TW201103899A - New use of histone deacetylase inhibitors in changing MRJP3 protein in royal jelly - Google Patents

Abstract

The invention provides a method of changing a ratio of 68 to 64 kDa protein of MRJP3 in a royal jelly, a method of producing a royal jelly comprising MRJP3 having a changed ratio of 68 to 64 kDa protein relative to a control royal jelly and the royal jelly produced thereform. Also provided is a method of promoting the growth of the larva of a queen bee comprising feeding the larva of the queen bee a royal jelly of the invention. Further provided is a method of producing bee larva, pupa and queen bees with sizes larger than normal.

Description

201103899 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a method for promoting the growth of a bee prince (a bee larvae), a bee venom, and a queen bee. The method is a tissue protein deacetylase inhibitor (HDACi). Or a mixture or formula containing one or more HDAC inhibitors. In particular, the ratio between the 68 and 64 kDa MRJP3 proteins was changed in the royal jelly secreted by the young worker bee hung by HDACi. [Prior Art] Fire bee is one of the most valuable species in modern agriculture. It produces a variety of bee products, such as royal jelly, honey, propolis and pollen, which provide a rich source of nutrients for humans (Hellner M纣&amp ;丨, 2〇〇8). Therefore, it is a very important topic to study the growth, evolution, and development of the poor bee. The bee's Duhui belongs to the matriarchal society and is led by the queen bee. In bee colony, worker bees and queen bees are hatched by fertilized eggs; and drones are grown by 4 fertilized eggs (Winston M. L., 1987). The queen bee will print the _ of the individual nest in the hive #令, ^ three to four days, the hatched larvae. The hatched larvae are fed by young worker bees and grow through several developmental stages in the nest. Worker bees will close the opening of the nest when the larva enters the pupation period. Usually, the queen bee will come out of the nest (four) within 16 days, while the guard bee and the drone will take 21 and 24 days each. The queen bee is larger, and its life is 1 (M5 times of the worker bee. Fertilization (4) develops into the X bee or the queen bee ^ is regulated by the bee colony. Originally, the group bee will only have - f queen 1 outside the bee king The foods eaten are also different from other bees in the same group. I41899.doc 201103899 The queen bee always uses royal jelly for food, while worker bees only eat royal jelly at the beginning of development. Some scholars believe that worker bees still eat during development. Royal Jelly, but the chemical composition of the royal jelly that it eats and the queen bee may be different. In any case, royal jelly can be regarded as the most important substance to continue the bee colony (Robinson GE et al., 1987) ° Royal jelly is The most important food and nutrient source of the bee prince and the queen bee is secreted by the pharyngeal glands and the large salivary glands of the young worker bees. The chemical composition of the queen bee may change with the different developmental stages of the bee prince. It is generally believed that the compositional changes of the aforementioned royal jelly are derived from changes in carbohydrates rather than protein composition (Peiren N. et al., 2005). It is known that royal jelly contains a variety of substances that promote human health and Various pharmacological properties (Takaki-Doi S. et al., 2009; Mannoor Μ K. et al., 2009; and Gasic S. et al., 2007). Therefore, royal jelly has been widely used to promote human health care. Products. Recent studies have found that royal jelly can promote immune regulation (Vuecvic D_ et al., 2007), antibacterial (Boukraa L., 2008), nourish the lunar nerve (Hashimoto M. et al., 2005), anti-cancer and Antioxidant (Gou H. et al., 2008). The study found that 烽王乳 is a milky white pulpy substance with a composition of about 60-70% water, 12-15% protein, and ΙΟ-ΐ 2%. Carbohydrates, 3-5% fat, and a variety of trace elements and minerals (Scarselli R. et al., 2005). Among the protein components, about 80-90% are water-soluble proteins, while the rest are water-insoluble proteins. In other words, the protein components contained in the royal jelly are mostly water-soluble proteins. Among the above water-soluble proteins, MRJP (Major King Jelly Proteins) family (MRJP 1-9) is dominant (Schmitzova J. 141899. Doc 201103899 et al., 1998). Amino groups of these MRJP proteins Although the sequence has been analyzed, its role and function are still to be studied. MRJP1 was found in the brain of bees, which may be related to bee behavior. MRJP 1 accounts for 44% of the water-soluble protein in the queen's milk, and is all MRJP The highest content of family proteins (Malecova B. et al., 2003). The current study on MRJP3 is a large-scale study and is generally considered to be involved in immune regulation (Kohno K. et al., 2004). MRJP3 accounts for 12% of the total water-soluble protein in the royal jelly, and its content accounts for the second of all MRJP proteins (MRJPs 1-9). MRJP3 is characterized by its anti-allergic anti-inflammatory activity. Furthermore, the highly polymorphic gene of MRJP can result in the production of MRJP3 protein variants (such as 60-70 kDa protein) (Stefan Albert et al., 1999). The MRJP protein provides a rich essential amino acid and other nutrients (Furusawa T. et al., 2008). Royal Jelly is the only source of nutrition for the bee prince. MRJP protein is the most important protein in the royal jelly. Therefore, the development of a special composition of royal jelly is required. SUMMARY OF THE INVENTION The present invention provides a method in which bee larvae grown by the method are at least twice as large (100%) or even several times larger than normal larvae; the bee stings cultivated by the method are compared with normal bees.蛹, the weight is at least 50%, or even one to several times; the bee king cultivated by this method is at least 50% larger, or even one to several times larger than the normal queen. The present invention provides a method of cultivating bee larvae at least twice as large (100%) as compared to a control larva; the method comprises feeding a young worker bee with a mixture of HDAC inhibitors or several HDAC inhibitors, and The 141899.doc 201103899 and other young worker bees secrete the royal jelly to feed the larvae. The larvae of the control group / the royal jelly consumed by the larvae were secreted by young worker bees who were not fed HDAC inhibitors or a mixture of several HDAC inhibitors. The present invention provides a method for cultivating bee stings having a weight of at least 50% greater than that of a control bee sting, or a bee king having a weight of at least 50% greater than that of a control bee king; the method comprising using an HDAC inhibitor or number a mixture of HDAC inhibitors is fed to young worker bees, and the larvae are fed by the queen bee secreted by the young worker bees to obtain the cockroaches or queen bees developed by the larvae, wherein the control group or the queen is consumed by the larvae Bee larvae of queen bee secreted by young worker bees that are not fed HDAC inhibitors or several HDAC inhibitor mixtures. The present invention further provides a royal jelly having a ratio of 68 kDa and 64 kDa MRJP3 protein which is different from that of the control group. The invention further provides a method of regulating epigenetics of a worker bee gene comprising feeding a worker bee with an HDAC inhibitor to control the gene expression of a worker bee. [Embodiment] The present invention has found that bee larvae bred by worker bees fed a HDAC inhibitor or a mixture of several HDAC inhibitors can rapidly grow and develop into large larvae, pupa, or queen bee. The bee larvae may have a weight that is at least twice (100%) or even several times greater than a normal larva; the cockroach may have a weight greater than at least 50% or even one to several times greater than normal cockroaches; and the queen bee may have at least 50% greater than a normal queen, or even One to several times the weight. The present invention finds that a HDAC inhibitor or a mixture of several HDAC inhibitors 141899.doc -6- 201103899 can change the ratio of protein to 68 and 64 kDa elbow in the royal jelly by epigenetic means. After feeding a HDAC inhibition Young worker bees with a mixture of agents or several hdac inhibitors can secrete special royal jelly by epigenetic, wherein the ratio of 68 kDa and 64 gamma in the royal jelly is changed. The main food of the queen bee prince and queen bee The present invention finds that the special queen bee can promote the growth of the bee prince who is eating the queen bee, and significantly increase the weight of the bee prince and the cockroach and queen bee that develops from the queen bee. In one aspect, the present invention provides a breeding comparison a method for control larvae, at least one-fold (100%) by weight of bee larvae, the method comprising a mixture of an HDAC inhibitor or several HDA c inhibitors (4) young worker bees and secreted by the young worker bees Royal Jelly is a fake bee larvae; the royal jelly of the control larvae is a young worker bee that is not a mixture of T or several HDAC inhibitors. According to one of the embodiments of the invention, the bee larvae can be fed by the worker bees with the hand secreted by the worker bees, or by the human beings with the bee king milk collected from the worker bees. According to one of the embodiments of the invention, the feeding is The weight of the larvae of the aforementioned royal jelly is increased by more than Μ times when it is small. Preferably, the weight is increased by about (1) times. Further, the weight is increased by about 3 to 5 times. According to the present invention, the above-mentioned royal jelly is included in the heart of the king. The ratio of MRJP3 protein was changed compared with the control group. The invention was made from the larvae of the bee larvae of the present invention and the queen bee, which has a higher weight respectively. The present month is for the yaw of the sergeant B private + person. The father is in the control group of bee stings, the weight is at least 50%, the bee worm, or the bee king compared to the control group, the weight is at least 5. 5% of the queen bee 141899.doc 201103899 Method; the method comprises feeding a young worker bee with a mixture of an HDAC inhibitor or a plurality of HDAC inhibitors, and feeding the larva with the royal jelly secreted by the young worker bees to obtain the larvae developed by the larvae Or queen bee; The cockroach or queen bee of the control group is developed by eating bee larvae which are not fed with royal jelly secreted by a young worker bee with an HDAC inhibitor or a mixture of several HDAC inhibitors. According to one of the embodiments of the present invention, The bee larvae can be fed by the worker bees with the royal jelly secreted by the worker bees, or by humans with the royal jelly collected from the worker bees. In one aspect, the present invention provides a method for changing the proportion of 68 kDa and 64 kDa MRJP3 proteins in the royal jelly. It includes an HDAC inhibitor or a mixture of several HDAC inhibitors to feed young worker bees to produce a royal jelly with a modified ratio of 68 kDa and 64 kDa MRJP3 protein compared to the control queen jelly. In another aspect, the present invention provides a method of producing royal jelly, wherein the ratio of the 68 kDa and 64 kDa MRJP3 proteins contained in the royal jelly is changed compared to the control royal jelly, the method comprising an HDAC inhibitor or Several HDAC inhibitor mixtures were fed to young worker bees and the royal jelly produced by the young worker bees was collected. In another aspect, the present invention provides a royal jelly having a ratio of 68 kDa and 64 kDa MRJP3 protein that is altered compared to the control queen bee. According to the present invention, the ratio of 68 kDa to 64 kDa MRJP3 protein can be increased by about 1.5 to 12 times, 1.5 to 5 times, 2 to 6 times, 2 to 10 times, 4 to 12 times, or 2-4 times (compared to Control group). More preferably, the ratio of 68 kDa to 64 kDa MRJP3 protein can be increased by about 1.5 to about 5 times, or 2 to 10 times (compared to the control 141899.doc 201103899 group). More preferably, the ratio of 68 kDa to 64 kDa MRJP3 protein can be increased by about 2 to 4 fold, or about 4 to 1 fold (compared to the control group). In another aspect, the invention provides a method of regulating the epigenetic inheritance of a worker bee gene comprising the use of a HDAC inhibitor or a mixture of several hdac inhibitors to feed worker bees to regulate the gene expression of the worker bees. According to the present invention, the aforementioned epigenetics may be inhibition of DNA thiolation or HDAC. DNA methylation is an epigenetic change that does not alter the DNA sequence, can be inherited, and can alter gene expression. DNA methylation is a covalent modification that induces heritable gene silencing, which can induce silence in two ways. The methylation can directly interfere with the binding between the transcription factor and the recognized position on the DNA; second, the methyl-CpG binding domain proteins (MBPs) can be inhibited by aggregation subsidies. CO-repressor complex (which contains tissue protein deacetylase or tissue protein thiol transferase to enhance the aforementioned silent phenomenon (Juile c. Kiefer, 2007). HDAC inhibitors can change young worker bees 68 and The performance of the 64 kDa MRJP3 protein suggests that HDAC inhibitors can regulate the hyperacetylation of tissue proteins and affect the gene splicing and translation of polymorphic mrjp3 genes in young worker bees. </ RTI> represents a straight or branched hydrocarbon chain; the alkyl group is preferably a Cl-IQ alkyl group. Preferably, the carbon number of the 'housing base is selected from the group consisting of 1 to 8; more preferably 'it is Ci_6 炫 or Cl·4 Examples of glazing groups include methyl (_Cpj3), ethyl (-CH2CH3), propyl (-CH2CH2CH3), isopropyl ((CH3)2CH), and butyl (-C4H9). "Wool" stands for a straight or branched unsaturated hydrocarbon group, of which [5; 141 899.doc _9- ^ ' 201103899 Unsaturated as a double bond. According to the invention, the alkenyl group includes - or a plurality of double bonds. The dilute group is preferably a &lt;: 2 · 6 alkenyl group. More preferably, an alkenyl group Examples of the carbon number selected from the group consisting of 2 to 12 include ethylene (-CH=CH2), acryl (_ch=chCH3 or CI^CH CH2); base (_CH2CH=CHCH3 or _CH= CHCH2CH3 or _CH2CH2CH=CH2) . -CH2CH=C(CH3) ch3 . -ch2-ch=ch-ch, CH2-CH=CH-CH3^-CH2-CH=C(CH3)-CH2-CH2-CH= C(CH3)-CH3〇 As used herein, the term "cycloalkyl" denotes an aliphatic ring (saturated carbocyclic ring). Preferably, the carbon number of the cycloalkyl group is selected from the group consisting of 3 to 8; more preferably, the ring The carbon number of the alkyl group is selected from the group consisting of 5 to 6. Examples of the cycloalkyl group include a ring: a group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. This: The term "unsaturated carbocyclic ring" includes carbon. The atom and the hydrogen atom are composed of a substituent, and the ? moiety is an unsaturated ring, such as an aryl group or a cycloaliphatic group, etc. The "cycloalkenyl group" includes a ring of a cyclized group having one or more double bonds. Base, such as cyclopropyl (such as W propylene), cyclobutyl (such as i ring , cyclopentenyl (such as b cyclopentanyl, 2-cyclopentanyl, and 3-cyclopenten-1-yl), ring, knee |) hexenyl (such as 1-cyclohexene) -i-yl, 2_cyclohexenyl, and 3-cyclohexene-1_yl), cycloheptenyl (such as 1-3⁄4 heptenyl), cyclooctyl

(female 1_ί 衣辛基) and so on.尤盆 I Α κ , preferably 1_cyclohexen-1-yl, 2-cyclohexenyl, and hongcyclohexene-1-yl. The use of at least one of the "squares" includes a condensed or fused ring (its / square (4)' such as stupid, naphthyl, and tetrahydroindenyl. In this article 'the term '5-member or 6 Chang you m if « ^ φ ^ ^ , - 贝 裱 裱 为 为 为 为 为 为 为 为 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少Or 6_member heterocyclic β white: 3⁄4 non-fragrance, whose sub-system is selected from N, 〇 and S. Miscellaneous: or unsaturated. Preferably, the heterogeneous ', 1 long example includes, but not Limited to furyl 141899.doc 201103899 (eg 2-furyl, 3-furyl), thienyl (eg 2-pyrimenyl, 3_p-septyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl) , 3-pyrrolyl) 'imidazolyl (such as 1-flavored β-spinyl, 2 β-m.), 4-pyranyl β-based, p-ratio. Sit-based (eg, 1 _ p than spyryl, 3-pyridyl) Azolyl, 4-pyrazolyl), triazolyl (such as hydrazine, 2,4-triazole-hydrazine-based, i, 2,4, 3-oxan-3-yl, 1,2,4-di. -4-base), four u sitting bases (such as 1_four π sitting base, 2_four squat base, 5 - four ° sitting base), ρ number β sitting base (such as 2 -1» "sitting base, 2 - β number. Sitting base , 5 - ρ ο 坐 base), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5 _$ D sitting) 'thiazolyl (eg 2-pyrazolyl, 4 - carbazolyl, 5-thiazolyl), thiadiazolyl, isoxazolyl (eg 3-isopyrazolyl, 4-isopyrazolyl, 5-iso-pyrazolyl), pyridyl (eg 2 -pyridyl, 3-pyridyl, 4-pyridyl)' 嗒p well (eg, 3 嗒 、, 4-嗒 基), pyrimidinyl (eg 2 -pyrimidinyl, 4 pyrimidinyl 5 -pyrimidine) Base), furazinyl (such as 3-furazyl), pyridinyl (such as 2_pyrroxy), oxadiazolyl (such as 1,3,4-diazole-2-yl), 丨_ Pyrrole p-based, 2_pyrrole p-linyl, pylorium forest, bismuth, 2 - p piroxime, 3 - p than fluorenyl, 1 -mi salivin, 2 _ m , 4-miwa P Linji, ^Mijun biting base, 2_imitonbite, rice succinyl 1_pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyridyl Wahridyl 3-pyrazolidinyl, 4-pyrazolidine, N-hexahydropyridyl, 2-hexahydropyridinium, 4-hexahydro-P-bite, hexahydro? Hexachloro-p-ratio, 3 -丄θ # , ,, wind P than well, morpholinyl, tetrahydropyran Or its analogues. Wooden Φ, the term "halogen" stands for fluorine, gas, bromine and iodine. In this article, the term "pharmaceutically acceptable salts" includes those with organic or inorganic acids or bases, soil... Former. Pharmaceutically acceptable acid addition salts include those with mineral acids (such as hydrogen chlorhexidine, guanidine bromate, sulfuric acid, and phosphoric acid) or organic acids (such as lemon 141899.doc 201103899 acid, tartaric acid, lactic acid, pyruvic acid' acetic acid , trifluoroacetic acid, succinic acid, oxalic acid, citric acid, fumaric acid, malic acid, oxalic acid, decanesulfonic acid, ethanesulfonic acid, P-methyl sulfonic acid, sulfonic acid and hydroxyethyl sulfonate Acid) formed. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as their sodium and potassium salts), alkaline earth metal salts (such as their calcium and magnesium salts), and basic base salts (including primary, secondary and tertiary). Grade amine salt). As used herein, the term "prodrug" means a compound that is converted in the body (e.g., hydrolyzed in blood) into its active form with a medical effect. As used herein, "solvate" refers to a complex comprising a compound of the invention and a solvent wherein they react or they precipitate or crystallize therefrom. In this context, the term "stereoisomers" is an isomer molecule with the same molecular connections but different spatial arrangements of the molecules. In this paper, "mirrible isomers" are used to represent each other with only a mirror structure but not to each other. Overlapping stereoisomers, such as a person's left and right hands are the same but opposite. In this article, the term “gongfeng” is a female peak lacking the complete reproductive capacity of the queen bee colony; in most cases, it is associated with an increase in the non-reproductive activities of the queen bee. The peak eggs are individually laid in the nest of the waxy honeycomb, which is manufactured and formed by Gongfeng. The bee prince (4) reads the royal jelly produced by the food bee, and then eats honey and powder. &lt;Outside the column, the bee prince slowly feeds the royal jelly, and (4) bred the queen. In the nest, I was licked and the scorpion scorpion was transformed several times and turned into cockroaches. The males hatch from the unfertilized, and the female bees (the queen bee and the worker bees) hatch from the insemination. The queen bee can choose to insefine the egg, usually depending on the hive at the print. The light worker bees clean the hive and proud of the bee prince. t Royal jelly produces atrophy of the gland, he 141899.doc 12 201103899 We started to build the hive. When they are older, they perform tasks within other bee colonies, such as collecting nectar and pollen and defending the hive. Then, the worker bees flew to the nest and finally left the hive and served as a field bee. In this article, the term “bee king milk” is a bee secretion used to nourish the queen bee. It is secreted from the hypopharyngeal gland located in the head of the young worker bee and used to feed the bee prince in the bee colony. According to the present invention, HDAC is an enzyme which affects transcription by selectively deacetylating an lysine ε-amine group located near the amine end of the core histone. HDAC inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies. The present invention unexpectedly found that HDAC inhibitors affect the performance of the 68 kDa and 64 kDa of MRJP3 of royal jelly produced by young worker bees. According to the present invention, HDAC inhibitors include, but are not limited to, four classes of HDAC inhibitors: short chain fatty acids, hydroxamic acids, benzinamides, and cyclic peptides, such as Medicinal Research Reviews, Vol. 26, No. 4, ρρ· 397-413, 2006, reported; as mentioned in the Journal of the National Cancer Institute, Vol. 92, No. 15, August 2, 2000, pp. 1210-1216, an acid-based heteropolar compound ( 1^(:); U.S. Patent No. 6,174,905, U.S. Patent No. 0,847,992, JP 258863/96, and Japanese Application No. 10138957; benzamine derivatives; compounds of WO 01/38322; benzamide M344 ( Hum Genet, 2006, 120, ρρ· 101-110); sodium butyrate (Human Molecular Genetics, 2004, Vol. 13, No. 11, pp. 1183-1192); Trichostatin A (Molecular Cancer 2006, 5:8; this document is available from http://www.molecular-cancer.eom/content/5/l/8; a compound of the formula ZQLM or ZLM disclosed in U.S. Patent No. 7,169,801; 141899.doc -13 - 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 038 (valproic acid) and its derivatives; hexamethylene bisacetamide; hexamethylene bisacetamide; oxime; and HMBA-related compounds as described in U.S. Patent No. 6,087,367 and RE 38,506; Compounds related to HMBA, such as suberoylanilide hydroxamic acid (SAHA); Blood, 1 October 2003, Vol. 102, No. 7, pp. 2615-2622, NVP-LAQ824 (hydroxamic acid derivative) and NVP-LAQ824 ( a derivative of 4-aminomethylcinnamic hydroxamic acid); LBH589 (Blood 105(4): 1768-76 February 15) for the first phase of clinical trials by inducing apoptosis-induced growth inhibition and tumor cell line degradation and acting as an anticancer agent. , 2005); the compounds mentioned in the U.S. Patent Application Serial Nos. 11/855,416 and 12/418,373; the propolis; the propolis and the compounds mentioned in the publication No. 20080242648, including pyroxamide, M-carboxycinnamic acid bishydroxamide (CBHA), trichostatin A (TSA), trichostatin C, salicylihydroxamic acid (SBHA), azelaic bishydroxamic acid (ABHA), azelaic-1 -hydroxamate-9-anilide (AAHA) ' 6-(3-chlorophenyl Ureido) carpoic hydroxamic acid (3Cl-UCHA), oxamflatin, A-161906, scriptaid, PXD-101, cyclic hydroxamic acid-containing peptide (CHAP), ITF-2357, MW2796, MW2996, trapoxin A, FR901228 (FK 228 or Depsipeptide ), FR225497, apicidin, CHAP, HC-toxin, WF27082, chlamydocin, sodium butyrate ' isovalerate ' valerate ' 4-phenylbutyrate (4-PBA) ' 4-phenylbutyrate sodium (PBS), arginine butyrate, propionate, butyramide 'isobutyramide ' phenylacetate ' 3-bromopropionate ' 141899.doc -14- 201103899 tributyrin ' valproic acid, valproate, CI-994, MS-27-275 3'-amine derivative, MGCD0103 and Depudecin. The disclosures of which are incorporated herein by reference. According to a specific embodiment of the present invention, the HDAC inhibitor used herein is a compound represented by the following formula (I):

R4 R? wherein 1 and 2 are each independently OH, 0C(=0)alkyl, 〇-alkyl 'S-alkyl, N-institutional, fluorenyl-alkenyl, S-alkenyl, N-alkenyl , 0-alkynyl, S-alkynyl, N-fast radical, o-c3_8 cycloalkyl, S_C3 8 cycloalkyl, N_C3 yt alkyl, oxime-unsaturated 5- to 10-membered monocyclic or bicyclic, s _Unsaturated 5_ to ι〇_ member single ring or double soil, N-unsaturated 5_ to ι〇_ member monocyclic or bicyclic, alkyl, alkenyl, alkynyl, C3·8 ring yard base 'unsaturated 5_至1〇_ member monocyclic or bicyclic or containing at least one hetero atom from the following groups: N, 〇 and s saturated or unsaturated 5 - to 1 〇 _ member heterocyclic ring; or 1 ^ and 1 ^ 2 together form a dioxane; R3 and R4 are each independently 〇H, 〇c(=〇)alkyl, 〇-alkyl, s-alkyl, N-alkyl, 0-alkenyl, s-alkenyl , N-alkenyl, 〇-alkynyl, s-alkynyl, N-blockyl, 〇-(: 3.8 cycloalkyl, s_c38 cycloalkyl, n_C38 cycloalkyl, 〇_unsaturated 5- to 1 〇 Monocyclic or bicyclic 'S-unsaturated 5- to 10-membered monocyclic or double 141899.doc •15·201103899 Ring, N-unsaturated 5- to 1〇_membered monocyclic or bicyclic, alkyl, alkenyl, Alkynyl, C: 3·8 cycloalkyl, unsaturated 5_ to 1 • membered monocyclic or bicyclic or contain at least one heteroatom selected from the group of: N, square, and a saturated or unsaturated 5- to 8-membered heterocyclic 1〇_;

Rs is C4,6 alkyl or (:4.1.1 alkenyl, wherein the alkyl or alkenyl group is unsubstituted or via one or more CN6 alkyl groups, halogen, CN, NO, Ν3, ΝΗ2, CHO, Or9, sr9, NR9 or C00R9 substituted; R6 is Cm alkyl or C2_u alkenyl, wherein alkyl or alkenyl is unsubstituted or substituted by one or more Cu, oh, halogen, CN, NO, N3, NH2 Substituting CHO, OR9, SR9 or NR9; or one of R5 or R6 is hydrogen, halogen or hydrazine H, and the other is Co丨6 alkyl or C4 heptyl, unsubstituted or via one or more Cl. 6 alkyl, OH, νη2, dentate, CN, &gt; 10 or hydrazine substituted; R7 or R8 are each independently hydrogen, halogen, OH, NH2, COOH, CHO, CN, NO, unsubstituted or via oh, NH2 ,COOH,halogen, CN 'NO or CHO substituted 〇V6 alkyl, 〇, 〇-alkyl, s_alkyl, Ν-alkyl, Ο-alkenyl 'S-dilute' Ν-dilth, 〇 - a fast radical 'S-alkynyl or fluorenyl-alkynyl; or R7 and Rs together form a double bond, a C3-6 cycloalkyl group or a hetero atom comprising at least one selected from the group consisting of hydrazine, hydrazine and s. Or unsaturated 5- to 1 〇-member jade, R9 is phenyl, C(=〇)R10, c(=〇)〇R10 Benzyl; and R10 are OH, NHOH, NH2, C -6 hexyl, phenyl or benzyl; and pharmaceutically acceptable salts thereof, stereoisomers, mirror image isomers, prodrugs 141899.doc • 16 - 201103899 or a solvate. Preferably, the compounds of formula (I) are at their centers and are each independently OH, OCk alkyl, OChCOCu alkyl, Ο-phenyl or Ο-benzyl or Ri and R2 — Forming dioxane; R3 and R4 are each independently OH, OChe alkyl, 0 (: (=0) (^-6 alkyl, 0-phenyl or 0-benzyl;

Ci.4alkyl\^OvJ ο

Phenyl 〇 I Ο

phenylO

Η

, or 141899.doc -17- 201103899 Preferably, the compound of formula (i) is selected from the group consisting of:

NBM-HD-1

141899.doc •18· 201103899

141899.doc -19- 201103899

OMe Ο 141899.doc -20- 201103899

Propolis G

And 141899.doc -21 - 201103899 ch3

OCH,

CH, ChU OH

OH

Propolis A

OH

Propolis B -22- 141899.doc 201103899

OH

Propolis C

CHi CH, OH

OH

Propolis D 141899.doc -23- 201103899

Propolis E 141899.doc

OH

Propolis F

Propolis G -24- 201103899

Propolis

OH

Propolis I

Propolis J 141899.doc -25- 201103899 According to another embodiment of the invention, the brain used by this #. The inhibitor is a compound represented by the following formula II:

among them

Ri is a milk, alkyl, alkenyl, CM cycloalkyl, 5- or 6-membered unsaturated carbocyclic ring or 5- or 6-membered heterocyclic ring; X is C, 〇, N or s; γ is 〇, NH or O-Cw alkyl; η is an integer from 0 to 1 ;; m is an integer from 0 to 5; R 2 and R 3 are each a C 6 alkyl group; R 4 is a C 5 · 6 cycloalkyl group or a 5 member or 6 _ An unsaturated carbocyclic or heterocyclic ring which may be substituted by halogen, cf3, OR74NR7R8 wherein each of the ruthenium and the heart is hydrogen or c alkyl; h is H NH2 or C5-6 cycloalkyl, 5_ member or 6_ member Unsaturated carbocyclic or octagonal octadecyl, carbocyclic and heterocyclic ring may be optionally halogen, Nli2, 2 1-6 alkoxy, cK6 alkylthio, 〇r7, and R6 are H, Ci .1 alkyl group, which may be via a hydroxyl group. 2丨. Alkenyl substitution, or with 141899.doc -26- 201103899

Ri together is -C2H2-; and its pharmaceutically acceptable salts, stereoisomers, mirror image isomers, prodrugs and solvates. Preferably, the compound of formula (II) is wherein each of Ri, R2 and R3 is CN4 alkyl; R4 is phenyl or phenyl substituted by halogen, CF3 or OC^alkyl; R5 is OH, phenyl or The phenyl group substituted with NH2 and R6 are hydrogen. More preferably, the compound of formula (II) is selected from the group consisting of:

NBM-HB-OS01

141899.doc -27- 201103899

NBM-C-BA-OSOl

NBM-C-BMA-OSOl 141899.doc

HO N

NBM-C-BX-OSOl 28- 201103899 141899.doc HO yNH n——r

NBM-C-BCX-OSOl HO yNH η-n

NBM-C-BMX-OSOl HO : NH n-n

NBM-C-BFX-OSOl 29- 201103899 141899.doc HO 'nh η-n

NBM-C-BBX-OSOl

NBM-T-BCA-OSOl 30- 201103899

NBM-T-BFA-OSOl

NBM-T-BMA-OSOl II NT Η Ο

NBM-T-BCX-OSOl 141899.doc -31 - 201103899

Me(

jT Cl NBM-T-L-BCX-OSOl

OCH3 NBM-T-BMX-OSOl n

Me NBM-UBMX-OSOl 141899.doc π

NBM-T-L-BMX-OSOl -32- 201103899

NBM-T-L-BTX-OSOl Ο

NBM-T-L-BBX-OSOl 141899.doc -33- 201103899 Ο

NBM-T-BFX-OSOl 141899.doc

HO NH

NBM-C-BBX-OSOl

HO NH

NBM-C-BFX-OSOl 34- 201103899

NBM-T-TMX-OSOl

HO,

.OH r r- ύ 141899.doc -35- 201103899 NBM-T-I-BMX-OSOl

O

Θ NBM-T-L-I-BMX-OSO1

NH one

OH

Br NBM-T-I-BBX-OSOl

NBM-T-L-I-BBX-OSOl 141899.doc 36- 201103899 ο

NBM-T-I-BCX-OSOl

NBM-T-I-MCX-OSOl * According to another embodiment of the present invention, the HDAC inhibitor used herein is SAHA, propolis or propolis (e.g., propolis A to J). Preferably, the HDAC inhibitor is Taiwan green propolis, propolis A, propolis B, propolis C, propolis D, propolis E, propolis F, propolis G, propolis H, propolis I, propolis J, SAHA or NBM-HD-1. 141899.doc -37- 201103899 The present invention unexpectedly finds that HDAC inhibitors can alter the ratio of 68 kDa protein to 64 kDa protein of MRJP3 of royal jelly secreted by worker bees fed HDAC inhibitors. The present invention suggests that this alteration is induced by epigenetic modification by Janet S. Graham et al. (Janet S. Graham et al., 2009) 'TJ Walton et al. (TJ Walton et al., 2008). Supported by Julie C. Kiefer (Julie C. Kiefer, 2007) and Ahmad Miremadi et al. (Ahmad Miremadi et al, 2007). The bee princes fed the above-mentioned royal jelly have a heavier weight and a larger size than the general bee prince, making their development period shorter. The snail and queen bee from the prince of the bee also have a heavier weight and a larger size. These queens have higher egg yields that increase the number of bees and the production of honey. Example 1: Preparation of Taiwan green propolis extract and propolis C and G (propolins C and G) Taiwan green propolis extract 50 g of Taiwan green propolis (TP) was extracted with 95% ethanol (250 mL×3) and treated with ultrasonic vibration. After 3 hours, it was allowed to stand at 25 ° C for 21 hours. After filtration, the ethanol extract was dried under reduced pressure to give a brown brown gum (34.5 g). The gel was stored at -20 ° C until use. Proplin C. 5 g of the TP extract was chromatographed on a Sephadex LH-20 column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) and eluted with methanol as a solvent to obtain six fractions ( Fraction). Performed on a Shixi rubber column 141899.doc •38- 201103899 Chromatography was performed on all eluates (including those obtained from subsequent layer folding) and eluted with a gradient solvent system of η-hexane and EtQAe. The highest activity fraction 4 was purified by reverse-phase preparative high high perf 〇 ance ance liquid chromatography (HPLC)/UV (n-hexane: EtOAc = 70:30), followed by The propolis fraction C was collected for 45 minutes of retenti〇n time. The test conditions used were as follows: Column: Luna Phenomenex (C18, 25 〇 mm x 10 mm), solvent system: methanol: water (7:3), flow rate: 2.5 mL/min, and detection: uv 28 〇 nm. The obtained compound was evaluated by the ball as the zeocin c, and the purity of the obtained propolis C was not less than 95% as estimated by HPLC/UV based on the peak region. Propolis G (Propolin G) 5 g of the TP extract was chromatographed on a Sephadex LH-20 column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) and eluted with methanol as a solvent to give six fractions. Chromatography on all eluates (including fractions from subsequent chromatography) was performed on a ruthenium cartridge and eluted with a gradient solvent system of η-hexanes and EtOAc. The most active fraction 3 was purified by reverse phase preparative high performance liquid chromatography/UV (n-hexane: EtOAc = 70: 30), followed by the fraction of propolis G which was retained for 25 minutes. The test conditions used were as follows: Column: Luna Phenomenex (C18, 250 mm x 10 mm)' Solvent system: methanol: water (8.5:1_5), flow rate: 3.5 1111^/min, and detection: UV 280 nm. The obtained compound was confirmed to be propolis G, and the purity of the obtained propolis G was not less than 95% as determined by HPLC/UV based on the peak region. Example 2: Collection and analysis of royal jelly and bee prince 141899.doc -39- 201103899 Screening of bee hives with similar MRJP3 protein expression was performed, and each control group and experimental group contained two beehives to be tested. On the first day, the honey originally contained in the beehive was removed by shaking, and the bee «pb we/AT'ero) was twitched twice in the next two days (control group: ordinary sugar water; experimental group: Special sugar water). The aforementioned special sugar water system is obtained by diluting the formulated sugar powder by water 1 time. On the third day, 1.5-day-old bee princes (from the same queen bee generation) were transferred to the beehive and fed once (control group: normal sugar water; experimental group: special sugar water). After 24, 48, and 72 hours, 20 bee princes and royal jelly in the nest of 20 bee princes were collected for quantitative, qualitative, and proteosome analysis. In qualitative analysis, the royal jelly is extracted at a weight ratio of royal jelly to sterilized water of 1:10, and the protein of the aqueous layer is taken, by Bradford dye-binding method (Bio-Rad protein assay, Bio- Rad laboratories Inc.) determines the protein content. Protein samples were quantified using Elisa Reader (Bio-TEK) at an absorbance of 595 nm and 10 pg of protein was used to separate different molecular weights using a 12.5% SDS-PAGE gel (60 volts, 30 minutes, and 120 volts, 2 hours). Protein. Next, Coomassie blue staining (Coomassie Brilliant Blue R, Sigma, B0630) was performed, and after 15 minutes, the de-staining buffer (sterol: acetic acid: ddH2O=20:7:73) was used for defection. The colloidal background is transparent. The larvae were washed with lx PBS, the residual royal jelly on the body surface was removed, and the worm body was ground. After grinding, an appropriate amount of sterilized water is added for protein extraction. The protein in the aqueous layer fraction was subjected to protein quantification as described above, and 10 pg of protein was taken, and the separation was performed using a 12.5% SDS-PAGE gel (60 volts, 30 141899.doc • 40·201103899 minutes and 120 volts, 2 hours). Molecular weight protein. After staining with Coomassie blue for 15 minutes, the staining was carried out using a de-staining buffer (sterol: acetic acid: ddH2O = 20:7:73) until the colloidal background was transparent. In terms of quantitative analysis, royal jelly and bee princes in the beehives of the control and experimental groups were collected at different time points (24, 48 or 72 hours). The queen bee or the bee prince is weighed and the bee prince is photographed for analysis and comparison. For proteomic analysis and protein identification, the suspension of royal jelly or bee prince supernatant was vacuum dried using a rotary vacuum concentrator (Speed Vac) and reconstituted with rehydration buffer. The protein content was determined by Brabford staining-binding method, followed by 10 pg of royal jelly and 1 〇〇pg of bee prince for two-dimensional electrophoresis (2-DE) analysis; the steps used were as follows: The sample was separated by isoelectric focusing (IEF) at a pH of 3 to 10, and after equilibration, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS) was used. -PAGE) (Stacking gel: 30% acrylamide (Bio-Rad), Tris pH 6.8, 10% APS, ddH20, 1% SDS; TEMED; separating gel: 30% propylene Sample separation was carried out with Bio-Rad, Tris pH 8.8, 10% APS, ddH20, 1% SDS; TEMED). The gel was imaged and analyzed with Image Master 2D Platinum 6.0 software. The color point to be measured is selected, and the in-gel trypsin digestion is performed, and mass spectrometry is performed by LC-ESI-Q-TOFMS/MS, and the result is compared with the database by Mascot software, and Protein identity identification. Example 3: Effect of Taiwan green propolis extract on the growth of induced bee prince 141899.doc -41 · 201103899 Taiwan green propolis ethanol extract contains γ 蜂 propolis, named propolis AJ, among which propolis C, D, F And G is the main type. The bee colony was fed three times per kilogram of sugar containing 1.25, 2.5 or 5.0 grams of Taiwan green propolis extract, and collected by the bee prince and the worker bee at 24, 48 and 72 hours after being transferred to the 1.5 day old bee prince. Production of royal jelly for analysis. As shown in Table 1 and Figure 1, Taiwan green propolis extract from 1.25 to 5.0 g/kg significantly promoted the growth of the bee prince. During the 24-48 hour period, the control group's queen bee was increased from 4.73 mg to 12.26 mg, which is an increase of about 1.59 times. Among the groups treated with high dose (5g/kg) Taiwan green propolis extract, the queen bee was increased from 6.78 mg to 26.72 mg, which is about 2.94 times the weight increase. During the 48-72 hour period, the bee prince of the control group increased from 12.26 mg to 31.70 mg, and the weight increased by about 1.58 times. Among the groups treated with high dose (5g/kg) Taiwan green propolis extract, the bee prince increased from 26.72 mg to 107.55 mg, and the weight increased by about 3.03 times. Table 1: Special royal jelly secreted by young worker bees fed with Taiwan green propolis extract can promote the rapid growth of bee princes. The weight of each bee prince (mg) Collection time group 24h 48h 72h Control group (U- 1 and 2) 4.73±0.54 12.26±0.74 31.70±11.08 Taiwan Green Propolis Extract - Low Dose Group (A-1 and 2) (1.25 g/kg) 5.05±2.19 12.43±3.52 60.71 ±6.56 Taiwan Green Propolis Extract - Medium dose group (B-1 and 2) (2.5 g/kg) 6.86 ± 1.14 11.77 ± 0.97 51.16 ± 11.61 Taiwan green propolis extract - high dose group (C-1 and 2) (5.0 g / kg) 6.78 ± 1.37 26.72士4_29 107_55士士3_47 141899.doc -42· 201103899 The above data shows that the bee colony can be produced by the honey bee extract containing Taiwan green propolis extract, and the special bee king milk can be used to promote the bee prince. Growing. Further analysis was performed on the aforementioned special royal jelly to determine whether the amount and quality were different from normal royal jelly. The results showed that the yield of the special royal jelly (from the treated group) was not significantly different from that of the normal royal jelly (from the control group) (see Table 2). This means that the young worker bees can indeed provide enough royal jelly for the bee king to eat, and the supply size is adjusted according to the size and consumption of the bee prince. Table 2: Taiwan green propolis extract did not significantly affect the amount of royal jelly produced by young worker bees (g/20 wells) Collection time group 24h 48h 72h Control group (U-1 and 2) 3_375±0·7 9.19±1.1 11.96 ±0.83 Taiwan Green Propolis Extract - Low Dose Group (A-1 and 2) (1.25 g/kg) 3.03±0·58 8_30±0.81 12.1±1.0 Taiwan Green Propolis Extract - Medium Dose Group (B-1 and 2 (2.5 g/kg) 2.04±0.50 6·50±0·69 10.21±1.08 Taiwan Green Propolis Extract - High dose group (C-1 and 2) (5.0 g/kg) 3.09±0.59 8.76±1.21 13.12± 2.38 There was no significant difference between the water-soluble protein content of normal royal jelly and special royal jelly (see Table 3). The results showed that the Taiwan green propolis extract only affected the ratio between the expressions of the various types of MRJP3 proteins, but did not induce the formation of new proteins; in other words, the total protein content did not change. 141899.doc -43- 201103899 Table 3: Taiwan green propolis extract did not significantly affect the content of water-soluble protein in the royal jelly produced by young worker bees mg water-soluble protein / g queen milk collection time group 24h 48h 72h control group (U -1 and 2) 48.94±0.29 38.37±0.29 41.02±9.20 Taiwan green propolis extract-low dose group (A-1 and 2) (1.25 g/kg) 44.47±4.89 29.43±6.04 32.68±1.44 Taiwan green propolis extract - medium dose group (B-1 and 2) (2.5 g/kg) 46.91 ± 3.16 38.78 ± 5.46 34.51 ± 2.30 Taiwan green propolis extract - high dose group (C-1 and 2) (5.0 g / kg) 37.76 ± 16.10 33.70±0.57 36.34±2.59 The experimental results also found that the consumption of special royal jelly not only induces the rapid growth of the bee prince, but also enhances the protein content of these bee princes (see Table 4); The weight of the prince with the bee increases by an approximation. Table 4: Taiwan green propolis extract can increase the protein content of the bee prince. μ g total protein / bee prince collection time group 24h 48h 72h control group (U-1 and 2) 60.9±24.89 383.35±39.24 1595.05±349.24 Taiwan Green Propolis Extract - Low Dose Group (A-1 and 2) (1.25 g^g) 80_4 ± 14.85 557.7 ± 268.42 1397.55 ± 122.26 Taiwan Green Propolis Extract - Medium Dose Group (B-1 and 2) (2-5 165.25±9.12 639.5士61.09 2922.2±776.97 Taiwan green propolis extract-high dose group (C-1 and 2) (5.0 g/kg) 193.95±48.01 1393.2±30.55 4679.05士436.50 Example 4: Propolis C on induced bee prince The effect of growth Propolis C is the main component of Taiwan green propolis, which is the highest in all propolis products 141899.doc -44- 201103899. By performing the above experimental method, the propolis C is dosed at 50-100 mg/kg. Treatment can significantly change the protein composition of the royal jelly secreted by young worker bees, causing the rapid growth of bee princes (see Table 5 and Figure 2). From this result, propolis C may need to increase the dose to 300 mg/kg. Only then can the driving multiple increase the growth ability of the bee prince. According to the results, during the 48-72 hour period, the control group increased from 13.45 per bee prince to 61.60 mg, an increase of 3.58 times, while the high-dose propolis C (100 mg/kg) group increased from 13.48 to 98.48 mg. Increased by 6.30 times. Table 5: Propolis C affects young worker bees to secrete special royal jelly to cause rapid growth of bees. Average weight per bee prince (mg) Collection time group 24h 48h 72h Control group (U2) 3.52 13.45 61.60 Propolis C (C2-1) (50 mg/kg) 2.40 15.2 70.17 Propolis C (C2-2) (100 mg/kg) 2.38 13.48 98.48 Example 5: Propolis D, F and G on MRJP3 protein expression and growth of bee princes The effects of propolis D, F and G are also the main components of Taiwan green propolis activity. In this study, the bee colony was fed three times with 150, 300 or 600 mg of propolis G per kg of sugar, and moved in separately. At 24, 48 and 72 hours after the 1.5-day-old bee prince, the bee prince and the royal jelly produced by the worker bee were collected for analysis. As shown in Fig. 3, the composition and generality of the water-soluble protein MRJP3 (experimental group) of royal jelly There was a significant change in royal jelly (control group). At 72 hours, the control group had a ratio of molecular weight of 68 kDa to 64 kDa of MRJP3 of 2:8; however, at 141899.doc -45·201103899 dose (300 mg/kg) of propolis G group, molecular weight of 68 and 64 kDa The MRJP3 ratio is 6.5:3.5. Obviously, the performance of MRJP3's 68 kDa is significantly increased, and the performance of 64 kDa is significantly reduced. This special composition of royal jelly significantly provided a better nutritional composition, resulting in rapid growth of the bee prince. During the 24-48 hour period, the control group increased from 5.23 mg to 1.57 mg per bee, which was increased by 1.60 times. High dose (5g/kg) Taiwan green propolis extract group was positive control group, increased from 5.53 to 30.27 mg, an increase of 4.47 times; while propolis G (300 mg/kg) group increased from 3.93 mg to 23.80 mg , about 5.05 times more. During the 48-72 hour period, the control group increased from 13.57 to 30.07 mg per bee prince, an increase of 1.22 times. The high dose (5g/kg) Taiwan green propolis extract group increased from 30.27 to 103.30 mg, an increase of 2.41 times, while the propolis G (300 mg/kg) group increased from 23.80 to 161.73 mg, an increase of 5.79 times. (Table 6). Propolins D and F also have similar effects, but the activity is weaker than PropolinG. Table 6: Propolis G affects young worker bees to secrete special royal jelly to cause rapid growth of bees. Average weight per bee prince (mg) Collection time group 24h 48h 72h Control group (U1) 5.23 13.57 30.07 Taiwan green propolis extract low dose group (T1) (5 g/kg) 5.53 30.27 103.30 Propolin G (Gl-l) (150 mg/kg) 5.73 54.2 156.63 Propolin G (G2-1) (300 mg/kg) 3.93 23.80 161.73 Propolin G (G3-1 ) (600 mg/kg) 2.70 13.67 85.67 141899.doc -46- 201103899 The above data suggests that special royal jelly has a better nutritional composition 'and therefore induces the rapid growth of bee princes.' Propolis D and F also have similar effects. , but the activity is weaker than propolis G. Example 6: HDAC inhibitor NBM-HD-1G on MRJP3 protein expression and bee. Effect of prince growth NBM-HD-1 is derived from one of the main components of Taiwan green propolis: propolis G synthesis derived and known as NBM-HD -1 is a novel HDAC (histone deacetylase) inhibitor. By performing the experimental method as described above, it was found that the treatment of NBM-HD-1 at a dose of 50 to 200 mg/kg significantly promoted the change in the protein composition ratio of the royal jelly secreted by young worker bees, of which 72 hours was used as an example, and the control group was The ratio of molecular weight 68 kDa to 64 kDa MRJP3 is 4:6. However, at the high dose (5 g/kg) Taiwan green propolis extract group was a positive control group, the ratio of molecular weight 68 kDa to 64 kDa MRJP3 was 7:3, while the NBM-HD-1 (200 mg/kg) group was The MRJP3 ratio of molecular weight 68 to 64 kDa is 9:1. As shown in Table 7, the NBM-HD-1 treatment induced the rapid recovery of the bee prince. Table 7: Painting Association riding 4 points _ scale king milk money prince growth fast average weight per bee prince (mg) ------------- Group 24h ^ ~ collection time ^ 1 Group 2.2^ 48h 72h (U1) 7.8 19.3 Taiwan green propolis extract low dose group (T1) (5 g/kg) 2.8 ^^ 12.7 51.9 NBM-HD-1 4.57^~ (Hl-1) (50 mg/kg 18.0 37.4 NBM-HD-1 3.5', (H2-1) (100 mg/kg) 14.3 79.9 NBM-HD-1 — (H3-1) (200 mg/kg) 17.8 82.6 —---- 141899. Doc •47- 201103899 The above data suggest that changes in the protein ratio between the different MRJP3 proteins will result in a significant increase in body weight of the bee prince.分析 Analysis of the water-soluble proteins of the bee princes in the control group and the experimental group. 'Analysis of one-dimensional electrophoresis and 咼 咼 显示 显示 显示 显示 显示 NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB NB And the amount of protein of 3, which is most obvious with MRJP3 (see Figure 5). Example 7: Effect of HDAC inhibitor SAHA on MRJP3 protein expression and growth of bee princes SAHA is a potent HDAC inhibitor, which can significantly promote the secretion of young worker bees when the virtual search is at 5-15 mg/kg. The change in the composition ratio of the protein of the π bovine soil. Taking 72 hours as an example, the ratio of MRJP3 in the control group at 68 kDa and 64 kDa was 2:8; however, at high dose (5 g/k phantom green propolis extract group and propolis G (150) Mg/kg) is a positive control, the ratio of ZK 68 kDa to 64 kDa MRJP3 is 5.5.4 sr. • and 8:2. However, the 15 mg/kg SAHA treatment group has a molecular weight of 68 ga and 64 The ratio of uncomfortable milk is 4:6 (see Figure 6). This special royal jelly provides a significant increase in body weight compared to the bee prince, as shown in Table 8. S, = Table 8: SAHA affects young worker bees to secrete special royal jelly Caused the rapid growth of bees. Average weight per bee prince (mg) Group control group (U1) Taiwan green propolis extract low dose group (T1) (5 g/kg) Propolin G (Gl) (150 mg/kg) SAHA ( Sl-1) (5 mg/kg)

4.0 41.2 72h 38.4 194.7 178.6 149.3 149.2 SAHA (S2-1) (15 mg/kg) 141899.doc -48- 201103899 Example 8: Cultivation of special queens Experimental study of young worker bees with Taiwan green propolis extract The development and metamorphosis of the special queen bee feeding the bee prince. As mentioned earlier, the green bay propolis extract treatment group significantly promoted the growth of bee princes. Found food; Taiwan propolis extract group (4) · G g / kg Taiwan green propolis extract treatment), apparently in the larval stage, lameness; 隹絵 ^ x 2, promote the birth of the bee prince I; and continue to observe into the worm period On days 4 to 8, the bee sting was significantly larger than the control group (see Fig. (10)). The measurement of "body and weight of the cockroach" found that on the third day of the larval stage, the body weight of the propolis extract group in the experimental group was (10)% heavier than that of the control group (see Fig. 9(b)). The day's 196.0 mg dropped to 136 1〇mg (the weight of each bee sting) on day 8 'about 30%. Taiwan propolis extract group, from the 4th = 271.30 mg to the 8th day of the 244.53 Mg (weight of each bee sting) decreased by about 9_8/ (see Figure 9(c)). However, the bee stings fed the Taiwan propolis extract group consumed less energy during the kg process. On the first day of the cosmic period, we also found that the bee worms fed the propolis extract group in Taiwan increased about 80% of the weight of the control group, which is about the difference of the weight difference from the larval stage. 9. The biological function of the special royal jelly of the present invention is directed to the anticancer function and the differentiation of brain neural stem cells secreted by young worker bees fed the green propolis extract of Taiwan. In the anti-cancer study, Hs683 cells (human gii〇ma cells) ) purchased from the Food Industry Development Research Institute (Taiwan 'Hsinchu) and cultivated in RPMI 164〇 (Gibco), including 2 mM glutamic acid and oi mM NEAA, 100 mg/L sodium pyruvate, 10% FBS and 1% diluted penicillin and streptomycin, maintained at 37 (&gt;c, 141899.doc • 49·201103899 95% The atmosphere of humidity and 5% C02. Cells (3x105 per plate) were grown in 6-well culture dishes overnight. The cells were then transferred to serum-deficient medium and water-soluble queen milk protein at different concentrations (15 and 45 pg/mL). Treatment. It was found that treatment with 45 pg/mL of royal milk protein for 48 hours significantly inhibited the growth of Hs683 cells in the B1 and C1 groups (see Figure 7). In differentiation studies, brain neural stem cells were cultured in B27 (Gibco)-containing cells. Neurobasic medium (Gibco). Neurospheres were treated with 10 pg/mL of water-soluble royal jelly protein. EGF (5 ng/mL) was used as a positive control group. As shown in Figure 8, at 10 pg/mL After treatment with royal milk protein for 72 hours, in the B 1 and C1 groups, neural stem cells were induced to differentiate into neuronal cells, glial cells and oligodendrocytes. The above data suggest that HDAC inhibitors can affect the pharyngeal glands and large parotid glands of young worker bees. Chromatin recombination, thus changing the 68 kDa and 64 kDa MRJP3 eggs White performance, but does not alter the performance of other MRJP proteins. Changes in the ratio of the 68 kDa and 64 kDa MRJP proteins can be identified in each of the enlarged bee princes, and the transformation tends to be 68 kDa or 64 kDa MRJP homologous Isoform. Selective cleavage of polymorphic MRJP3 can be affected by HDAC inhibitors, which result in altered expression of 68 kDa and 64 kDa homologues. The regulation of the expression of two homologous isomers determines the growth of the bee prince. References [Simple description of the diagram] Figure 1 shows that young worker bees fed by Taiwan green propolis extract secrete special royal jelly, which induces rapid growth of larvae. U-1 and U-2: control group; A-1 and A-2: treated by 1.25 g/kg of Taiwan green propolis extract; 141899.doc -50- 201103899 Β-l and B-2: via 2.5 0 g/kg of Taiwan green propolis extract processor; C-1 and C-2: treated with 5.0 g/kg of Taiwan green propolis extract. Figure 2 shows that young worker bees fed with propolis C secrete special royal jelly, which induces rapid growth of larvae. U-2: control group; C1-2: treated with 50 mg/kg propolis C; C2-2: treated with 100 mg/kg propolis C. Figure 3 shows the composition of the water-soluble protein identified in the royal jelly secreted by young worker bees fed with propolis G. These samples are collected at different time points. U-1: control group; T-1: positive control group treated with 5.0 g/kg Taiwan green propolis extract; G1-1: treated with 150 mg/kg propolis G; G2-1: 3 000 mg /kg propolis G treatment; G3-1: treated with 600 mg/kg propolis G. Figure 4 shows the composition of the water-soluble protein identified in the royal jelly secreted by young worker bees fed with NBM-HD-1. These samples are collected at different time points. U-1: control group; T-1: positive control group treated with 5.0 g/kg Taiwan green propolis extract; m-1: treated with 50 mg/kg NBM-HD-1; H2-1: 100 Mg/kg NBM-HD-1 processor; H3-1: treated with 200 mg/kg NBM-HD-1. Fig. 5 shows the results of two-dimensional gel electrophoresis analysis for the purpose of analyzing the water-soluble protein extracted from the larvae of the group treated with NBM-HD-1 at 72 hours. L-l : MRJP1 ; L-2 : MRJP3 ; L-3 : MRJP2 ; L-4 : MRJP2 ; L-5 : MRJP3 ; L-6 : MRJP3 ; L-7 : MRJP3 ; L-8 : MRJP2. U1-1: control group; H3-1: treated with 200 mg/kg NBM-HD-1. Figure 6 shows the composition of the water-soluble protein identified in the royal jelly secreted by SAHA-fed young worker bees 141899.doc -51 - 201103899. These samples were collected at the 72 hour time point. U-1: control group; T-1: positive control group treated with 5.0 g/kg Taiwan green propolis extract; G-1: positive control group treated with 150 mg/kg propolis G; S1-1: 5 mg/kg SAHA treatment; S2-1: treated with 15 mg/kg SAHA. Figure 7 shows that Taiwan green propolis extract induces young worker bee to secrete special. Royal jelly, which inhibits the proliferation of human glioma Hs683 cells. U1: control group; A1: treated with 1.25 g/kg Taiwan green propolis extract; B1: treated with 2.5 g/kg Taiwan green propolis extract; C1: treated with 5.0 g/kg Taiwan green propolis extract . Figure 8 shows that Taiwan green propolis extract induces young worker bees to secrete special royal jelly, which can induce differentiation of mouse neural stem cells. U1: control group; A1: treated with 1.25 g/kg Taiwan green propolis extract; B1: treated with 2.50 g/kg Taiwan green propolis extract; C1: treated with 5.0 g/kg Taiwan green propolis extract; EGF: Positive control. Figures 9(a) to (c) show that Taiwan green propolis extract induces young worker bees to secrete special royal jelly, which promotes the growth and development of queen bee larvae. U: control group; T: treated with 5.0 g/kg Taiwan green propolis extract. References 1. Hellner M, Winter D, von Georgi R, Miinstedt K. Apitherapy: usage and experience in german beekeepers. Evid Based Complement Altemat Med. 2008;5(4):475-9. 2. Winston M L. The Biology of the Honeybee. Harvard University Press: Cambridge, MA, 1987. 141899.doc -52- 201103899 3. Robinson G E. In Neurobiology and Behavior of Honeybee; Menzel R, Mercer R, Eds.; Springer-Verlag: New Yorl, 1987; pp 266-279 ° 4. Peiren N, Vanrobaeys F , de Graaf DC, Devreese B, Van Beeumen J, Jacobs FJ. The protein composition of honeybee venom reconsidered by a , proteomic approach· Biochim Biophys Acta· 2005; 1752(1): 1-5. 5. Takaki-Doi S, Hashimoto K, Yamamura M, Kamei C. Antihypertensive activities of royal jelly protein hydrolysate and its fractions in spontaneously hypertensive rats. Acta Med Okayama. 2009;63(1):57-64 ° 6. Mannoor MK , Shimabukuro I, Tsukamotoa M, Watanabe H, Yamaguchi K, Sato Y. Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB x NZWFI mice. Lupus. 2009; 18( 1):44-52 o 7. Gasic S, Vucevic D , Vasilijic S, Antunovic M, Chinou I, Colic M. Evaluation of the immunomodulatory activities of royal jelly components in vitro. Immunopharmacol Immunotoxicol. 2007;29(3-4):521-36 ° 8. Vucevic D, Melliou E, Vasilijic S, Gasic S, Ivanovski P, Chinou I, Colic M. Fatty acids isolated from royal jelly modulate dendritic cell-mediated immune response in vitro. Int Immunopharmacol. 2007;7(9): 1211-20. 9. Boukraa L. Additive activity of royal jelly and honey against Pseudomonas aeruginosa. Altem Med Rev. 2008; 13(4): 330-3 ° 10. Hashimoto M, Kanda M, Ikeno K, Hayashi Y, Nakamura T, Ogawa Y , Fukumitsu H, Nomoto H, Furukawa S. Oral administration of royal jelly facilitats mRNA expression of glial cell line-derived neurotrophic factor and neurofilament H in the hippocampus of the adult mouse brain. Biosci 14J899.doc -53- 201103899

Biotechnol Biochem. 2005;69(4):800-5. 11. Guo H, Ekusa A, Iwai K, Yonekura M, Takahata Y, Morimatsu F. Royal chloride peptides inhibit lipid peroxidation in vitro and in vivo. J Nutr Sci Vitaminol (Tokyo). 2008;54(3):191-5 . 12. Scarselli R, Donadio E, Giuffrida MG, Fortunato D, Conti A, Balestreri Ε» Felicioli R, Pinzauti M, Sabatini AQ Felicioli A. Towards royal jelly proteome. Proteomics· 2005;5(3):769-76 o 13 Schmitzova J, Klaudiny J, Albert S, Schroder W, Schreckengost W, Hanes J, Jiidova J, Simuth J. A family of major royal jelly proteins of the honeybee Apis mellifera L. Cell Mol Life Sci. 1998;54(9): 1020-30 ° 14. Kohno K, Okamoto I, Sano O, Arai N, Iwaki K, Ikeda M, Kurimoto M. Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages. Biosci Biotechnol Biochem. 2004;68(1): 138-45. 15. Malecova B, Ramser J, O'Brien JK, Janitz M, Jiidova J, Lehrach H, Simiith J. Honeybee (Apis mellifera L.) mrjp gene family: computational analysis of putative promoters and genomic structure of mrjpl, the gene coding Gene. 2003 ;303:165-75 〇16. Furusawa T, Rakwal R, Nam HW, Shibato J, Agrawal GK, Kim YS, Ogawa Y, Yoshida Y, Kouzuma Y, Masuo Y Yonekura M. Comprehensive royal jelly (RJ) proteomics using one- and two-dimensional proteomics platforms reveals novel RJ proteins and potential phospho/glycoproteins. J Proteome Res. 2008;7(8):3194-229. 17. Djupedal I, Ekwall K. Epigenetics: heterochromatin meets RNAi. Cell 141899.doc • 54· 201103899

Res. 2009;19(3): 282-95. 18. Selvi RB, Kundu TK. Reversible acetylation of chromatin: implication in regulation of gene expression, disease and therapeutics. Biotechnol J. 2009;4(3):375-90 » 19. Fiskus W, Buckley K} Rao R, Mandawat A, Yang Y, Joshi R, Wang Y, Balusu R, Chen J, Koul S, Joshi A, Upadhyay S, Atadja P, Bhalla KN. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss Of survival of human acute leukemia cells. Cancer Biol Ther. 2009;8(10). 20. Foumel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, Liu J, Lu AH, Zhou NZ, Robert MF, Gillespie J, Wang JJ, Ste-Croix H, Rahil J, Lefebvre S , Moradei O, Delorme D, Macleod AR, Besterman JM, Li Z. MG.CD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008;7(4) : 759-68. 21. Charrier C, Roche J, Gesson JP, Bertrand P. Antiproliferative activities of a library of hybrids between indanones and HD AC inhibitor SAHA and MS-275 analogues. Bioorg Med Chem Lett. 2007; 17(22): 6142-6. 22. Spurling CC, Godman CA, Noonan EJ, Rasmussen TP, Rosenberg DW, Giardina C. HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol Carcinog. 2008;47(2): 137-47. 23. Shankar S, Srivastava RK. Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. Adv Exp Med Biol. 2008;615:261-98. Is 141899.doc -55- 201103899 24. Wu LP, Wang X, Li L, Zhao Y, Lu S, Yu Y, Zhou W, Liu X, Yang J, Zheng Z, Zhang H, Feng J, Yang Y, Wang H, Zhu WG Histone deacetylase inhibitor depsipeptide activates silenced genes through reducing both CpG and H3K9 methylation on the promoter. Mol Cell Biol. 2008;28(10):3219-35. 25. Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res. 2004;64(3): 1079-86. 26. Tost J. DNA methylation: an introduction to the biology and the disease-associated changes of a promising biomarker. Methods Mol Biol. 2009;507:3-20. 27. Ghoshal K, Bai S. DNA methyltransferases as targets for cancer therapy. Drugs Today (Bare). 2007;43(6):395-422 e 28. Janet S. Graham, Stanley B. Kaye, Robert Brown. The promises And pitfalls of epigenetic therapies in solid tumours. European Journal of Cancers 45 (2009) 1129-1136. 29. TJ Walton, G. Li, R. Seth, SE McArdle, MC Bishop, and RC Rees. DNA Demthylation and Histone Deacetylation Inhibition Co-Operate to Re-Express Estrogen Recetpor Beta and Induce Apoptosis in Prostate Cancer Cell-Lines. The Prostate 68:210-222 (2008). 30. Julie C. Kiefer. Epigenetics in Development. Developmental Dynamics 236:1144-1156, 2007. 31. Ahmad Miremadi, Mikkel Z. Oestergaard, Paul DP Pharoah, and Carlos

Caldas. Cancer genetics of epigenetic genes. Human Molecular Genetics, 2007, vol. 16, Review Issue 1, R28-R49. 141899.doc -56-

Claims (1)

201103899 VII. Scope of Application: ^ A method of cultivating a larvae of larvae that is at least twice as large (100%) compared to the control larvae; the method comprises feeding a mixture of HDAC inhibitors or several HDAC inhibitors Feeding young worker bees and feeding the bee larvae with the royal jelly secreted by the young worker bees; one of the larvae of the control group was eaten by a mixture of untreated silver HDAC inhibitors or several HDAC inhibitors. The young worker bee secreted. 2. If the request item „ ^ &lt; 万法, the weight of the larvae after feeding the royal jelly for 72 hours is more than 1.5 times. 3 · For example, the method of clearing the item 1 d d 曰,, 丄 ,, After 72 hours, the larvae increased by about 2 to 5 times. 4. If the method of item 1 is cut, the amount of the royal jelly is increased by about 3 to 5 times after 72 hours. 5. The method of claim 1 The ratio of 68 kE to 64 kDa in the milk 3 protein in milk was changed. 6· ^ Method 5 of the method] The ratio of 68 kE and 4 ^ of the tender protein in the royal jelly was increased by about 1.5 to 12 relative to the control group. Multiply-fold, 2 to 6-fold, 2 to 1-fold, 4 to 12-fold or 2 to 4-fold. The method of the method of 1, wherein the TM^ inhibitor is selected from the following formula (1 1:: :: a group or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of a compound of the following formula (11) (4) dissolved; = an acceptable salt, a stereoisomer , mirror image isomers, prodrugs and sputum. 'SAHA, propolis and bee succulent group, I41899.doc 201103899 Each of the scales 1 and 112 is independently OH, 〇c(=〇)alkyl, 〇-alkyl, s-alkyl, N-institutional, fluorenyl-alkenyl, S-alkenyl, N-alkenyl, fluorene- Alkynyl, S-alkynyl, N_fastyl' 〇_C3-8 cycloalkyl, S-C3.8 cycloalkyl, N-C3-8 cycloalkyl, 〇-unsaturated 5- to 10-member Monocyclic or bicyclic, s_unsaturated 5_ to 1〇_membered monocyclic or bicyclic, N-unsaturated 5_ to 1〇_membered monocyclic or bicyclic, alkyl, alkenyl, fast-radical, CM cycloalkyl , unsaturated 5_ to ι〇_ member monocyclic or bicyclic or containing at least one hetero atom selected from the group consisting of: N, 〇 and s saturated or unsaturated 5- to 10-membered heterocyclic ring; or Forming dioxane together; R3 and R4 are each independently 〇H, 〇c(=〇)alkyl, 〇-alkyl, s-alkyl, N-alkyl, 0-alkenyl, s-alkenyl, N-alkenyl, decynyl, synyl, N-fast, 0-C3_8 cyclohexyl, S_C3 8 cycloalkyl, n_C3 8 cycloalkyl, 0-unsaturated 5· to 10-membered single ring Or bicyclic, s_unsaturated 5 to ι 单 member monocyclic or bicyclic, N-unsaturated 5 _ to 1 〇-membered monocyclic or bicyclic, alkyl, alkenyl, alkynyl, C3·8 ring dazzle &gt; , unsaturated 5_ to 1〇_member single or double ring or included to One less heteroatom selected from the group consisting of N, hydrazine and s saturated or unsaturated 5- to 10-membered heterocyclic ring; Rs is C^6 alkyl or C:4·!6 alkenyl, wherein alkyl Or an alkenyl group which is unsubstituted or substituted by one or more Cr6 alkyl hydrazines, halogens, CN, NO, N, 141899.doc 201103899 NH2, CHO, or9, SR9, NR9 or COOR9; R_6 is C2_12 alkyl Or a C2_1S alkenyl group wherein the alkyl or alkenyl group is unsubstituted or substituted with one or more Ci-6 alkyl, OH, halogen, CN, NO, N3, NH2, CHO, OR9, SR9 or NR9; or R54R6 One is hydrogen 'iS or 〇H, the other is C4_16 alkyl or C4_16 alkyl, unsubstituted or substituted by one or more Ck alkyl 'OH, NH2, halogen, CN, NO or N3; R7 Or Rs each independently hydrogen, halogen, OH, NH2, COOH, CHO, CN, NO, unsubstituted or substituted by H, NH2, COOH, halogen, CN, NO or CHO Ci 6 alkyl, = 〇, 〇-alkyl, s_alkyl, N-alkyl, 〇-alkenyl, s-alkenyl, N-alkenyl, 〇-alkynyl, s-alkynyl or N-alkynyl; or R7 and Rs a double bond, a C3 6 cycloalkyl group or a heterogeneous group comprising at least one selected from the group consisting of Sub: N, 〇 and S saturated or unsaturated 5_ to 1 〇 _ member heterocyclic ring; R9 is phenyl, C (=0) R10, R 丨 0 is OH, NHOH, bribe C (= 〇) 〇 R1Q Or benzyl; and !, alkyl, phenyl or benzyl; 141899.doc 201103899 A member or a 6-membered unsaturated h is hydrogen, alkyl, alkenyl, Cs 6 cycloalkyl, carbocyclic or 5- or 6-membered heterocyclic ring; X is C, hydrazine, N or s; Y is an anthracene, NH or O-Cw alkyl group; η is an integer from 0 to 10; m is an integer from 0 to 5; r2 and r3 are each a Ci 6 alkyl group; R4 is a C5_6 cycloalkyl group or a 5 member or 6婉A winter shell unsaturated rock annoyed or heterocyclic ring, which can be, the working halogen 'CF3, 〇R7 or nr7r8 is simple, or C, _6 alkyl; the generation, center and heart are each hydrogen or heterocyclic, of which 哕Produce p. Beck or 6_ berylic acid ring NH nucleus, &amp; ring and heterocyclic ring can be seen by dentin, CF3; and 丨.6 alkylene, 〇R7, nr7r8 or 6 is H Ci-l An alkyl group which may be substituted by 戎ρ X y., gonghong or C2-10 alkenyl, or -C2H2-. 8· If the request item 1 $古,,土, 习,,八中, the HDAC inhibitor is Taiwan green propolis, = gelatin A, propolis B, bee shengsin c' bee succulent bee sinus e, bee wins F, propolis G, propolis quinone, beein I, propolis J, SAHA or NBM-HEM 〇 9. As claimed in claim 1, the method of HDAC is selected from the following groups: I41899.doc 201103899 Och3 141899.doc 201103899 OMe OMe OMe 141899.doc 201103899 141899.doc 201103899 OMe 141899.doc 201103899 CHi CH OCH, OCH3 CH, CHi OCH, OCH3 141899.doc 201103899 CH. CH. OCHa 〇CH3 CH, CH, OH propolis A OH Propolis B •10- 141899.doc 201103899 η〇Ύ^/0, ch3 propolis c CH 3 OH O CH, CH, OH OH propolis D 141899.doc -11 - 201103899 Propolis E OH Propolis F Propolis G 12- 141899.doc 201103899 Propolis Η OH Propolis I Propolis J 141899.doc ·13- 201103899 NBM-HB-OSOl 141899.doc 14- 201103899 HO , 'NH -n NBM-C-BX-OSOl 141899.doc 15- 201103899 141899.doc HO NH NBM-C-BCX-OSOl HO N NBM-C-BMX-OSOl HO : NH n-n NBM-C-BFX-OSOl 16- 201103899 HO 'nh n-r’ NBM-C-BBX-OSOl NBM-T-BX-OSOl H3CO NBM-T-BA-OSOl 141899.doc 17- 201103899 141899.doc H3co NBM-T-BMA-OSOl OII NBM-T-BCX-OSOl 18- 201103899 NBM-T-L-BCX-OSOl H3C o NH och3 NBM-T-BMX-OSOl NBM-T-K-BMX-OSOl O 141899.doc -19- 201103899 NBM-T-BTX-OSOl π NBM-T 丄-BTX-OSOl NBM-T-L-BBX-OSOl 141899.doc •20- 201103899 Ο H3co* NBM-T-BFX-OSOl 141899.doc HO V HO NH NBM-C-BFX-OSOl •21 - 201103899 NBM-I-BCX-OSOl Ο 141899.doc 22 201103899 NBM-T-I-BMX-OSOl NBM-T-L-I-BMX-OSOl NBM-T-I-BBX-OSOl NBM-T-L-I-BBX-OSOl 141899.doc -23- 201103899 ο NBM-T-I-BCX-OSOl Ο NBM-T-I-MCX-OSOl 10. The method of claim 1, wherein the bee larvae can be fed by the worker bees with the royal jelly secreted by the worker bees or by the human beings feeding the royal jelly collected from the worker bees. 11 · A method of cultivating bee stings that are at least 50% heavier than the control bee stings, or a bee king that is at least 50% heavier than the control queen, including one HDAC inhibitor or several HDAC suppresses the mixture of Fj agents 141899.doc -24- 201103899 The compound feeds the young worker bees, and feeds the larvae with the royal jelly secreted by the young worker bees, and obtains the cockroach or queen bee developed by the larvae, wherein The sputum or queen of the control group was developed from bee larvae of royal jelly secreted by young worker bees who were not fed HDAc inhibitors or several HDAC inhibitor mixtures. 12 'A method of claim U' wherein the bee larvae can be fed by a worker bee by a bee king milk or a bee king milk collected from a worker bee. 13. A method of 'species' includes HDAC inhibitors or several species. The inhibitor mixture was fed a young worker bee to produce a royal jelly with a modified ratio of 68 kDa and 64 kDa MRJP3 protein compared to the control queen bee. 14. The method of claim 13, wherein the ratio of gamma to μ kDa of MR; p3 protein f is increased by about 15 to η times, 1 to 5 times, 2 to 6 times ' 2 to 1 relative to the control group 〇 times, 4 to 12 times or 2 to 4 times. 15. The method of claim 13, wherein the prison inhibitor is selected from the group consisting of the compound of the formula (1) according to claim 7 or a pharmaceutically acceptable salt thereof, a stereoisomer, a mirror image isomer, a prodrug and a solvent. Group of compounds. 16. The method of claim 13 wherein: (4) the prison inhibitor is selected from the group consisting of the compound of the formula (11) according to the item 7, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mirror image isomer, a prodrug And groups of solvates. The method of claim 13 wherein the Cheng (four) inhibitor is Taiwan green bee ^, beexin A, propolis B, propolis c, propolis beta, propolis, propolis F, propolis G, hormone H, propolis Prime t, bee (10) BU SAHA or NBM-HD-1. 18. The method of claim </ RTI> wherein the _AC inhibitor is selected from the group consisting of the compounds described in claim 1 141899.doc -25- 201103899. 19. A royal jelly prepared by the method of claim 13, comprising a ratio of 68 kDa and 64 kDa MRJP3 protein relative to the control group of royal jelly. 20. The royal jelly of claim 19, wherein the ratio of 68 kDa to 64 kDa of MRJP3 protein in royal jelly is increased by about 1.5 to 12 times, 1.5 to 5 times, 2 to 6 times, 2 to 10 relative to the control group. Multiple, 4 to 12 times or 2 to 4 times. 21. A method for altering the ratio of 68 kDa and 64 kDa MRJP3 protein in royal jelly, comprising an HDAC inhibitor or a mixture of several HDAC inhibitors to feed young worker bees to produce 68 kDa compared to the control queen jelly And the 64 kDa MRJP3 protein ratio changed queen bee. 22. A method of regulating epigenetics of a worker bee gene comprising feeding a worker bee with a .HDAC inhibitor or a mixture of several HDAC inhibitors to control the gene expression of the worker bee. 23. The method of claim 22, wherein the epigenetic is inhibition of DNA thiolation or inhibition of HDAC activity. 141899.doc -26-