiological efficacy of ethyl acetate extract (named as PLEA) obtained through ethanol precipitation and ethyl acetate fraction after hot water extraction using mushroom fruiting body. As a result, it was found that the ethyl acetate fraction (PLEA) derived from the mushroom fruiting body inhibits neuronal cell death due to oxidative stress induced by H 2 O 2 and protects neuronal cells from oxidative stress And their mechanism of action was clarified to complete the present invention.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
It is an object of the present invention to provide a mushroom having a nerve cell protective effect ( Phellinus linteus) fruit body to provide the resulting ethyl acetate extract.
It is another object of the present invention Phellinus (Phellinus linteus) fruit body to provide a degenerative brain neurological disease prevention or treatment a pharmaceutical composition comprising the resulting ethyl acetate extract as an active ingredient.
It is another object of the present invention Phellinus (Phellinus linteus) fruiting body to provide a degenerative neurological brain disease preventing or improving health food comprising the resulting ethyl acetate extract as an active ingredient.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
In order to solve the above problems the present invention provides a Phellinus (Phellinus linteus) derived from fruit bodies ethyl acetate extract having a neuroprotective effect.
According to a preferred embodiment of the present invention, the ethyl acetate extract derived from the mushroom fruiting body may include hispolon as an active substance.
In addition,( Phellinus linteus ) A pharmaceutical composition for preventing or treating a degenerative brain nervous system disease comprising an ethyl acetate extract derived from fruiting body as an active ingredient.
According to a preferred embodiment of the present invention, the pharmaceutical composition for preventing or treating the degenerative brain nervous system disease may contain ethyl acetate extract of mushroom fruiting body at a concentration of 1 to 50 μg / ml.
According to another preferred embodiment of the present invention, Wherein said degenerative brain nervous system disease is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease and Creutzfeld- Lt; / RTI >
The invention also Phellinus (Phellinus linteus) fruiting body provides health food for the brain, nervous system degenerative disease prevention or improvement containing the extract derived ethyl acetate as the active ingredient.
According to a preferred embodiment of the present invention, the health functional food for preventing or ameliorating the degenerative brain nervous system disease may contain ethyl acetate extract of mushroom fruiting body at a concentration of 1 to 50 μg / ml.
According to another preferred embodiment of the present invention, the degenerative brain neurological disease is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease and Creutzfeld- Jakob disease). ≪ / RTI >
The ethyl acetate extract of the mushroom fruiting body having the neuroprotective effect of the present invention inhibited the expression of the antioxidant enzyme hemoxigenase (HO-1) against the oxidative stress-induced neuronal cell death (SK-N-MC) (ERK, JNK, P38) neurotransmission pathway that is involved in apoptosis and ultimately suppresses the activity of caspase-3 and PARP, thereby resulting in excellent neuronal apoptosis Inhibitory effect.
Therefore, the ethyl acetate extract derived from the mushroom fruiting body of the present invention can be applied to pharmaceutical composition for prevention or treatment of degenerative brain nervous system diseases and health functional food for prevention or improvement of degenerative brain nervous system diseases, It can be used safely in the human body because it has less toxicity and side effects as compared with conventional therapeutic agents for degenerative brain diseases.
Fig. 1 is a schematic view showing the contents of a mushroom fruiting body ( Phellinus linteus fruiting bodies. The results show that the ethyl acetate extract was finally obtained by hot-water extraction of the mushroom fruiting body, followed by 70% ethanol precipitation and ethyl acetate fractionation.
FIG. 2 shows the result of performing HPLC analysis to identify the main phenolic compound contained in the extract of Phellinus lucidum ethyl acetate (PLEA). FIG. 2 (A) (B) shows the HPLC results of PLEA.
FIG. 3 shows the increase of neuronal cell viability and toxicity of ethyl acetate extract derived from mushroom fruiting body against SK-N-MC cell death and cytotoxicity induced by H 2 O 2. FIG. 2 (A) The neurons were pretreated with 0.1-5 μg / ml ethyl acetate extract of mushroom fruiting body for 2 hours and then treated with 200 μM H 2 O 2 for 24 hours to reduce the survival rate of neurons induced by H 2 O 2 2 (B) shows the cytotoxicity due to H 2 O 2 , and FIG. 2 (B) shows the cytotoxicity of ethyl acetate extract from the mushroom fruiting body The effect of acetate extract on neuronal cytotoxicity was examined by LDH assay.
FIG. 4 shows the results of pretreatment of neurons for 2 hours with H 2 O 2 for 24 hours, and addition of Annexin V / propidium iodide (PI) And then analyzed by flow cytometry for nerve cell death.
FIG. 5 is a fluorescence microscope photograph showing the change of DNA fragmentation caused by H 2 O 2 when pretreated ethyl acetate extract from a mushroom fruiting body was treated with PI / FITC-dUTP After fluorescence staining of nuclei and DNA in the cells, DNA fragmentation was analyzed using a fluorescence microscope.
Figure 6 is a variation of intracellular reactive oxygen species (ROS) that is generated when after 2 hours pretreatment of Phellinus fruit bodies derived ethyl acetate extract on neurons, processes the H 2 O 2 24 sigan CM-H 2 DCF-DA This is the result of the study through dyeing.
FIG. 7 shows the results of pretreatment of neuronal cells with ethyl acetate extract from the mushroom fruiting body, followed by treatment with H 2 O 2 and changes in mRNA level and
FIG. 8 shows the effect of inhibiting the activation of MAPK (ERK, JNK, P38) induced by H 2 O 2- induced oxidative stress by the ethyl acetate extract from the mushroom fruiting body. FIG. 7 (A) Figure 7 (B) is a graph showing the degree of phosphorylation of ERK, JNK, and P38, respectively, in graphs.
FIG. 9 shows the inhibitory effect of caspase-3 and PARP on the activation of caspase-3 and PARP, which are enzymes involved in neuronal cell death induced by H 2 O 2 , from ethyl acetate extract of mushroom fruiting body , FIG. 8 (A) shows the results of Western blot analysis of the degree of activation of caspase-3 and PARP, and FIG. 8 (B) shows the degree of activation of caspase- Results.
As described above, the conventional therapeutic and therapeutic agents for neurodegenerative diseases of the degenerative brain have often been shown to exhibit side effects and toxicity due to long-term use, and there is only an effect of delaying the progress of symptoms or temporarily alleviating the symptoms rather than treatment of complete diseases It is urgent to find and develop a material having a decisive therapeutic effect by reducing side effects and toxicity.
The present invention Phellinus (Phellinus having a neuroprotective effect linteus ) fructose- derived ethyl acetate extract. The ethyl acetate extract derived from the mushroom fruiting body of the present invention has an antioxidant effect by increasing the expression of antioxidant enzyme, hemoxigenase (HO-1), against the death of oxidative stress-induced neuron (SK-N-MC) (ERK, JNK, P38) neurotransmitter pathway that is involved in neuronal apoptosis and ultimately suppresses the activity of caspase-3 and PARP, It can effectively prevent or treat the cranial nervous system diseases and is extracted from the natural mushroom fruiting body. Therefore, it can be safely used for the human body because it has less toxicity and side effects compared to the existing therapeutic agents for the degenerative brain nervous system disease.
Hereinafter, the present invention will be described in more detail.
The terms used in the present invention are defined as follows.
The term " pharmaceutical composition " refers to a mixture of other chemical components, such as a diluent or carrier, in the ethyl acetate extract from the mushroom fruiting body of the present invention.
The term " carrier " is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.
The term " diluent " is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes in water to which the compound is dissolved. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution. Since buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.
The term " treatment " means an approach to obtaining beneficial or desired clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of disease, stabilization (i.e., not worsening) of the disease state, (Either partially or totally), detectable or undetected, whether or not an improvement or temporary relief or reduction Also, " treatment " may mean increasing the survival rate compared to the expected survival rate when not receiving treatment. &Quot; Treatment " refers to both therapeutic treatment and prophylactic or preventative measures. Such treatments include treatments required for disorders that have already occurred as well as disorders to be prevented. &Quot; Palliating " a disease may reduce the extent of disease states and / or undesirable clinical manifestations and / or slow the time course of progression, It means to lose.
All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. Also, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention.
The present invention relates to a mushroom having a nerve cell protecting effect ( Phellinus linteus ) fructose- derived ethyl acetate extract.
The scientific name of the mushroom used in the present invention is Phellinus It is also called linteus , woody mud mushroom, and in Donggobo, it is recorded in the name of the hot water in the name of mulberry tree ear. It has a diameter of 6 ~ 12cm and a thickness of 2 ~ 10cm and has various shapes such as semicircular shape, flat shape, round mountain shape and horseshoe shape. The dark brown hairs on the surface are short and densely packed, then disappear and grow to become crisp. It has a dark brown-brown ring groove, and the back and the back are divided. The edges are bright yellow, the lower side is tan, and the flesh is yellowish brown. The spores are pale yellowish brown and ball shaped. It is a perennial wood spruce that is overlaid on mulberry trees. It looks like clumps of clay in the early days. After it is grown, it is called "tree tongue" because it is shaped like a stump on a tree stump. It is known to have excellent anticancer effect, and it is cultivated in Korea as a valuable medicinal substance in large quantities. For medicinal purposes, the moon is yellow or light yellow, and is characterized by lack of flavor and aroma. The taste is sweet and it is good for eating. It grows in Korea, Japan, Australia and North America.
The above-mentioned mushroom ( Phellinus linteus) fruit body may be finally obtained from the resulting ethyl acetate extract was, after the fruiting bodies of Phellinus by the hot water extraction, ethanol precipitation method and this 70% ethyl acetate fraction as shown in Figure 1;
The ethyl acetate extract derived from the condition mushroom fruiting body Hispolon may be included as the active material.
The above-mentioned hyspolone is a yellow (yellow) coloring matter contained in the mushroom fruiting body and is one of the major phenolic compounds.
As a result of HPLC analysis for PLEA, as shown in Fig. 2, the main phenolic compound contained in PLEA is a hyspolone, and hepsolone exhibits an effect of protecting brain cells from oxidative stress through antioxidative activity of PLEA It was found to be the main active substance.
The invention also Phellinus (Phellinus linteus) fruit bodies provides the brain degenerative nervous system disease prevention or treatment a pharmaceutical composition comprising the resulting ethyl acetate extract as an active ingredient.
The present inventors have sought to develop a novel physiological activity of the ethyl acetate extract derived from the mushroom fruiting body. As a result, the ethyl acetate extract derived from the mushroom fruiting body was confirmed to be effective in inhibiting neuronal cell death by oxidative stress induced by H 2 O 2 , and the expression of antioxidant enzyme hemoxigenase-1 (HO-1) (ERK, JNK, P38), which is involved in neuronal cell death, by inhibiting activation of MAPK signaling pathways (ERK, JNK, P38).
It was confirmed that the ethyl acetate extract derived from the condition mushroom fruiting body of the present invention has an effect of preventing and improving the degenerative brain nervous system diseases due to the nerve cell death inhibitory activity due to oxidative stress.
More specifically, when cell viability of SK-N-MC cells was measured after inducing oxidative stress by H 2 O 2 , as shown in FIG. 3 (A) Ethyl acetate extract increased the survival rate of neurons, and it was confirmed that the cytotoxicity was reduced by LDH assay as shown in FIG. 3 (B).
In order to confirm neuronal apoptosis, Annexin V-FITC / PI fluorescence staining was performed and FACs were used. As a result, as shown in FIG. 4, the ethyl acetate extract derived from the mushroom fruiting body inhibited cell death In addition, TUNEL assay was performed to confirm DNA fragmentation, which is a characteristic phenomenon in neuron apoptosis. As a result of observation with a fluorescence microscope, the ethyl acetate extract from the mushroom fruiting body showed DNA fragmentation Inhibition of cell death.
Further, as shown in FIG. 6, it is known that the ethyl acetate extract derived from the mushroom fruiting body inhibits or eliminates the production of reactive oxygen species in the evaluation of the inhibition or elimination of reactive oxygen species (ROS) induced by H 2 O 2 there was.
In addition, as shown in FIG. 7, in the nerve cell protection mechanism study from the oxidative stress, the ethyl acetate extract derived from the mushroom fruiting body increased the mRNA level and the protein level of the antioxidant enzyme hemeoxygenase-1 (HO-1) (ERK, JNK, P38), which is known to be involved in the neuronal apoptosis, is activated by the ethyl acetate extract derived from the mushroom fruiting body. As a result, as shown in FIG. 8, Ethyl acetate extract from mushroom fruiting body inhibited the activation of MAPK signaling pathway (ERK, JNK, P38). As a result of measuring the degree of activation of caspase-3 and PARP, enzymes involved in neuronal cell death, it was confirmed that the ethyl acetate extract derived from mushroom fruiting body inhibited the activity of caspase-3 and PARP as shown in Fig.
Therefore, it can be seen that the ethyl acetate extract derived from the mushroom fruiting body is useful for the prevention and improvement of the degenerative brain nervous system diseases through the antioxidative effect against the oxidative stress caused by H 2 O 2 through the nerve cell death inhibitory activity.
Based on these experimental results, it is expected that the ethyl acetate extract derived from mushroom fruiting body can be used as an effective ingredient for the prevention or treatment of degenerative brain diseases caused by oxidative stress.
At this time, the ethyl acetate extract derived from the mushroom fruiting body is, for example, at a concentration of 0.01 to 500 μg / ml, preferably 0.1 to 200 μg / ml, more preferably 1 to 50 μg / Is contained in the pharmaceutical composition of the present invention, and the concentration of 0.01 to 500 占 퐂 / ml is a concentration range capable of achieving the aforementioned physiological effect.
If the ethyl acetate extract derived from the mushroom fruiting body is contained at a concentration of less than 0.01 μg / ml, the effect of preventing or treating the degenerative brain nervous system disease of the pharmaceutical composition may be difficult to be used as a medicine, / Ml, an excessive amount of mushroom fruiting bodies are required, which may cause economic problems.
The degenerative brain nervous system disease of the present invention may be a disease caused by oxidative stress and includes but is not limited to stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, , And Creutzfeld-Jakob disease. ≪ RTI ID = 0.0 >
The present invention relates to a method for producing a mushroom fruiting body Ethyl acetate extracts from linteus fruiting bodies derived from hydrothermal extracts reduced oxidative stress-induced neurotoxicity, resulting in decreased DNA damage and extracellular exposure to phosphatidylserine (PS), inhibition of neuronal cell death, (HO-1) mRNA and protein by increasing the expression of heme oxygenase (ROS) and inhibiting the activity of MAPK signaling pathway We confirmed that it inhibits apoptosis - related enzymes caspase - 3 and PARP, and ultimately inhibits apoptosis of neurons by oxidative stress.
Therefore, the present invention relates to a mushroom ( Phellinus linteus ) ethyl acetate extract is a natural material useful for the prevention or treatment of degenerative brain diseases and can effectively prevent or treat degenerative brain diseases including them.
The pharmaceutical composition according to the present invention may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or other oral formulations, external preparation, suppository and sterilized injection solution, .
Examples of carriers, excipients and diluents that can be contained in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ( sucrose), lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
The pharmacological composition containing the ethyl acetate extract derived from the mushroom fruiting body of the present invention as an active ingredient can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
In particular, it can be administered by any medically appropriate method, for example by injection into normal cerebrospinal fluid, such as normal intravenous or intraarterial administration. In some cases, intradermal administration, intracavity administration, intrathecal administration, tumor or direct administration to the arteries supplying the tumor is advantageous. When the tumor or a portion thereof has previously been removed by surgical operation, the therapeutic agent can be delivered directly to the tumor site (and, in particular, the enclosed cavity or "ablation "Quot; resection cavity ").
The composition of the present invention is appropriately selected depending on the degree of absorption of the active ingredient in the body, the excretion rate, the age and weight of the patient, the sex and condition of the patient, the severity of the disease to be treated and the like, but is generally 0.01 to 250 mg / 0.0 > mg / kg. ≪ / RTI > The unit dosage formulations thus formulated may be administered several times at predetermined time intervals as necessary.
The invention also Phellinus (Phellinus linteus) fruiting body provides health food for the brain, nervous system degenerative disease prevention or improvement containing the extract derived ethyl acetate as the active ingredient.
The health functional food may be prepared by dissolving the ethyl acetate extract from the mushroom fruiting body at a concentration of 0.01 to 500 μg / ml, preferably 0.1 to 200 μg / ml, more preferably 1 to 50 μg / And the concentration of 0.01 to 500 占 퐂 / ml is a concentration range capable of achieving the aforementioned physiological effect.
If the extract contains ethyl acetate extract from mushroom fruiting body at a concentration of less than 0.01 μg / ml, the problem of deterioration or improvement of the degenerative brain nervous system disease of the health functional food may deteriorate, and a concentration of 500 μg / Excessive amounts of mushroom fruiting bodies are required, resulting in economic problems.
The degenerative brain diseases include, but are not limited to, stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, or Creutzfeld- And may be one or more diseases selected from the group consisting of.
The health functional food may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate etc.), pectic acid and its salts, alginic acid and its salts, Organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. It can also contain natural fruit juices and pulp for the production of fruit juices and vegetable drinks. These components may be used independently or in combination. The health functional food may be any one of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin .
In addition, the health functional food may further include food additives, and the suitability of the food functional food as a " food additive " is not limited to the corresponding items in general rules and general test methods approved by the Food and Drug Administration Shall be determined according to the relevant standards and standards.
Examples of the products that have been used in the above-mentioned "food additives" include natural products such as ketones, chemical products such as glycine, potassium citrate, nicotinic acid and cinnamic acid, sensory coloring matter, licorice extract, crystalline cellulose, high- - Mixed preparations such as a sodium glutamate preparation, a noodle-added alkaline agent, a preservative preparation, a tar coloring agent and the like.
In this case, the composition for enhancing anticancer activity according to the present invention, which is added to foods in the course of manufacturing a health functional food, can appropriately increase or decrease the content of the anticancer activity enhancing composition according to need, The dose may be used in accordance with the effective dose of the pharmaceutical composition, and the amount of the active ingredient to be mixed may be appropriately determined depending on the purpose of use such as prevention or therapeutic treatment. In the case of long-term consumption intended for health and hygiene purposes or for health control purposes, it may be below the above range.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Fruit body extraction and fractionation
Situation mushroom fruiting body Heat number extraction
20 g of mushroom fruiting body was dissolved in 500 ml of distilled water and extracted with stirring at 100 ° C for 3 hours. It is firstly filtered through nylon socks, and then filtered with a filter paper (Whatman No. 4). This was lyophilized to obtain about 0.94 g of hot water extract. The supernatant was separated by centrifugation (13,000 rpm, 4 ° C, 30 min), concentrated under reduced pressure, and freeze-dried. This was dissolved in distilled water, and then the mixture was partitioned with ethyl acetate (1: 1 v / v) and concentrated under reduced pressure to obtain lyophilized ethyl acetate extract (PLEA, 0.018 g).
Situation for Mushroom Ethyl Acetate Extract HPLC (high-performance liquid chromatography) analysis
High-performance liquid chromatography (HPLC) analysis was carried out to identify the major phenolic compounds contained in the mushroom ethenyl acetate extract (PLEA). The column was analyzed using a Gemini 5u C18 110A (250 x 4.60 mm) column (Phenomenex, Torrance, Calif., USA) and an HPLC of Waters 2600 equipped with a Waters 2998 photodiode array detector system (Waters, Milford, Mass., USA) separation modules) system.
In his mushroom fruiting body, hispolon, which is known as yellow (yellow) coloring matter, has been reported as one of the major phenolic compounds [Toopmuang P, Khamchum C, Punsuvon V. Detection and confirmation of hispolon in the mushroom Phellinus linteus . Science Asia 2014; 40: 141-4], and hyspolone was purchased from Enzo Life Sciences (Farmingdale, New York) and used as a reference material in this experiment. The column was placed in a 30 ° C chamber, and 10 μl of the sample solution was injected at a rate of 0.8 ml (0.8 ml / min) per minute. The elution solvent was a 20: 80 mixture of water and acetonitrile (20% water: 80% acetonitrile ) In an isocratic mode and analyzed at a wavelength of 300 nm.
As a result, as shown in FIG. 2, two substances (
This indicates that PLEA is the main active substance in the PLEA, which is the main substance contained in the PLEA, in protecting the brain cells from oxidative stress through antioxidant activity.
Cell survival rate and cytotoxicity measurement
Measurement of cell viability by MTT assay
A change in cell viability according to the pre-treatment of Phellinus resulting ethyl acetate extract (PLEA) against nerve cell death caused by H 2 O 2 treatment was measured by the MTT assay. SK-N-MC cells, human neuroblastoma cells, were cultured in 96-well plates at 37 ° C, 5% CO 2 for 24 hours at a density of 1 × 10 5 cells / ml. 0.1-5 μg / ml PLEA was pretreated for 2 hours and then treated with 200 μM H 2 O 2 for 24 hours. After the reaction, 3- [4,5-dimethyl-thiazol] -2,5-diphenyl-tetrazolium bromide (MTT) reagent at a concentration of 1 mg / ml was added and reacted for 4 hours. Then, 200 μl of dimethyl sulfoxide (DMSO) was added and the absorbance was measured at 570 nm using a microplate reader (Molecular devices, USA). The relative cell viability of each treatment group was determined using a control group to which no sample was added as 100%. The cell viability was decreased up to 53.6% in the group treated with H 2 O 2 alone, and the cell survival rate was significantly increased when PLEA was pretreated in a concentration dependent manner. In particular, when H 2 O 2 was pretreated with the highest concentration of 5 μg / ml of PLEA, the cell viability was increased by about 70.69% compared to the group treated with H 2 O 2 alone (FIG. 3 A)).
Cytotoxicity measurement by LDH assay
After pretreatment with PLEA, the cytotoxicity of neurons was measured by the LDH assay when treated with H 2 O 2 . SK-N-MC cells, a 6-
Nerve cell death analysis
H 2 O 2 treatment was performed using Annexin V-FITC Cell Death Detection Kit (Bio Vision, USA). Neuronal cells (SK-N-MC) were cultured in 6-well plates for 24 hours, and 0.1-5 μg / ml PLEA was pretreated with neurons for 2 hours and treated with H 2 O 2 for 24 hours. Cells were collected by trypsin-EDTA treatment and centrifuged to remove the supernatant. After the supernatant was suspended in 500 μl of each buffer, 5 μl of Annexin V-FITC and 5 μl of propidium iodide were added The reaction was carried out at room temperature for 5 minutes with blocking of light. Annexin V-FITC and PI-reacted cells were analyzed by flow cytometry.
In the group treated with H 2 O 2 , apoptotic cell apoptosis was increased by about 22.1%, and apoptotic cell apoptosis was decreased in a dose-dependent manner when H 2 O 2 was pretreated with PLEA , And apoptosis was reduced to about 4.7% when the highest concentration of 5 μg / ml PLEA was pretreated (FIG. 4).
Identification of DNA fragmentation changes in nerve cells
We confirmed the inhibitory activity of PLEA against DNA fragmentation, one of the characteristics of apoptosis, in order to further confirm the effect of PLEA on the neuronal death induced by H 2 O 2 . The neurons (SK-N-MC) were cultured in cover glasses for 24 hours and PLEA was pretreated for 2 hours at a concentration of 0.1, 5 μg / ml and treated with H 2 O 2 for 24 hours. After fluorescent staining using the poDIRECT In Situ DNA fragmentation assay kit (Biovision Research Products, Mountain View, Calif., USA), morphological changes of neuronal DNA were observed by fluorescence microscopy (× 200).
When PLEA was pretreated at concentrations of 0.1 and 5 μg / ml and then treated with H 2 O 2 , compared with the control group treated with H 2 O 2 alone, DNA fragmentation in the group pretreated with 0.1 μg / ml PLEA . However, in the group pretreated with 5 ug / ml of PLEA, DNA fragmentation was markedly reduced, and it was confirmed that cell death was reduced by inhibiting DNA fragmentation of neurons 5).
Intracellular activity Oxygen species ( ROS )
H 2 O 2 Treatment-induced The amount of reactive oxygen species (ROS) produced in SK-N-MC cells was measured using a fluorescent probe, 2'7'-dichlorofluorescin diacetate (CM-H 2 DCF-DA, Molecular Probes Inc., OR). SK-N-MC cells are plated in 96-well plates at a density of 1 × 10 5 cells / ml and cultured for 24 hours. PLEA at 0.1 to 5 μg / ml was pretreated for 2 hours and treated with 200 μM H 2 O 2 for 24 hours. After completion of the reaction, the cells were washed twice with 1 × PBS, treated with 100 μl each of CM-H 2 DCF-DA (10 mM in DMSO) to a final concentration of 10 μM and incubated at 37 ° C for 45 minutes , Fluorescence emission was measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.
As a result, the treatment with H 2 O 2 for 24 hours compared to the control group not treated with H 2 O 2 cells was observed that the active oxygen species by about 1.46 times. PLEA was pretreated at a concentration of 0.1-5 μg / ml for 2 hours, and the amount of intracellular reactive oxygen species was significantly decreased in the group treated with H 2 O 2. Particularly, at a concentration of 5 μg / ml, H 2 O 2 treated group was reduced by about 26.91% compared to the group treated with only 2 O 2 (FIG. 6).
Observation of mRNA Expression of Hemoxigenin-1 (HO-1)
RT-PCR was performed to investigate the effect of PLEA on the mRNA level of hemoxigenase-1 (HO-1). Nerve cells (SK-N-MC) were cultured in 6-well plates for 24 hours, treated with PLEA at a concentration of 0.1-5 μg / ml for 2 hours, and then treated with H 2 O 2 for 6 hours.
Isolation of Total RNA
Cells are lysed with TRIzol reagent (Invitrogen, USA), then chloroform (Sigma, USA) is added and centrifuged at 13,000 rpm for 10 minutes at 4 ° C. RNA is isolated using the Total RNA Extraction Kit (Intron, Korea). Add 400 μl of binding buffer to the separated RNA and wash with washing buffer A and B. Finally, 50 μl of the RNA is eluted with an elution buffer. The isolated total RNA was quantitated with a spectrophotometer and the concentration was 1 μg.
Synthesis of 1st Strand cDNA
First strand complementary DNA (cDNA) was synthesized using the Power cDNA Synthesis Kit (Intron, Korea). One μg of Oligo (dT) 15primer was added to 1 μg of total RNA, followed by reaction at 75 ° C for 5 minutes and reaction at 4 ° C for 1 minute. RNase inhibitor, 5X RT buffer, dNTP, DTT, AMV RT enzyme, and reacted at 42 ° C for 1 hour. The obtained cDNA was reacted at 75 ° C for 5 minutes and used for RT-PCR.
RT-PCR using cDNA
10 μl of 2X Master Mix Solution (Applied Biosystems, Foster City, CA), 1 μl of each synthesized cDNA, 1 μl of primers (HO-1, Hs01110250_m1; and 18s rRNA, Hs99999901_s1, Applied Biosystems) And then RT-PCR was performed using the StepOnePlus ™ system (Applied Biosystems, Foster City, Calif.).
As a result, as shown in Fig. 7 (A), HO-1 mRNA levels in the H 2 O 2 -treated group were 2.36 times higher than those in the control group without any treatment, and 0.1-5 μg / The mRNA level of HO-1 was increased by concentration. In particular, in the group pretreated with 5 μg / ml of PLEA, the HO-1 mRNA level increased 2.95-fold when compared to the group treated with H 2 O 2 alone Respectively.
Observation of protein level change by Western blotting
Western blot
Nerve cells (SK-N-MC) were cultured in 6-well plates for 24 hours, treated with PLEA at a concentration of 0.1-5 μg / ml for 2 hours, and then treated with H 2 O 2 . (Lysis buffer (20 mM Tris-HCl (pH 7.4), 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 150 mM NaCl) supplemented with a protease inhibitor and a phosphatase inhibitor (Roche, Germany) ) For 30 min on ice and centrifuge (13,000 rpm, 10 min, 4 ° C) to take the supernatant.
Proteins were quantitated using Bradford (Bio-Rad, Hercules, Calif., USA) reagent and the whole proteins were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Nitrocellulose membranes (Amersham Biosciences, Buckinghamshire, UK). The primary antibody HO-1, t-ERK, p-ERK, t-JNK, p-JNK and t-p38 were then blocked with 5% skim milk for 1 hour. , cleaved-caspase-3, truncated-PARP, β-tubulin (1: 1000, overnight, 4 ° C, Cell signaling) and HRP-conjugated secondary antibody , 4 ° C, and cell signaling), and proteins were detected using an enhanced chemiluminescent (ECL) system (AbClon, Seoul, Korea). Images were analyzed using NIH (Bethesda, MA, USA) software.
Measurement of protein level of hemoxigenase-1 (HO-1)
The effect of PLEA on the protein level of HO-1 was 1.40 times higher than that of the control group in the H 2 O 2 -treated group. When pretreated with 0.1-5 μg / ml of PLEA, the HO -1 protein levels were increased by concentration, and in the group pretreated with 5 ug / ml of PLEA, the HO-1 protein level was increased by 60.20% when compared with the group treated with H 2 O 2 alone 7 (B)).
Phosphorylation measurement of MAPK (ERK, JNK, P38) signaling mechanism
The effect of PLEA pretreatment on phosphorylation of MAPK (ERK, JNK, P38) signal transduction pathways was investigated. The degree of phosphorylation of ERK, JNK and P38 in H 2 O 2 treated group was significantly And increased by 1.37, 6.31, and 1.87 times, respectively. However, pretreatment of PLEA by concentrations (0.1, 0.5, 1, 5 μg / ml) before treatment with H 2 O 2 reduced the degree of phosphorylation of MAPK by concentration and the highest concentration of 5 μg / ml PLEA was pretreated , Phosphorylation of ERK, phosphorylation of JNK, and phosphorylation of P38 decreased by 15.58%, 79.74%, and 30.4%, respectively, when compared with the group treated with H 2 O 2 alone. The phosphorylation of MAPK pathway by PLEA (FIG. 8A and FIG. 8B).
Measurement of activation of caspase-3 and PARP
The effect of PLEA pretreatment on the activation of caspase-3 and PARP, the enzymes involved in apoptosis, was investigated. In the H 2 O 2 -treated group, activation of caspase-3 and PARP Respectively, by 1.61 and 1.34 times, respectively. However, pretreatment of 0.1-5 μg / ml of PLEA before treatment with H 2 O 2 reduced the level of activation of caspase-3 and PARP by concentration, and when PLEA at the highest concentration of 5 μg / ml was pretreated, The activation level of caspase-3 was decreased by 36.35% and the activation level of PARP was decreased by 15.04% (Fig. 9A and B), as compared to the group treated with H 2 O 2 alone.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
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| CN107496391A (en) * | 2017-09-20 | 2017-12-22 | 东北师范大学 | A kind of application of compound in terms of antagonism amyloid beta accumulation |
| CN112574893A (en) * | 2020-12-16 | 2021-03-30 | 广东省微生物研究所（广东省微生物分析检测中心） | Phellinus baumii, and preparation method and application of fermentation product thereof |
| KR102557645B1 (en) * | 2021-02-15 | 2023-07-21 | 주식회사 기운찬 | Composition comprising extracts of mushroom mixed mycelia for improving cognitive function or memory |
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| 부경대학교 학위논문, 2008, 식품생명과학과, 정다미* |
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