CN116458647B - Cordyceps sinensis fermentation composition - Google Patents
Cordyceps sinensis fermentation composition Download PDFInfo
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- CN116458647B CN116458647B CN202310711044.4A CN202310711044A CN116458647B CN 116458647 B CN116458647 B CN 116458647B CN 202310711044 A CN202310711044 A CN 202310711044A CN 116458647 B CN116458647 B CN 116458647B
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- ergothioneine
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Abstract
The invention provides a cordyceps sinensis fermentation composition, which contains erythritol, wherein the erythritol content is more than 1 wt percent, and the fermentation composition has excellent antioxidation and synergistic technical effects.
Description
Technical Field
The invention relates to a fermented cordyceps sinensis composition, and belongs to the field of microbial fermentation.
Background
Erythritol, i.e., erythritol, is a four-carbon polyol with the chemical name 1,2,3, 4-butaneTetraols of the formula C 4 H 10 O 4 The relative molecular mass was 122.12. As a natural sweetener, erythritol is widely found in nature, and it is naturally present in small amounts in vegetables and fruits such as pears, grapes, mushrooms, etc., and in small amounts in fermented foods such as wine, beer, soy sauce, sake, and in small amounts in animal serum, eyeball.
Erythritol has small molecular weight, strong hydrophilicity, no reducing aldehyde group and high stability to heat and acid; is easily soluble in water, has a solubility of 37% at 25deg.C, is soluble in water and absorbs heat, and gives a cool feel when taken in solid form; good crystallinity, low hygroscopicity, and no moisture absorption in an environment with a relative humidity of 90% at 20 ℃; the sweetness of the sucrose is 60% -80%, and the sweet taste is pure, clean and no bad bitter taste.
The low energy and specific metabolic pathways are one of the metabolic properties of erythritol. Erythritol has an energy coefficient of 0.88 kJ/g and is the lowest energy of the currently used polyol sweeteners. After human body ingests erythritol, about 80% -90% of erythritol is absorbed by small intestine through passive diffusion, and the rest 10% enters large intestine to ferment as carbon source. And as the dosage of erythritol intake increases, the rate of erythritol into the large intestine increases. Wherein, the erythritol absorbed by human body through small intestine is widely distributed in tissue, about 5% -10% of the erythritol is oxidized into erythrose in blood, then rapidly oxidized further to form erythrose ester, and finally discharged from urine. The remaining non-oxidized erythritol cannot be decomposed by the enzyme system in the body, and can only be filtered from blood through the kidney and discharged out of the body through urine. Erythritol entering the large intestine is fermented and converted into Short chain fatty acids (Short-chain fatty acids, SCFAs) by intestinal flora, and after being absorbed into the intestinal tract, the SCFAs can improve diet-induced metabolic disorder by the anti-inflammatory effect of the SCFAs, and have a protective effect on obesity and inflammatory intestinal diseases.
Intestinal tolerability is another property of erythritol. Compared with other sugar alcohols, the Maximum non-cathartic dosage (Maximum non-cathartic dose) of the erythritol is 0.66-1.0+g/kgbw, which is obviously higher than that of the other sugar alcohols. Research on intestinal tolerance conditions of human bodies shows that when 18-24 years old healthy volunteers ingest 20-35 g erythritol in a liquid form, the intestinal tolerance is good, and no bad symptoms exist; diarrhea and nausea were observed when erythritol intake reached 50 g. Meanwhile, clinical studies show that no diarrhea and/or severe intestinal symptoms are observed after a 4-6 year old child ingests a beverage containing 15 g erythritol. Furthermore, it should be noted that diarrhea caused by excessive intake of sugar alcohol is not a disease, but a simple osmotic reaction to slow absorption of carbohydrates in the intestinal lumen, i.e. sugar alcohol not absorbed in the small intestine may cause abdominal distension, diarrhea and flatulence due to osmotic effects. Some people develop the symptoms after eating for 1 time, and with continuous eating, most people can develop a certain tolerance to sugar alcohol, and the related gastrointestinal symptoms can be weakened or eliminated. In addition, erythritol has positive significance in oral cavity protection. Studies have shown that erythritol is not only not utilized by Streptococcus mutans in the oral cavity, but also inhibits its growth and adhesion in the oral cavity, thereby exerting a beneficial effect on the oral cavity. In a 3-year clinical trial, both acetic acid and propionic acid levels in plaque were significantly lower in subjects receiving erythritol than in subjects receiving xylitol or sorbitol.
Currently, erythritol is produced industrially mainly by microbial fermentation. In nature, many microorganisms capable of synthesizing erythritol are available, such as hypertonic yeasts such as Brevibacterium (Moniliella pollinis), trigonella, trichosporon, and yarrowia lipolytica, and bacteria such as Pediococcus, leuconostoc, and Lactobacillus. The synthetic pathways of erythritol in yeast and bacteria are different. In yeast, erythritol is synthesized by the pentose phosphate pathway, and erythrose-4-phosphate produced by the pathway is dephosphorylated to form erythrose, and then the erythrose is formed under the action of erythrose reductase; in bacteria, erythritol can be produced by the reduced coenzyme II (NADPH) regeneration loop in the phosphoketolase pathway.
Ergothioneine (EGT or ERG), a naturally rare chiral amino acid strong antioxidant first discovered in fungi Claviceps purpurea in 1909, is a water-soluble, naturally occurring thiol compound, has been recognized as an antioxidant substance in vivo and a protective factor helping cells resist oxidative stress, has various functions of resisting oxidation, scavenging free radicals, chelating metal ions, preventing ultraviolet radiation damage, regulating oxidation-reduction reactions in cells, participating in intracellular energy regulation, cytophysiological protective agents and the like, and is an important active substance in the body.
Ergothioneine is distributed in certain tissues and organs of mammals, mainly in erythrocytes and semen of certain animals, and the content of ergothioneine in human and mammalian tissues is 1-2 mM (corresponding to 229.3-458.6 mg/L) (Melville, 1959; hartman, 1990 or The Natural Antioxidant Ergothioneine, lipid Oxidation, 2013), which indicates that ergothioneine may act as a nontoxic antioxidant in vivo, and that cell deficiency of ergothioneine is easily affected by oxidative stress, resulting in increased mitochondrial DNA damage, protein Oxidation and Lipid peroxidation. However, so far, no experimental study has shown that there is an animal capable of synthesizing the substance, and there is certainly a way to absorb and retain ergothioneine in animal cells. Ergothioneine has the advantages of unique biological and pharmacological properties, safety, stability and the like, has good application prospect in the fields of cosmetics, functional foods, pharmacy, biomedicine and the like, and is widely focused by scholars at home and abroad.
Ergothioneine is mainly found in mushrooms, and the melville.d.b and eieh.s studies found that cereal plants also have ergothioneine present. Subsequent studies by melville. D.b and genghof. D.s et al show that ergothioneine is a common component of many microbial cells and can be synthesized in several fungi, but cannot be synthesized in bacteria. Since mushrooms are a rich source of antioxidants including ergothioneine, this is another reason for the incorporation of mushrooms into the human diet. To further enhance the content of ergothioneine in mushrooms, wi Yong Lee et al (Ergothioneine Contents in Fruiting Bodies and Their Enhancement in Mycelial Cultures by the Addition of Methionine, myciology, 2009 (37) 1:43-7) reported that the addition of methionine to enhance the content of ergothioneine in mushroom fruiting bodies in mycelium culture, the difference between ergothioneine mushrooms and mushrooms was up to 92.3 times, and the addition of 2 mM methionine (Met) to mycelium culture medium increased the content of ergothioneine in the tested mushroom species, indicating that methionine is a beneficial additive to mushroom production of ergothioneine.
Cordyceps militaris is also called as Cordyceps militaris, and the school name of Cordyceps militaris is: cordyceps militairs (Vuill) Fr, english name: pupa insect grass the asexual form is Verticillium (Verticillium), liang Zongqi (1990) is considered to be a Cehalosporium. Patent document WO2014/055035 discloses a cordyceps militaris strain cbs 132098 and bioactive fruit bodies, mycelium biomass and extracts thereof, of which the ergothioneis in the cordyceps militaris mycelium biomass corresponds to the fourth grade fractionation by Chen et al (Chang et al 2012) because of 130.65 mg/kg (0.013%). Bai-Xiong et al (Enhancement of ergothioneine production by discovering and regulating its metabolic pathway in Cordyceps militaris. Bai-Xiong Chen et al, microb Cell face 2022 Aug 23;21 (1): 169) constructed a novel route for ergothioneine synthesis which, by further introducing this route into the genome of Cordyceps militaris, successfully increased the component yield of the engineered strain with a maximum content of ergothioneine of up to 2.5 g/kg dry weight.
Cordyceps sinensis (Cordyceps sinensis (berkeler) sacc.) and Cordyceps militaris are two different species, and the specificity of Cordyceps sinensis hosts is very strong, and only can be parasitic to larva bodies of hepialus (Hepialus armorieanus Oberthur), and the school name of Cordyceps sinensis: cordyceps sinensis (Berk) Sacc, english name: chinese caterpillar fungus asexual name is confirmed by scholars expert as hirsutella sinensis @ Hirsutella sinensis). Hui-Chen Lo et al (A Systematic Review of the Mysterious Caterpillar Fungus Ophiocordyceps sinensis in DongChongXiaCao (Cordyceps sinensis Do ̄ ng Cho ́ ng Xia ̀ Ca ̌ o) and Related Bioactive Ingredients, journal of Traditional and Complementary Medicine 2013 (3) 1:16-32) believe that wild Cordyceps sinensis fruiting bodies contain detectable ergothioneine, wherein the ergothioneineAlthough Shin-Yu Chen et al reported that the Cordyceps sinensis mycelia contained 142.0.+ -. 38.5IJK ergothioneine, shin-Yi Lin et al (Comparative Study of Contents of Several Bioactive Components in Fruiting Bodies and Mycelia of Culinary-Medicinal Mushrooms, international Journal of Medicinal Mushrooms, 2013 (15) 3:315-323) reported that the Cordyceps sinensis (Ophiocordyceps sinensis) mycelia contained 35.70.+ -. 1.28K, the fruiting body content was lower, and 12.20.+ -. 1.51E,Nachshol Cohen et al (Chemical Composition and Nutritional and Medicinal Value of Fruit Bodies and Submerged Cultured Mycelia of Culinary-Medicinal Higher Basidiomycetes Mushrooms, international Journal of Medicinal Mushrooms, 2014 (16) 3:273-291) reported that the Cordyceps sinensis (Ophiocordyceps sinensis) mycelia contained 52.18.+ -. 2.75ug/g, there was no wild Cordyceps sinensis or natural Cordyceps sinensis or wild Cordyceps sinensis mycelia that contained higher ergothioneine as yet. Moreover, cordyceps sinensis belongs to the order of Ascomycetes, order of Hypocreaceae, order of Ophiospordypitaceae, order of Ophiospordytaceae, order of Ophiospordyceps, ophiocondyceps sinensis (technical specification for pollution-free cultivation and production of Chinese medicinal materials, 2018), the natural Cordyceps sinensis is short of medicine source and expensive, the use of the mycelium of Cordyceps sinensis as a substitute for natural Cordyceps sinensis is a trend of technical development, fungi separated from Cordyceps sinensis collected from various production places by researchers have more than 30 species, such as Paecilomyces hepiali, paecilomyces china, mortierella hepiali, cephalosporium sinensis, mortierella sinensis, curvularia sinensis, and Golgi, and the like, and in metabolome researches (Zhang Zhou, university of Anhui, 2018) of Cordyceps sinensis at different growth stages, the metabolites among different parts of Cordyceps sinensis have obvious differences, and the same part also has obvious differences at different development stages.
Therefore, the combination of Cordyceps fermentation and beneficial components thereof is still a technical problem to be solved.
Disclosure of Invention
The inventors have surprisingly found that by optimizing the process, the provided cordyceps sinensis fermentation composition contains more than 1% by weight of erythritol, preferably 1% -6% by weight, further preferably 2-5% by weight, still further preferably 2.5-4%. Moreover, it is generally considered by those skilled in the art that erythritol is only one sweetener, but the present invention unexpectedly found that the combination of erythritol and adenosine together exhibited a synergistic effect of hydroxyl radical scavenging rate, thereby enhancing the overall effect of the Cordyceps sinensis fermented composition.
According to the invention, on one hand, the cordyceps sinensis bacteria capable of producing erythritol are obtained through screening of the cordyceps sinensis bacteria, and further the fermentation composition containing the erythritol is obtained through fermentation.
Specifically, on one hand, the inventor screens hirsutella sinensis from the strains of the natural cordyceps sinensis through screening cordyceps sinensis strainsHirsutella sinensis) Has the function of producing erythritol, on the other hand, the inventor obtains fermentation mycelium or fungus powder which can exist stably and contains higher erythritol through the fermentation of hirsutella sinensis. According to the invention, erythritol with the natural cordyceps sinensis content level is obtained for the first time through liquid fermentation culture, and the wider functions of the cordyceps sinensis fermentation composition are exerted.
Hirsutella sinensis (L.) KuntzeHirsutella sinensis) The strain is Cordyceps [ cordyceps sinesis (Berk.) Sacc which is Cordyceps belonging to Clavicorniaceae and isolated from fresh Cordyceps sinensis (L.) Sacc.]The hirsutella sinensis of the invention can be any hirsutella sinensis strain, for example, can be obtained by the marketThe product can be purchased from a selling platform or obtained by autonomous screening and separation, and can be identified as hirsutella sinensis according to the identification principles of microorganism molecular genetics and the likeHirsutella sinensis) Commercial approaches include, but are not limited to, obtaining hirsutella sinensis (China center for type culture collection (CCTCC) or China general microbiological culture collection center (CGMCC)Hirsutella sinensis) For example, those obtained from China Center for Type Culture Collection (CCTCC) include, but are not limited to, hirsutella sinensis @, a Hirsutella sinensis) Cctccc No: m2011278, for example, obtained from China general microbiological culture collection center (CGMCC) including but not limited to Mortierella sinensisHirsutella sinensis) CGMCC 3.14240 and hirsutella sinensisHirsutella sinensis) CGMCC3.14243, for example, cordyceps sinensis (hirsutella hepiali Chen et Shen) purchased from China industry microbiological culture Collection center (CICC)Ophiocordyceps sinensisOr Cordyceps sinensis (hirsutella sinensis )Cordyceps sinensisStandard strains include, but are not limited to, strain number: CICC 14016, CICC 14017, CICC 14088, CICC 14089, CICC 14090, CICC 14094, CICC 14096, CICC 14091, CICC 14092, CICC 14093, CICC 14095, CICC 14097, CICC 14098, CICC 14099, CICC 14100, CICC 14101, CICC 14102, CICC 14103, CICC 14104, CICC 14105, CICC 14106, CICC 14107, CICC 14108, CICC 14109, CICC 14110, CICC 14111, CICC 14112, CICC 14113, CICC 14114, CICC 14115, CICC 14117, CICC 14118, CICC 14119, CICC 14120, CICC 50002, e.g., cordyceps sinensis (hirsutella hepiali, hirsutella sinensis) purchased from Tex living beingsOphiocordyceps sinensisOr Cordyceps sinensis (hirsutella sinensis )Cordyceps sinensisOr hirsutella sinensis Hirsutella sinensis) Including but not limited to, those of the order TS324838, TS325049, TS325054, TS326189, TS326195, TS326196, TS326197, TS326198, TS326199, TS326200, TS326201, TS326202, TS326203, TS326204, TS326205, TS326206, TS326207, TS326210, TS326212, TS326213, TS326214, TS326408, TS326410, TS326412, TS342791, TS342792, TS342793, TS342794, TS342795, TS,TS342796、TS342797、TS342798、TS342800、TS342809、TS361737、TS392986。
The growth period of hirsutella sinensis is longer than that of most fungi, and the hirsutella sinensis generally grows in an environment of 14-20 ℃ and belongs to medium-low temperature bacteria. Culturing on solid culture medium with diameter up to 1.5cm, and bacterial colony with meat color and milky white color, and with grown mycelium on the surface, the bacterial colony surface will be smooth and gully with gradually reduced aerial mycelium. Culturing in liquid culture medium, wherein mycelium is in the shape of filament or gray sphere, different in size, and brown with culture, the mycelium pellet has tough and elastic texture and is hollow. It is known that the mycelia obtained by liquid fermentation and culture of hirsutella sinensis are dried to obtain fermented Cordyceps sinensis powder, and various active substances including polysaccharide, amino acid, nucleoside substances, sterol substances, mannitol, trace metals, etc. can be obtained. Wherein the marker component is adenosine, mannitol, polysaccharide, amino acid, etc. The fermented Cordyceps powder has effects of enhancing immunity, resisting fibrosis, protecting kidney function, resisting tumor, and relieving inflammation, and can be used for protecting kidney, lung, liver, etc.
The fermentation in the invention refers to the process of carrying out slant culture, seed bottle/shake bottle culture and fermentation culture on the traditional Chinese cordyceps sinensis asexual generation strain, namely the Chinese hirsutella sinensis.
The invention relates to a slant culture method, which comprises the steps of growing hirsutella sinensis on the inclined surface of a solid culture medium, inoculating hirsutella sinensis, coating the hirsutella sinensis on the slant, and culturing for 20-60 days, preferably for 30-50 days at a low temperature, for example at a temperature of 8-18 ℃, wherein the main raw materials of the slant culture medium are glucose, potato juice (powder), corn flour, agar (powder), yeast extract (powder), wheat bran (skin), silkworm chrysalis powder, peptone, naCl and MgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof); for example, the slant medium may be (the following%Weight to volume ratio g/100 ml):
peptone 0.05-2.0%, yeast extract 0.05-2.0%, glucose 1.0-5.0%, agar 1.0-3.0%, wheat bran 2.0-10%, KH 2 PO 4 0.02～0.2%、MgSO 4 0.01 to 0.1 percent and the balance of water;
or (b)
Silkworm chrysalis meal 1.0-2.0%, corn meal 1.0-2.0%, glucose 2.0-5.0%, mgSO 4 0.01～0.1%，KH 2 PO 4 0.01 to 0.1 percent of oatmeal, 1.0 to 3.0g/60ml of agar powder, 0.5 to 1 percent of water and the balance;
or (b)
Silkworm chrysalis meal 1.8%, corn meal 1.5%, glucose 2.0%, mgSO 4 0.01%，KH 2 PO 4 0.02 percent of oatmeal 1.0-3.0 g/60ml, 0.65 percent of agar powder and the balance of water;
or (b)
Peptone 0.1%, yeast extract 0.1%, glucose 2.0%, KH 2 PO 4 0.1%、MgSO 4 0.05 percent of agar, 1.0 to 2.0 percent of wheat bran and 5.0 percent of wheat bran, adding water, boiling for 30 minutes, and sub-packaging;
or (b)
Peptone 0.5-2.0%, broad bean powder 2.0-5.0%, corn powder 1.0-4.0%, glucose 2.0-5.0%, agar 0.5-2.0%, bran 0.5-4%, KH 2 PO 4 0.01～1.0%，MgSO 4 0.01 to 1.0 percent and the balance of water;
or (b)
Glucose 2.0%, corn flour 1.0%, potato juice 0.5%, dextrin 0.5%, yeast powder 0.5%, bran 1.0%, silkworm chrysalis powder 2.0%, peptone 1.0%, mgSO 4 0.05%、KH 2 PO 4 0.05 percent of agar powder and 1.0 percent of solvent which is water;
or (b)
Silkworm chrysalis meal 2.0-3.0%, corn meal 1.5%, bran 1.0-5.0%, glucose 2.0%, agar 1.8%, KH 2 PO 4 0.02%、MgSO 4 0.01% of water and the balance of water;
it will be appreciated by those skilled in the art that the specific slant culture media listed above are merely illustrative of the invention and are not to be construed as limiting the invention, and that it may include other commonly used slant culture media for fermentation of hirsutella sinensis, or slant culture media for fermentation of hirsutella sinensis known in the art.
After inoculating the shake flask/seed flask culture strain to the seed flask from the inclined plane, carrying out shaking culture, or inoculating the test tube strain to the sterilized (sterilized) cooled triangular flask culture solution, and carrying out shaking culture on a shaking table, wherein the seed amount is 2-6 inclined planes, preferably 2-3 inclined planes, the culture temperature is 10-18 ℃, preferably 12-16 ℃, the culture time is 8-16 days, and preferably 9-14 days. In mass production, mycelia cultured in shake flasks can be inoculated into seed pots as seed strains. In shake flask liquid culture, the mycelium is required to grow fast, the yield is high, the formed mycelium pellets are small, if the mycelium pellets are bigger, mycelium in the center of the mycelium pellets can show anoxic and nutritional starvation conditions, and the quality of fermentation and the yield of mycelium are affected due to the adverse mycelium proliferation and the generation of secondary metabolites. Wherein the main raw materials of the culture medium are peptone, fish peptone, beef extract, silkworm chrysalis meal, glucose, corn flour, dextrin, yeast extract (powder), wheat bran (skin), naCl, and MgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof); for example, the shake flask/seed flask medium may be (the following% by weight volume g/100 ml):
Silkworm chrysalis meal 2.0-3.0%, corn meal 2.0-3.0%, wheat bran 2.0-3.0%, fish peptone 0.1-0.5%, peptone 0.1-1%, KH 2 PO 4 0.01 to 0.1 percent, 2.0 to 5.0 percent of glucose and MgSO 4 0.01 to 0.1 percent and the balance of water;
or (b)
Silkworm chrysalis meal 2.0-3.0%, corn meal 1.5%, bran 1.0-5.0%, glucose 2.0%, KH 2 PO 4 0.02%、MgSO 4 0.01% of water and the balance of water;
or (b)
Silkworm chrysalis meal 2.0%, corn meal 2.5%, bran 2.5%, fish peptone 0.25%, peptone 0.75%, KH 2 PO 4 0.02%, glucose 3.0%, mgSO 4 0.01Percent, the rest is water;
or (b)
Glucose 2.0%, corn flour 1.0%, dextrin 0.5%, yeast powder 0.5%, bran 1.0%, silkworm chrysalis powder 2.0%, peptone 1.0%, mgSO 4 0.05%、KH 2 PO 4 0.05% of water as solvent;
or (b)
Peptone 5.0%, glucose 2.0%, KH 2 PO 4 0.1%、MgSO 4 0.05% of wheat bran and 5.0% of solvent, wherein the solvent is water;
or (b)
0.5% of fish peptone, 0.5% of peptone, 2.0% of glucose and KH 2 PO 4 0.1%、MgSO 4 0.05 percent of wheat bran, 5 percent of wheat bran and the balance of water;
or (b)
2.0 to 4.5 percent of glucose, 2.0 to 4.5 percent of beef extract, 1.0 to 2.5 percent of potato powder, 1.0 to 2.5 percent of peptone and KH 2 PO 4 0.02～0.25%、MgSO 4 0.01 to 0.05 percent, inulin 0.2 to 1.5 percent, vitamin B0.05 to 0.15 percent, zinc acetate 0.01 to 0.06 percent and the balance of water;
it will be appreciated by those skilled in the art that the specific shake flask/seed flask media listed above are merely illustrative of the invention and are not to be construed as limiting the invention, and that it may include other commonly used shake flask/seed flask media for hirsutella sinensis fermentation, or shake flask/seed flask media for hirsutella sinensis fermentation known in the art.
Fermentation culture in the present invention refers to a medium for accumulating a large amount of metabolites by microorganisms. The fermentation of the invention comprises the use of a fermentation medium, and the deep fermentation refers to a method of performing aerobic or anaerobic culture on pure microbial cells in a liquid deep medium, wherein the deep fermentation is generally performed in a large-scale fermentation tank, and can be automatically and mechanically produced. The fermentation tank deep culture process flow of hirsutella sinensis can be as follows: primary seed tank, secondary seed tank, fermentation tank; it may also be: seed pot→fermenter; continuous fermentation processes may also be employed. For example, the cultivation temperature is 10 to 18 ℃, preferably 12 to 16 ℃, the cultivation time is 6 to 20 days, preferably 7 to 15 days, preferablyThe culture time is 10-15 days. The main raw materials of the fermentation medium comprise one or more of the following materials: silkworm chrysalis meal, glucose, corn meal (pulp), yeast extract (extract or powder), naCl and MgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof), a polypeptide powder series (e.g., polypeptide powder 101, polypeptide powder 102, polypeptide powder 203, polypeptide powder 305, polypeptide powder 308, polypeptide powder 607, polypeptide powder 702, polypeptide powder 705) (the polypeptide powder series is purchased from Dou Shiwen peak biotechnology Co., ltd.).
The fermentation medium comprises organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder '1' series, wherein the polypeptide powder '1' series takes rice protein, corn protein and hydrolysate thereof as main raw materials. The powder product is prepared by adopting various hydrolysis method sectional hydrolysis processes, separating, refining, concentrating and drying. The polypeptide powder "1" series includes polypeptide powder 101 and polypeptide powder 102. Polypeptide powder "2" series, such as polypeptide powder 203, is prepared from corn protein as main raw material by multiple hydrolysis steps (the process makes the product possess different molecular weights, peptone and peptide distributed reasonably, and is beneficial to continuous utilization of microorganism), separating, refining, concentrating, and spray drying.
The fermentation medium comprises peptone series (non-animal source) of organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder 305, polypeptide powder 308 and polypeptide powder 607, wherein the peptone series takes corn protein and yeast as main raw materials. Adopts various hydrolysis processes (the process ensures that the product has different molecular weights, the peptone and the peptide are reasonably distributed, and the continuous utilization of microorganisms is facilitated), and the powdery product is prepared by separation, refining concentration and spray drying.
The fermentation medium comprises peptone series (non-animal source) of organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder 702 and polypeptide powder 705, and the polypeptide powder 7 series takes rice protein and corn protein as main raw materials. Adopts the modern biological method and the multi-hydrolysis method sectional hydrolysis technology (the technology ensures that the products have different molecular weights, the peptone and the peptide are reasonably distributed, and the continuous utilization of microorganisms is facilitated), and the powdery products are prepared by separation, refining concentration and spray drying.
The fermentation medium of the invention can be (the following weight percent and volume percent):
glucose 1-5%, yeast extract 0.5-5%, KH 2 PO 4 0.01～0.1%、MgSO 4 0.01-0.1%, the polypeptide powder 0.5-5%, and the balance of water;
it is preferred that the composition is,
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, 1% of the polypeptide powder and the balance of water;
or alternatively
Glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, 203% of polypeptide powder, and the balance of water;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 305% and water in balance;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 702% and the balance of water;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 705% and water for the rest;
Glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 607 1%, and the rest is water.
The cordyceps sinensis fermentation composition disclosed by the invention is mycelium, wet fungus flakes and dry fungus powder of mycelium or dry fungus powder of mycelium and fermentation filtrate obtained through hirsutella sinensis slant culture, seed bottle/shake flask culture and fermentation culture, and preferably is mycelium dry fungus powder, mycelium and fermentation filtrate dry fungus powder. The fermentation filtrate comprises fermentation filtrate obtained by solvent separation and chromatographic column separation (membrane separation), or effective parts, effective components or various metabolites thereof.
According to the invention, through optimizing the fermentation process, the obtained cordyceps sinensis fermentation composition has obviously improved mycelium and metabolite content, wherein the erythritol content is more than 1% (by weight), preferably 1-6% (by weight), more preferably 2-5% (by weight), still more preferably 2.5-4% (by weight).
The present inventors have unexpectedly found that the presence of more than 1% by weight, preferably 1-6% by weight, more preferably 2-5% by weight, still more preferably 2.5-4% by weight of erythritol in the Cordyceps sinensis fermented composition not only results in a first Cordyceps sinensis fermented product having a stable erythritol content, but also enhances the effect of adenosine, and have unexpectedly found that the combination of erythritol and adenosine exhibits a remarkable synergistic effect of hydroxyl radical scavenging rate. That is, the present invention ensures that erythritol of the obtained fermented Cordyceps sinensis composition is stably present in an amount of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), particularly preferably 0.02% or more (weight percent), 0.03% or more (weight percent), preferably 0.03 to 1.00% (weight percent), preferably 0.03 to 0.80% (weight percent), preferably 0.03 to 0.60% (weight percent), preferably 0.03 to 0.40% (weight percent), preferably 0.03 to 0.20% (weight percent), preferably 0.03 to 0.10% (weight percent), preferably 0.03 to 0.08% (weight percent).
Further, since the previous studies indicate that adenosine may be converted from adenosine triphosphate, adenosine diphosphate or adenosine monophosphate, but nucleoside substances represented by adenosine triphosphate, adenosine diphosphate or adenosine monophosphate have important physiological activities as well, for example Qian Jia (study of 5 '-acid adenosine (5' -AMP) in vitro antioxidation, food and machinery, 24, 1 st 2008, volume 1) indicate that AMP has a strong activity of scavenging hydroxyl radicals, thereforeOn the basis of ensuring that erythritol and adenosine stably exist and have a synergistic technical effect, the method controls the conversion amount of adenosine to a certain extent, so that the whole cordyceps sinensis fermentation composition shows more excellent technical effect. As Chen Guming (influence of different carbon sources and nitrogen sources on hirsutella sinensis solid fermentation process, chinese edible fungi 2017, 37 (1): 55-60) researches show that the different carbon sources and nitrogen sources have effects on hirsutella sinensisHirsutella sinensis) The influence of the solid fermentation process is that the adenosine obtained by the solid fermentation method is only 63.76 mug.g-1 in the formula G7 at most, while Zhang Ping and the like (the quality evaluation and control research progress of cordyceps sinensis fermentation products, the volume 56 of the journal of Chinese pharmacy 2021, 7 th month, 14) record that the liquid fermentation culture condition of hirsutella sinensis is optimized, the dry weight of the optimized hirsutella sinensis mycelium is improved by 36.2%, and the adenosine content is improved by 46.8%. Amino nitrogen is the most important limiting substrate for the growth of thalli in the fermentation process, so the amino nitrogen obtained in the liquefaction process is important for improving the yield of cordyceps sinensis and effectively utilizing raw materials (CN 103444434A), but researches show that the growth rate of thalli is the fastest under the condition of low carbon source and nitrogen source concentration, and the growth rate of thalli is reduced along with the increase of the carbon source and nitrogen source concentration, so that the higher carbon source and nitrogen source concentration is unfavorable for the growth of thalli (CN 103430777A).
It has been unexpectedly found that the higher the adenosine content is, the better the Cordyceps sinensis fermented composition of the present invention is, preferably the adenosine content is 0.02% or more (weight percent), 0.03% or more (weight percent), preferably 0.03 to 1.00% (weight percent), preferably 0.03 to 0.80% (weight percent), preferably 0.03 to 0.60% (weight percent), preferably 0.03 to 0.40% (weight percent), preferably 0.03 to 0.20% (weight percent), preferably 0.03 to 0.10% (weight percent), preferably 0.03 to 0.08% (weight percent) based on the erythritol content of 1% or more.
More specifically, the present invention preferably has an adenosine content of 0.02% or more (weight percent) based on an erythritol content of 1% or more; or alternatively, the process may be performed,
more specifically, the invention preferably has an adenosine content of 0.02% -1.00% (weight percent) based on 1-6% of erythritol; or alternatively, the process may be performed,
more specifically, the present invention preferably has an adenosine content of 0.03% to 0.80% by weight, based on an erythritol content of 1-6%; or alternatively, the process may be performed,
more specifically, the invention preferably has an adenosine content of 0.02% to 1.00% by weight, based on an erythritol content of 2-5%; or alternatively, the process may be performed,
more specifically, the invention preferably has an adenosine content of 0.03% -0.80% or more (weight percent) based on 2-5% of erythritol; or alternatively, the process may be performed,
More specifically, the present application preferably has an adenosine content of 0.02% to 1.00% by weight based on an erythritol content of 2.5 to 4% or more.
More specifically, the present application preferably has an adenosine content of 0.03% to 0.80% by weight based on an erythritol content of 2.5 to 4% or more.
Those skilled in the art will appreciate that the foregoing list is merely illustrative of the present application and is not to be construed as limiting the present application. The fermented composition obtained in the above range has a very excellent antioxidant effect, particularly a synergistic technical effect of the hydroxyl radical scavenging rate, due to studies on the erythritol and adenosine contents.
Therefore, the application also provides the cordyceps sinensis fermentation composition, and the fermentation composition further comprises one or more of mannitol, polysaccharide and amino acid.
Further, the mannitol content of the Cordyceps sinensis fermentation composition is above 4% (weight percentage), preferably above 5% (weight percentage), preferably above 6% (weight percentage), preferably above 7% (weight percentage).
Further, the polysaccharide content of the cordyceps sinensis fermentation composition is more than 2% (weight percent), preferably more than 3% (weight percent), preferably more than 4% (weight percent), and preferably 2-10% (weight percent).
Further, the total amino acid content is 20% or more (weight percent), preferably 25 to 50% (weight percent).
Those skilled in the art will appreciate that the foregoing list is merely illustrative of the present invention and is not to be construed as limiting the present invention. The fermented composition obtained in the above range has very excellent technical effects due to studies on erythritol, adenosine content, mannitol, and polysaccharide.
In another aspect, the present invention provides a fermented Cordyceps sinensis composition, wherein the erythritol content is 1% or more (weight percentage), preferably 1 to 6% (weight percentage), more preferably 2 to 5% (weight percentage), still more preferably 2.5 to 4% (weight percentage), the adenosine content is 0.02% or more (weight percentage), and the mannitol content is 4% or more (weight percentage).
Further, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), an adenosine content of 0.02% or more (weight percent), a mannitol content of 4% or more (weight percent), and a polysaccharide content of 2% or more (weight percent).
Further, the Cordyceps sinensis fermented composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), an adenosine content of 0.02% or more (weight percent), a mannitol content of 4% or more (weight percent), and a total amino acid content of 20% or more (weight percent), preferably 25 to 50% (weight percent).
Further, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), an adenosine content of 0.02% or more (weight percent), a mannitol content of 4% or more (weight percent), a polysaccharide content of 2% or more (weight percent), and a total amino acid content of 20% or more (weight percent), preferably 25 to 50% (weight percent).
More specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), further preferably 2 to 5% (weight percent), still further preferably 2.5 to 4% (weight percent), preferably an adenosine content of 0.02% or more (weight percent), and a mannitol content of 5% or more (weight percent); or alternatively, the process may be performed,
More specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), further preferably 2 to 5% (weight percent), still further preferably 2.5 to 4% (weight percent), preferably an adenosine content of 0.03% or more (weight percent), and a mannitol content of 5% or more (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), further preferably 2 to 5% (weight percent), still further preferably 2.5 to 4% (weight percent), preferably adenosine content of 0.02% or more (weight percent), mannitol content of 5% or more (weight percent), and polysaccharide content of 2% or more (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), further preferably 2 to 5% (weight percent), still further preferably 2.5 to 4% (weight percent), preferably adenosine content of 0.02% or more (weight percent), mannitol content of 5% or more (weight percent), and total amino acid content of 20% or more (weight percent); or alternatively, the process may be performed,
More specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), further preferably 2 to 5% (weight percent), still further preferably 2.5 to 4% (weight percent), preferably an adenosine content of 0.02 to 1.0% (weight percent), and a mannitol content of 5% or more (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), preferably adenosine content of 0.02 to 1.0% (weight percent), mannitol content of 5% or more (weight percent), and polysaccharide content of 2% or more (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), preferably adenosine content of 0.02 to 1.0% (weight percent), mannitol content of 5% or more (weight percent), and total amino acid content of 20% or more (weight percent); or alternatively, the process may be performed,
More specifically, the Cordyceps sinensis fermentation composition of the present invention has an erythritol content of 1% or more (weight percent), preferably 1 to 6% (weight percent), more preferably 2 to 5% (weight percent), still more preferably 2.5 to 4% (weight percent), preferably adenosine content of 0.02 to 1.0% (weight percent), mannitol content of 5% or more (weight percent), polysaccharide content of 2% or more (weight percent), and total amino acid content of 20% or more (weight percent).
The cordyceps sinensis fermentation composition can be directly prepared into various dosage forms, including powder, granules, tablets, pills, capsules, or mixed with the components, and the mixture is filled into capsules or prepared into a tablet form to obtain a single preparation. The term "acceptable carrier" in the context of orally administrable compositions (e.g., tablets and capsules) also includes carriers such as conventional excipients, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose and starch; lubricants such as magnesium stearate, sodium stearate and other stearates, glyceryl stearate, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring and the like may also be used. It may be desirable to add coloring agents to differentiate dosage forms. Tablets may also be coated by methods well known in the art. The tablets may be compressed or molded, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the free-flowing form of the active ingredient, such as a powder or granules, optionally mixed with one or more binders, lubricants, inert diluents, preservatives, surfactants or dispersants.
In summary, the Cordyceps sinensis fermented composition of the present invention is not only the first Cordyceps sinensis fermented product containing stable erythritol content, but also the fermented composition obtained in the above range has very excellent antioxidant effect due to the study of erythritol and adenosine content, so that the Cordyceps sinensis fermented composition of the present invention shows more excellent technical effects as a whole than the prior art.
The pharmaceutical composition of the present invention can be directly prepared into various dosage forms including powder, granule, tablet, pill, capsule, or a mixture of the parts and encapsulating the mixture or preparing the mixture into a tablet form to obtain a single preparation. Can also be prepared into various dosage forms by using acceptable carriers.
The pharmaceutical composition provided by the invention has excellent antioxidation and has a synergistic technical effect.
In addition, according to the invention, through screening of cordyceps sinensis bacteria, research on cordyceps sinensis fermentation and beneficial component combination thereof is performed, meanwhile, cordyceps sinensis bacteria capable of producing ergothioneine are obtained, and a fermentation composition containing the ergothioneine is obtained through fermentation, namely, the ergothioneine in cordyceps sinensis mycelia or fungus powder is sufficiently and stably existing through a low-temperature liquid fermentation technology, and reasonable existence of active components such as ergothioneine and adenosine is realized through a low-temperature fermentation technology, so that the composition of fermented cordyceps sinensis is more stable, and a new utilization direction of fermented cordyceps sinensis fungus powder is provided.
Specifically, on one hand, the inventor screens hirsutella sinensis from the strains of the natural cordyceps sinensis through screening cordyceps sinensis strainsHirsutella sinensis) The method has the function of producing erythritol and the function of producing ergothioneine, and on the other hand, the inventor obtains fermentation mycelium or fungus powder which can exist stably and contains high content of ergothioneine through fermentation of hirsutella sinensis. According to the invention, the fermentation composition with the natural Cordyceps sinensis content level of ergothioneine or higher than the natural Cordyceps sinensis content level of ergothioneine is obtained for the first time through liquid fermentation culture, and the wider functions of the Cordyceps sinensis fermentation composition are exerted.
Hirsutella sinensis (L.) KuntzeHirsutella sinensis) The strain is Cordyceps [ cordyceps sinesis (Berk.) Sacc which is Cordyceps belonging to Clavicorniaceae and isolated from fresh Cordyceps sinensis (L.) Sacc.]The hirsutella sinensis can be any hirsutella sinensis strain, for example, can be purchased through a commercial platform, can also be obtained through autonomous screening and separation, and can be identified as hirsutella sinensis according to the identification principles of microorganism molecular genetics and the likeHirsutella sinensis) Commercial approaches include, but are not limited to, obtaining hirsutella sinensis (China center for type culture collection (CCTCC) or China general microbiological culture collection center (CGMCC) Hirsutella sinensis) For example, those obtained from China Center for Type Culture Collection (CCTCC) include, but are not limited to, hirsutella sinensis @, aHirsutella sinensis) Cctccc No: m2011278, for example, obtained from China general microbiological culture collection center (CGMCC) including but not limited to Mortierella sinensisHirsutella sinensis) CGMCC 3.14240 and hirsutella sinensisHirsutella sinensis) CGMCC3.14243, for example, cordyceps sinensis (hirsutella hepiali Chen et Shen) purchased from China industry microbiological culture Collection center (CICC)Ophiocordyceps sinensisOr Cordyceps sinensis (hirsutella sinensis )Cordyceps sinensisStandard strains include, but are not limited to, strain number: CICC 14016, CICC 14017, CICC 14088, CICC 14089, CICC 14090, CICC 14094, CICC 14096, CICC 14091, CICC 14092, CICC 14093, CICC 14095, CICC 14097, CICC 14098, CICC 14099, CICC 14100, CICC 14101, CICC 14102, CICC 14103, CICC 14104, CICC 14105, CICC 14106, CICC 14107, CICC 14108, CICC 14109, CICC 14110, CICC 14111, CICC 14112, CICC 14113, CICC 14114, CICC 14115, CICC 14117, CICC 14118, CICC 14119, CICC 14120, CICC 50002, e.g., cordyceps sinensis (hirsutella hepiali, hirsutella sinensis) purchased from Tex living beings Ophiocordyceps sinensisOr Cordyceps sinensis (hirsutella sinensis )Cordyceps sinensisOr hirsutella sinensisHirsutella sinensis) Including but not limited to, those of the order TS324838, TS325049, TS325054, TS326189, TS326195, TS326196, TS326197, TS326198, TS326199, TS326200, TS326201, TS326202, TS326203, TS326204, TS326205, TS326206, TS326207, TS326210, TS326212, TS326213, TS326214, TS326408, TS326410, TS326412, TS342791, TS342792, TS342793 TS342794, TS342794 TS342794, TS 342794.
The growth period of hirsutella sinensis is longer than that of most fungi, and the hirsutella sinensis generally grows in an environment of 14-20 ℃ and belongs to medium-low temperature bacteria. Culturing on solid culture medium with diameter up to 1.5cm, and bacterial colony with meat color and milky white color, and with grown mycelium on the surface, the bacterial colony surface will be smooth and gully with gradually reduced aerial mycelium. Culturing in liquid culture medium, wherein mycelium is in the shape of filament or gray sphere, different in size, and brown with culture, the mycelium pellet has tough and elastic texture and is hollow. It is known that the mycelia obtained by liquid fermentation and culture of hirsutella sinensis are dried to obtain fermented Cordyceps sinensis powder, and various active substances including polysaccharide, amino acid, nucleoside substances, sterol substances, mannitol, trace metals, etc. can be obtained. Wherein the marker component is adenosine, mannitol, polysaccharide, amino acid, etc. The fermented Cordyceps powder has effects of enhancing immunity, resisting fibrosis, protecting kidney function, resisting tumor, and relieving inflammation, and can be used for protecting kidney, lung, liver, etc.
The fermentation in the invention refers to the process of carrying out slant culture, seed bottle/shake bottle culture and fermentation culture on the traditional Chinese cordyceps sinensis asexual generation strain, namely the Chinese hirsutella sinensis.
The invention relates to a slant culture method, which comprises the steps of growing hirsutella sinensis on the inclined surface of a solid culture medium, inoculating hirsutella sinensis, coating the hirsutella sinensis on the slant, and culturing for 20-60 days, preferably for 30-50 days at a low temperature, for example at a temperature of 8-18 ℃, wherein the main raw materials of the slant culture medium are glucose, potato juice (powder), corn flour, agar (powder), yeast extract (powder), wheat bran (skin), silkworm chrysalis powder, peptone, naCl and MgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof); for example, the slant medium may be (the following% by weight volume g/100 ml):
peptone 0.05-2.0%, yeast extract 0.05-2.0%, glucose 1.0-5.0%, agar 1.0-3.0%, wheat bran 2.0-10%, KH 2 PO 4 0.02～0.2%、MgSO 4 0.01 to 0.1 percent and the balance of water;
or (b)
Silkworm chrysalis meal 1.0-2.0%, corn meal 1.0-2.0%, glucose 2.0-5.0%, mgSO 4 0.01～0.1%，KH 2 PO 4 0.01 to 0.1 percent of oatmeal, 1.0 to 3.0g/60ml of agar powder, 0.5 to 1 percent of water and the balance;
or (b)
Silkworm chrysalis meal 1.8%, corn meal 1.5%, glucose 2.0%, mgSO 4 0.01%，KH 2 PO 4 0.02 percent of oatmeal 1.0-3.0 g/60ml, 0.65 percent of agar powder and the balance of water;
or (b)
Peptone 0.1%, yeast extract 0.1%, glucose 2.0%, KH 2 PO 4 0.1%、MgSO 4 0.05% of agar1.0 to 2.0 percent of fat and 5.0 percent of wheat bran, adding water, boiling for 30 minutes, and sub-packaging;
or (b)
Peptone 0.5-2.0%, broad bean powder 2.0-5.0%, corn powder 1.0-4.0%, glucose 2.0-5.0%, agar 0.5-2.0%, bran 0.5-4%, KH 2 PO 4 0.01～1.0%，MgSO 4 0.01 to 1.0 percent and the balance of water;
or (b)
Glucose 2.0%, corn flour 1.0%, potato juice 0.5%, dextrin 0.5%, yeast powder 0.5%, bran 1.0%, silkworm chrysalis powder 2.0%, peptone 1.0%, mgSO 4 0.05%、KH 2 PO 4 0.05 percent of agar powder and 1.0 percent of solvent which is water;
or (b)
Silkworm chrysalis meal 2.0-3.0%, corn meal 1.5%, bran 1.0-5.0%, glucose 2.0%, agar 1.8%, KH 2 PO 4 0.02%、MgSO 4 0.01% of water and the balance of water;
it will be appreciated by those skilled in the art that the specific slant culture media listed above are merely illustrative of the invention and are not to be construed as limiting the invention, and that it may include other commonly used slant culture media for fermentation of hirsutella sinensis, or slant culture media for fermentation of hirsutella sinensis known in the art.
After inoculating the shake flask/seed flask culture strain to the seed flask from the inclined plane, carrying out shaking culture, or inoculating the test tube strain to the sterilized (sterilized) cooled triangular flask culture solution, and carrying out shaking culture on a shaking table, wherein the seed amount is 2-6 inclined planes, preferably 2-3 inclined planes, the culture temperature is 10-18 ℃, preferably 12-16 ℃, the culture time is 8-16 days, and preferably 9-14 days. In mass production, mycelia cultured in shake flasks can be inoculated into seed pots as seed strains. In shake flask liquid culture, the mycelium is required to grow fast, the yield is high, the formed mycelium pellets are small, if the mycelium pellets are bigger, mycelium in the center of the mycelium pellets can show anoxic and nutritional starvation conditions, and the quality of fermentation and the yield of mycelium are affected due to the adverse mycelium proliferation and the generation of secondary metabolites. Wherein the main raw materials of the seed bottle/shake flask culture medium comprise peptone, fish peptone, beef extract, silkworm chrysalis meal, glucose,Corn flour, dextrin, yeast extract (powder), wheat bran (skin), naCl, mgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof); for example, the shake flask/seed flask medium may be (the following% by weight volume g/100 ml):
Silkworm chrysalis meal 2.0-3.0%, corn meal 2.0-3.0%, wheat bran 2.0-3.0%, fish peptone 0.1-0.5%, peptone 0.1-1%, KH 2 PO 4 0.01 to 0.1 percent, 2.0 to 5.0 percent of glucose and MgSO 4 0.01 to 0.1 percent and the balance of water;
or (b)
Silkworm chrysalis meal 2.0-3.0%, corn meal 1.5%, bran 1.0-5.0%, glucose 2.0%, KH 2 PO 4 0.02%、MgSO 4 0.01% of water and the balance of water;
or (b)
Silkworm chrysalis meal 2.0%, corn meal 2.5%, bran 2.5%, fish peptone 0.25%, peptone 0.75%, KH 2 PO 4 0.02%, glucose 3.0%, mgSO 4 0.01% of water and the balance of water;
or (b)
Glucose 2.0%, corn flour 1.0%, dextrin 0.5%, yeast powder 0.5%, bran 1.0%, silkworm chrysalis powder 2.0%, peptone 1.0%, mgSO 4 0.05%、KH 2 PO 4 0.05% of water as solvent;
or (b)
Peptone 5.0%, glucose 2.0%, KH 2 PO 4 0.1%、MgSO 4 0.05% of wheat bran and 5.0% of solvent, wherein the solvent is water;
or (b)
0.5% of fish peptone, 0.5% of peptone, 2.0% of glucose and KH 2 PO 4 0.1%、MgSO 4 0.05 percent of wheat bran, 5 percent of wheat bran and the balance of water;
or (b)
2.0 to 4.5 percent of glucose, 2.0 to 4.5 percent of beef extract, 1.0 to 2.5 percent of potato powder, 1.0 to 2.5 percent of peptone and KH 2 PO 4 0.02～0.25%、MgSO 4 0.01 to 0.05 percent, inulin 0.2 to 1.5 percent and vitamin B1.05 to 0 percent.15 percent of zinc acetate 0.01 to 0.06 percent, and the balance of water;
it will be appreciated by those skilled in the art that the specific shake flask/seed flask media listed above are merely illustrative of the invention and are not to be construed as limiting the invention, and that it may include other commonly used shake flask/seed flask media for hirsutella sinensis fermentation, or shake flask/seed flask media for hirsutella sinensis fermentation known in the art.
Fermentation culture in the present invention refers to a medium for accumulating a large amount of metabolites by microorganisms. The fermentation of the invention comprises the use of a fermentation medium, and the deep fermentation refers to a method of performing aerobic or anaerobic culture on pure microbial cells in a liquid deep medium, wherein the deep fermentation is generally performed in a large-scale fermentation tank, and can be automatically and mechanically produced. The fermentation tank deep culture process flow of hirsutella sinensis can be as follows: primary seed tank, secondary seed tank, fermentation tank; it may also be: seed pot→fermenter; continuous fermentation processes may also be employed. For example, the cultivation temperature is 10 to 18 ℃, preferably 12 to 16 ℃, the cultivation time is 6 to 20 days, preferably 7 to 15 days, preferably 10 to 15 days. The main raw materials of the fermentation medium comprise one or more of the following materials: silkworm chrysalis meal, glucose, corn meal (pulp), yeast extract (extract or powder), naCl and MgCl 2 (magnesium chloride or hydrate thereof) MgSO 4 (magnesium sulfate or hydrate thereof), KCl, caCl 2 (calcium chloride or its hydrate), KH 2 PO 4 (potassium dihydrogen phosphate or a hydrate thereof), a polypeptide powder series (e.g., polypeptide powder 101, polypeptide powder 102, polypeptide powder 203, polypeptide powder 305, polypeptide powder 308, polypeptide powder 607, polypeptide powder 702, polypeptide powder 705) (the polypeptide powder series is purchased from Dou Shiwen peak biotechnology Co., ltd.).
The fermentation medium comprises organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder '1' series, wherein the polypeptide powder '1' series takes rice protein, corn protein and hydrolysate thereof as main raw materials. The powder product is prepared by adopting various hydrolysis method sectional hydrolysis processes, separating, refining, concentrating and drying. The polypeptide powder "1" series includes polypeptide powder 101 and polypeptide powder 102. Polypeptide powder "2" series, such as polypeptide powder 203, is prepared from corn protein as main raw material by multiple hydrolysis steps (the process makes the product possess different molecular weights, peptone and peptide distributed reasonably, and is beneficial to continuous utilization of microorganism), separating, refining, concentrating, and spray drying.
The fermentation medium comprises peptone series (non-animal source) of organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder 305, polypeptide powder 308 and polypeptide powder 607, wherein the peptone series takes corn protein and yeast as main raw materials. Adopts various hydrolysis processes (the process ensures that the product has different molecular weights, the peptone and the peptide are reasonably distributed, and the continuous utilization of microorganisms is facilitated), and the powdery product is prepared by separation, refining concentration and spray drying.
The fermentation medium comprises peptone series (non-animal source) of organic nitrogen sources for fermentation by using novel microorganisms, such as polypeptide powder 702 and polypeptide powder 705, and the polypeptide powder 7 series takes rice protein and corn protein as main raw materials. Adopts the modern biological method and the multi-hydrolysis method sectional hydrolysis technology (the technology ensures that the products have different molecular weights, the peptone and the peptide are reasonably distributed, and the continuous utilization of microorganisms is facilitated), and the powdery products are prepared by separation, refining concentration and spray drying.
The fermentation medium of the invention can be (the following weight percent and volume percent):
glucose 1-5%, yeast extract 0.5-5%, KH 2 PO 4 0.01～0.1%、MgSO 4 0.01-0.1%, the polypeptide powder 0.5-5%, and the balance of water;
it is preferred that the composition is,
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, 1% of the polypeptide powder and the balance of water;
or alternatively
Glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, 203% of polypeptide powder, and the balance of water;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 305% and water in balance;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 702% and the balance of water;
glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 705% and water for the rest;
Glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%、MgSO 4 0.01%, polypeptide powder 607 1%, and the rest is water.
The cordyceps sinensis fermentation composition disclosed by the invention is mycelium, wet fungus flakes and dry fungus powder of mycelium or dry fungus powder of mycelium and fermentation filtrate obtained through hirsutella sinensis slant culture, seed bottle/shake flask culture and fermentation culture, and preferably is mycelium dry fungus powder, mycelium and fermentation filtrate dry fungus powder. The fermentation filtrate comprises fermentation filtrate obtained by solvent separation and chromatographic column separation (membrane separation), or effective parts, effective components or various metabolites thereof.
The invention improves the quantity of mycelium and metabolite of Cordyceps sinensis fermentation composition by optimizing fermentation process, wherein, the content of ergothioneine is more than 0.004% (weight percent), preferably more than 0.006% (weight percent), preferably more than 0.008% (weight percent), preferably more than 0.01% (weight percent), preferably 0.01-0.10% (weight percent), preferably 0.01-0.08% (weight percent), or preferably more than 0.02% (weight percent), preferably 0.02-0.10% (weight percent), preferably 0.02-0.08% (weight percent); the adenosine content is 0.02% or more (wt%), 0.03% or more (wt%), preferably 0.03 to 1.00% (wt%), preferably 0.03 to 0.80% (wt%), preferably 0.03 to 0.60% (wt%), preferably 0.03 to 0.40% (wt%), preferably 0.03 to 0.20% (wt%), preferably 0.03 to 0.10% (wt%), preferably 0.03 to 0.08% (wt%).
The ratio of ergothioneine to adenosine content was 1:1-1: 20. preferably 1:1-1: 15. preferably 1:1-1: 10. preferably 1:1-1: 8. preferably 1:1-1: 7. preferably 1:1-1: 6. preferably 1:1-1: 5. preferably 1:1-1: 4. preferably 1:1-1: 3. preferably 1:1-1:2.
further, the Cordyceps sinensis fermented composition has erythritol content of 1% or more (weight percentage), preferably 1-6% (weight percentage), more preferably 2-5% (weight percentage), still more preferably 2.5-4% (weight percentage);
further, the mannitol content of the cordyceps sinensis fermentation composition is more than 4 percent (weight percent), preferably more than 5 percent (weight percent), preferably more than 6 percent (weight percent), preferably more than 7 percent (weight percent); the ratio of ergothioneine to mannitol content is 1:1-1: 1200. preferably 1:1-1: 1100. preferably 1:1-1: 1000. preferably 1:1-1: 900. preferably 1:1-1: 800. preferably 1:1-1: 700. preferably 1:1-1: 600. preferably 1:1-1: 500. preferably 1:1-1: 400. preferably 1:1-1:300.
further, the polysaccharide content of the cordyceps sinensis fermentation composition is more than 2 percent (weight percent), preferably more than 3 percent (weight percent), preferably more than 4 percent (weight percent), preferably 2-10 percent (weight percent); the ratio of ergothioneine to polysaccharide content is 1:1-1: 500. preferably 1:1-1: 400. preferably 1:1-1:300. preferably 1:1-1: 200. preferably 1:1-1: 100. preferably 1:1-1:50.
Further, the total amino acid content is 20% or more (weight percent), preferably 25 to 50% (weight percent).
Therefore, on the one hand, the invention aims at realizing that the ergothioneine in the cordyceps sinensis mycelium or fungus powder is stably present in a sufficient quantity by a low-temperature fermentation technology, and the ergothioneine is at least 0.004 percent (weight percent).
Ergothioneine (EGT) is a white, odorless, colorless crystalline powder in the solid state. Also in this solid state only the thioketone form is present, ergothioneine is readily soluble in water, tautomers (thioketone and thiol forms) are present in solution, but the thermal stability of ergothioneine is very high, with decomposition temperatures as high as 262-265 ℃. The ergothioneine cannot be synthesized by animal organisms and can only be taken from foods, the ergothioneine belongs to rare amino acids, mammals and humans are mainly obtained through diet, the human body can be highly absorbed after eating the ergothioneine, the ergothioneine has strong oxidation resistance, plays a unique role in the synthesis process of organism cells, has good effects in preventing diabetes, kidney diseases, tissue fibrosis, eye diseases and cancers, resisting ultraviolet injury, resisting inflammation, resisting oxidation, promoting neuron differentiation, enhancing memory and learning ability and the like, and the European food safety agency and the American food and drug administration both confirm the importance of the ergothioneine in novel functional foods, and recognize the safety of producing the ergothioneine through fermentation, and even consider that the ergothioneine can be added into pregnant women diet and mother and infant foods. The oxidation resistance of ergothioneine is related to at least four molecular activities: directly scavenging active oxygen; chelating various divalent metal cations; activating antioxidant enzymes such as glutathione peroxidase and manganese superoxide dismutase, and inhibiting superoxide kinases such as cytochrome C reductase (NADPH); affecting the oxidation of various heme proteins, such as heme and myoglobin.
The invention surprisingly discovers that more than 0.004 percent (weight percent), preferably more than 0.006 percent (weight percent), preferably more than 0.008 percent (weight percent), preferably more than 0.01 percent (weight percent) of ergothioneine exists in the cordyceps sinensis fermentation composition, not only is the first cordyceps sinensis fermentation product with the ergothioneine, but also the effect of adenosine is greatly enhanced, and research experiments prove that the ergothioneine in the cordyceps sinensis fermentation composition is helpful for enhancing the antioxidation effect of the adenosine, so that the ergothioneine and the adenosine produce a synergistic effect, and the inventor simultaneously surprisingly discovers that the hirsutella sinensis fermentation product or the fermentation composition overall shows more excellent technical effects through optimizing the adenosine content range.
Thus, in another aspect of the present invention, it is especially preferred that the adenosine content is 0.02% or more (weight percent), 0.03% or more (weight percent), preferably 0.03-1.00% by weight, preferably 0.03-0.80% by weight, preferably 0.03-0.60% by weight, preferably 0.03-0.40% by weight, preferably 0.03-0.20% by weight, preferably 0.03-0.10% by weight, preferably 0.03-0.08% by weight, while ensuring that ergothioneine of the obtained fermented Cordyceps composition is stably present in an amount of 0.004% or more (weight percent), preferably 0.006% or more (weight percent), preferably 0.008% or more (weight percent), preferably 0.01% or more (weight percent); the ratio of ergothioneine to adenosine content was 1:1-1: 20. preferably 1:1-1: 15. preferably 1:1-1: 10. preferably 1:1-1: 8. preferably 1:1-1: 7. preferably 1:1-1: 6. preferably 1:1-1: 5. preferably 1:1-1: 4. preferably 1:1-1: 3. preferably 1:1-1:2.
Adenosine is slightly soluble in cold water, soluble in normal temperature water, easily soluble in hot water, insoluble in alcohol, and researches show that, for example, li Heyu and the like (measurement of 5 nucleoside components in cordyceps products and mass analysis of cordyceps militaris, chinese herbal medicine, 2018 (49) 22:5410-5417) indicate that guanosine, uridine and adenosine can be converted in the process of extraction, for example, adenosine triphosphate, adenosine diphosphate and adenosine monophosphate can be converted into adenosine in the process of ultrasonic extraction by using water or mixed reagents with high water content. And, for example, qian Zhengming et al (study of adenosine conversion pathway in Cordyceps sinensis water extraction process, world Chinese medicine, 2016 (11) 5:758-762), found that adenosine monophosphate is converted to adenosine and adenosine is converted to inosine under Cordyceps sinensis room temperature water extraction conditions, and also found that adenosine triphosphate and adenosine diphosphate are converted to adenosine under room temperature water extraction conditions, where ATP is highly soluble in water, very stable in solution between pH 6.8 and 7.4, but rapidly hydrolyzes at extreme pH values. The research of adenosine in cardiovascular diseases, such as Feng Yangong (the influence of adenosine on the isolated cardiac function and myocardial apoptosis of rats) shows that SOD is the most important antioxidant enzyme, and can effectively remove redundant free radicals in the organism, and the SOD activity index in the myocardial tissue of an adenosine group is superior to that of an ischemia-reperfusion group.
The present invention surprisingly found that the presence of more than 0.004%, preferably more than 0.006%, preferably more than 0.008%, preferably more than 0.01% by weight of ergothioneine in the Cordyceps sinensis fermented composition not only enhances the effect of adenosine, but also enhances the effect of the first Cordyceps sinensis fermented product with ergothioneine, and the inventors have unexpectedly found that the combination of ergothioneine and adenosine shows a remarkable synergistic effect of hydroxyl radical scavenging rate. That is, the present invention ensures that ergothioneine of the obtained fermented composition of Cordyceps sinensis is stably present in an amount of 0.004% or more (weight percent), preferably 0.006% or more (weight percent), preferably 0.008% or more (weight percent), preferably 0.01% or more (weight percent), particularly preferably adenosine content of 0.02% or more (weight percent), 0.03% or more (weight percent), preferably adenosine content of 0.03% or more (weight percent), preferably 0.03-1.00% (weight percent), preferably 0.03-0.80% (weight percent), preferably 0.03-0.60% (weight percent), preferably 0.03-0.40% (weight percent), preferably 0.03-0.20% (weight percent), preferably 0.03-0.10% (weight percent), preferably 0.03-0.08% (weight percent); the ratio of ergothioneine to adenosine content was 1:1-1: 20. preferably 1:1-1: 15. preferably 1:1-1: 10. preferably 1:1-1: 8. preferably 1:1-1: 7. preferably 1:1-1: 6. preferably 1:1-1: 5. preferably 1:1-1: 4. preferably 1:1-1: 3. preferably 1:1-1:2.
Further, since the previous studies indicate that adenosine may be converted from adenosine triphosphate, adenosine diphosphate or adenosine monophosphate, but nucleoside substances represented by adenosine triphosphate, adenosine diphosphate or adenosine monophosphate have important physiological activities as well, such as Qian Jia (5 '-acid adenosine (5' -AMP) in vitro antioxidant studies, foods and machinery, 24, 2008 1 st, etc.) indicate that AMP has a strong activity of scavenging hydroxyl radicals, and therefore, on the basis of ensuring a synergistic technical effect of ergothioneine and adenosine, the invention has a synergistic effect on adenosineThe conversion amount of the cordyceps sinensis fermentation composition is controlled to a certain degree, so that the cordyceps sinensis fermentation composition has more excellent technical effects. As Chen Guming (influence of different carbon sources and nitrogen sources on hirsutella sinensis solid fermentation process, chinese edible fungi 2017, 37 (1): 55-60) researches show that the different carbon sources and nitrogen sources have effects on hirsutella sinensisHirsutella sinensis) The influence of the solid fermentation process is that the adenosine obtained by the solid fermentation method is only 63.76 mug.g-1 in the formula G7 at most, while Zhang Ping and the like (the quality evaluation and control research progress of cordyceps sinensis fermentation products, the volume 56 of the journal of Chinese pharmacy 2021, 7 th month, 14) record that the liquid fermentation culture condition of hirsutella sinensis is optimized, the dry weight of the optimized hirsutella sinensis mycelium is improved by 36.2%, and the adenosine content is improved by 46.8%. Amino nitrogen is the most important limiting substrate for the growth of thalli in the fermentation process, so the amino nitrogen obtained in the liquefaction process is important for improving the yield of cordyceps sinensis and effectively utilizing raw materials (CN 103444434A), but researches show that the growth rate of thalli is the fastest under the condition of low carbon source and nitrogen source concentration, and the growth rate of thalli is reduced along with the increase of the carbon source and nitrogen source concentration, so that the higher carbon source and nitrogen source concentration is unfavorable for the growth of thalli (CN 103430777A).
The present invention surprisingly found that the higher the adenosine content is, the better the Cordyceps sinensis fermented composition of the present invention is, preferably 0.02% or more (weight percent) and 0.03% or more (weight percent), preferably 0.03-1.00% (weight percent), preferably 0.03-0.80% (weight percent), preferably 0.03-0.60% (weight percent), preferably 0.03-0.40% (weight percent), preferably 0.03-0.20% (weight percent), preferably 0.03-0.10% (weight percent) and preferably 0.03-0.08% (weight percent) of ergothioneine content is based on 0.004% or more; the ratio of ergothioneine to adenosine content was 1:1-1: 20. preferably 1:1-1: 15. preferably 1:1-1: 10. preferably 1:1-1: 8. preferably 1:1-1: 7. preferably 1:1-1: 6. preferably 1:1-1: 5. preferably 1:1-1: 4. preferably 1:1-1: 3. preferably 1:1-1:2.
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:20, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:15; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:10; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:8, 8; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:7, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:6, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:5, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:4, a step of; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:3, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:2; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:20, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:15; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:10; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:8, 8; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:7, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:6, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:5, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:4, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:3, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.01 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:2; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:20, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:15; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:10; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:8, 8; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:7, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:6, preparing a base material; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:5, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:4, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:3, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine of more than 0.02 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:2; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:20, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:15; or alternatively, the process may be performed,
More specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:10; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:8, 8; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:7, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:6, preparing a base material; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:5, a step of; or alternatively, the process may be performed,
more specifically, the invention is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:4, a step of; or alternatively, the process may be performed,
More specifically, the application is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:3, a step of; or alternatively, the process may be performed,
more specifically, the application is based on the content of the ergothioneine of more than 0.02 percent, preferably the content of the adenosine is 0.03 to 0.08 percent (weight percent), and the ratio of the ergothioneine to the adenosine is 1:1-1:2.
those skilled in the art will appreciate that the foregoing list is merely illustrative of the present application and is not to be construed as limiting the present application. The fermented composition obtained in the range has very excellent antioxidant effect, especially the synergistic technical effect of the hydroxyl radical scavenging rate, due to the research on the content of ergothioneine and adenosine.
On the other hand, the inventor further researches the yield of the dry weight of the mycelium on the basis of the content of the ergothioneine, the erythritol and the adenosine by combining the conversion behavior of the content of the ergothioneine and the adenosine, namely, the inventor obtains the cordyceps sinensis fermentation composition with higher mycelium yield by optimizing the fermentation process on the basis of ensuring the content of the ergothioneine, the erythritol and the adenosine, and the mycelium fermentation yield is more than 7g/L, preferably 7g/L-15g/L, 7g/L-20g/L, 8g/L-15g/L and 8g/L-20g/L, and the mycelium dry weight water content is less than 8%, preferably less than 7% and preferably less than 6%.
More specifically, the cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of more than 0.02% (weight percent) based on the content of the ergothioneine of more than 0.01%, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, and the dry weight of mycelium contains less than 7% of water; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of more than 0.02% (weight percent) based on the content of the ergothioneine of more than 0.01%, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, and the mycelium fermentation yield is more than 7 g/L; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has 0.02 to 0.2 percent (weight percent) of adenosine based on the content of the ergothioneine of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine is 1:1-1:20, and the dry weight of mycelium contains less than 7% of water; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has 0.02 to 0.2 percent (weight percent) of adenosine based on the content of the ergothioneine of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine is 1:1-1:20, and the mycelium fermentation yield is more than 7 g/L.
Further, through intensive researches of the inventors, on the basis that 0.004% or more (weight percent), preferably 0.006% or more (weight percent), preferably 0.008% or more (weight percent), preferably 0.01% or more of ergothioneine is present, the present inventors have unexpectedly found that the presence of 0.004% or more of ergothioneine in the fermented composition of Cordyceps sinensis is not only the first fermented product of Cordyceps sinensis having ergothioneine, but also the effects of other beneficial ingredients are greatly enhanced, and experiments of the present invention have shown that the ergothioneine in the fermented composition of Cordyceps sinensis helps to enhance the effects of adenosine and the like, and produces a synergistic effect, especially in terms of antioxidant effect, so that the fermented composition of Cordyceps sinensis as a whole exhibits more excellent technical effects.
Therefore, in another aspect, the present invention also provides a Cordyceps sinensis fermentation composition, wherein the content of ergothioneine is above 0.004% (wt%) and preferably above 0.006% (wt%) and preferably above 0.008% (wt%) and preferably above 0.01% (wt%) and one or more of adenosine, mannitol, amino acids, polysaccharides and erythritol are included in the fermentation composition.
Further, the content of erythritol in the Cordyceps sinensis fermented composition is 1% or more (weight percentage), preferably 1 to 6% (weight percentage), more preferably 2 to 5% (weight percentage), still more preferably 2.5 to 4% (weight percentage).
Further, the mannitol content of the Cordyceps sinensis fermentation composition is above 4% (by weight), preferably above 5%, preferably above 6%, preferably above 7%.
More specifically, the cordyceps sinensis fermentation composition has the erythritol content of more than 1 percent (weight percent) on the basis of the ergothioneine content of more than 0.01 percent; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition has the erythritol content of more than 1 percent (weight percent) and the adenosine content of more than 0.02 percent (weight percent) on the basis of the ergothioneine content of more than 0.01 percent; or alternatively, the process may be performed,
More specifically, the cordyceps sinensis fermentation composition has the erythritol content of more than 1 percent (weight percent), the adenosine content of more than 0.02 percent (weight percent) and the mannitol content of more than 5 percent (weight percent) on the basis of the ergothioneine content of more than 0.01 percent; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition has the adenosine content of more than 0.02 percent (weight percent) and the mannitol content of more than 5 percent (weight percent) on the basis of more than 0.01 percent of ergothioneine content; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition has the adenosine content of more than 0.02 percent (weight percent) and the mannitol content of more than 6 percent (weight percent) on the basis of the ergothioneine content of more than 0.01 percent; or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition disclosed by the invention has the adenosine content of more than 0.02% (weight percent) and the mannitol content of more than 7% (weight percent) on the basis of the ergothioneine content of more than 0.01%.
In another aspect, the present invention also provides a Cordyceps sinensis fermentation composition, where the content of ergothioneine is above 0.004% (wt%) and preferably above 0.006% (wt%) and preferably above 0.008% (wt%) and preferably above 0.01% (wt%) and preferably above 2% (wt%) and polysaccharide content; or alternatively, the process may be performed,
Further, the polysaccharide content of the Cordyceps sinensis fermentation composition is more than 2% (weight percentage), preferably more than 3% (weight percentage), and preferably 2-10% (weight percentage).
Furthermore, the cordyceps sinensis fermentation composition of the invention has more than 2 percent of polysaccharide content (weight percent) and more than 20 percent of total amino acid on the basis of more than 0.01 percent of ergothioneine content;
more specifically, the Cordyceps sinensis fermentation composition of the invention preferably contains polysaccharide 2% -10% (weight percentage) and total amino acids 25-50% based on ergothioneine content of more than 0.01%.
Those skilled in the art will appreciate that the foregoing list is merely illustrative of the present invention and is not to be construed as limiting the present invention. The fermented composition obtained in the range has very excellent technical effects due to the research on ergothioneine, adenosine content, mannitol, polysaccharide, erythritol.
In another aspect, the present invention provides a Cordyceps sinensis fermentation composition, wherein the content of ergothioneine is above 0.004% (wt%) and preferably above 0.006% (wt%) and preferably above 0.008% (wt%) and preferably above 0.01% (wt%) and the content of erythritol is above 1% (wt%) and preferably 1-6% (wt%) and further preferably 2-5% (wt%);
In another aspect, the present invention also provides a Cordyceps sinensis fermentation composition, wherein the content of ergothioneine is above 0.004% (wt%) and preferably above 0.006% (wt%) and preferably above 0.008% (wt%) and preferably above 0.01% (wt%) and the content of adenosine is above 0.02% (wt%) and the content of mannitol is above 4% (wt%).
Further, the cordyceps sinensis fermentation composition provided by the invention has the ergothioneine content of more than 0.01 percent (weight percent), the adenosine content of more than 0.02 percent (weight percent), the mannitol content of more than 4 percent (weight percent) and the polysaccharide content of more than 2 percent (weight percent).
Further, the Cordyceps sinensis fermentation composition of the invention has the ergothioneine content of more than 0.01 percent (weight percent), the adenosine content of more than 0.02 percent (weight percent), the mannitol content of more than 4 percent (weight percent), and the total amino acid content of more than 20 percent (weight percent), preferably 25-50 percent.
Further, the Cordyceps sinensis fermentation composition of the invention has the ergothioneine content of more than 0.01 percent (weight percent), the adenosine content of more than 0.02 percent (weight percent), the mannitol content of more than 4 percent (weight percent), the polysaccharide content of more than 2 percent (weight percent), and the total amino acid content of more than 20 percent (weight percent), preferably 25-50 percent.
More specifically, the Cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of 0.02% or more (weight percentage) based on 0.01% or more of ergothioneine, and the ratio of ergothioneine to adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of 0.03% or more (weight percent) based on 0.01% or more of ergothioneine, and the ratio of ergothioneine to adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of 0.02% or more (weight percentage) based on 0.01% or more of ergothioneine, and the ratio of ergothioneine to adenosine content is 1:1-1:20, mannitol content is more than 5 percent (weight percent), and polysaccharide content is more than 2 percent (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of 0.02% or more (weight percentage) based on 0.01% or more of ergothioneine, and the ratio of ergothioneine to adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage), total amino acid content is above 20% (weight percentage); or alternatively, the process may be performed,
More specifically, the cordyceps sinensis fermentation composition of the invention preferably has the adenosine content of 0.02 to 1.0 percent (weight percent) based on the ergothioneine content of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage); or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has the adenosine content of 0.02 to 1.0 percent (weight percent) based on the ergothioneine content of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is more than 5 percent (weight percent), and polysaccharide content is more than 2 percent (weight percent); or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has the adenosine content of 0.02 to 1.0 percent (weight percent) based on the ergothioneine content of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage), total amino acid content is above 20% (weight percentage); or alternatively, the process may be performed,
more specifically, the cordyceps sinensis fermentation composition of the invention preferably has the adenosine content of 0.02 to 1.0 percent (weight percent) based on the ergothioneine content of more than 0.01 percent, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is above 5% (weight percentage), polysaccharide content is above 2% (weight percentage), and total amino acid content is above 20% (weight percentage).
In another aspect, the invention also provides a cordyceps sinensis fermentation composition, which comprises adenosine, wherein the fermentation composition further comprises ergothioneine, and the content (weight percent) of the ergothioneine is more than 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine, and the content (weight percentage) of the ergothioneine is more than 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol and polysaccharide, wherein the fermentation composition further comprises ergothioneine, and the content (weight percent) of the ergothioneine is more than 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol, polysaccharide and amino acid, wherein the fermentation composition further comprises ergothioneine, and the content (weight percentage) of the ergothioneine is more than 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine, the content (weight percent) of the ergothioneine is above 0.01%, and the adenosine content is 0.02-1.0% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine, the content (weight percentage) of the ergothioneine is above 0.01%, and the ratio of the ergothioneine to the adenosine is 1:1-1:20.
further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine, the content (weight percent) of the ergothioneine is above 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the ratio of the ergothioneine to the adenosine content is 1:1-1:20.
further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine, the content (weight percent) of the ergothioneine is more than 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the mannitol content is more than 4% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine, the content (weight percent) of the ergothioneine is more than 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is more than 4% (weight percentage).
Therefore, in another aspect, the present invention also provides a fermented composition of hirsutella sinensis, wherein the content of ergothioneine is 0.004% or more (weight percent), preferably 0.006% or more (weight percent), preferably 0.008% or more (weight percent), preferably 0.01% or more (weight percent), and the adenosine content is 0.02% or more (weight percent), and erythritol is 1.0% or more (weight percent).
More specifically, the cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of more than 0.02% (weight percent) based on the content of the ergothioneine of more than 0.01%, and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, erythritol 1.0% or more (weight percent); or alternatively, the process may be performed,
more specifically, the Cordyceps sinensis fermentation composition of the invention preferably has an adenosine content of 0.02% -1.0% (by weight) and erythritol content of 1.0% (by weight) based on 0.01% or more of ergothioneine content.
In another aspect, the present invention also provides a fermented composition of Cordyceps sinensis, comprising adenosine, wherein the fermented composition further comprises ergothioneine and erythritol, and the content (weight percentage) of ergothioneine is above 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine and erythritol, and the content (weight percentage) of the ergothioneine is above 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol and polysaccharide, wherein the fermentation composition further comprises ergothioneine and erythritol, and the content (weight percentage) of the ergothioneine is above 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol, polysaccharide and amino acid, wherein the fermentation composition further comprises ergothioneine and erythritol, and the content (weight percent) of the ergothioneine is above 0.01%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is above 0.01%, and the adenosine content is 0.02-1.0% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percentage) of the ergothioneine is above 0.01%, and the ratio of the ergothioneine to the adenosine is 1:1-1:20.
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is more than 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the ratio of the ergothioneine to the adenosine content is 1:1-1:20.
further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is above 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the mannitol content is above 4% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is more than 0.01%, the adenosine content is 0.02-1.0% (weight percent), and the ratio of the ergothioneine to the adenosine content is 1:1-1:20, mannitol content is more than 4% (weight percentage).
In another aspect, the present invention also provides a fermented composition of Cordyceps sinensis, comprising adenosine, wherein the fermented composition further comprises ergothioneine and erythritol, and the erythritol is more than 1% (by weight).
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine and erythritol, and the erythritol is more than 1% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol and polysaccharide, wherein the fermentation composition further comprises ergothioneine and erythritol, and the erythritol is more than 1% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, mannitol, polysaccharide and amino acid, wherein the fermentation composition further comprises ergothioneine and erythritol, and the erythritol is more than 1% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, the erythritol is more than 1% (weight percent), and the adenosine content is 0.02-1.0% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, and the content (weight percent) of the ergothioneine is more than 0.01%, and the content (weight percent) of the erythritol is more than 1%.
Further, the cordyceps sinensis fermentation composition comprises adenosine, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is above 0.01%, the content (weight percent) of the erythritol is above 1%, and the adenosine content is 0.02-1.0% (weight percent).
Further, the cordyceps sinensis fermentation composition comprises adenosine and mannitol, wherein the fermentation composition further comprises ergothioneine and erythritol, the content (weight percent) of the ergothioneine is above 0.01%, the content (weight percent) of the erythritol is above 1%, the adenosine content is 0.02-1.0% (weight percent), and the mannitol content is above 4% (weight percent).
The cordyceps sinensis fermentation composition can be directly prepared into various dosage forms, including powder, granules, tablets, pills, capsules, or mixed with the components, and the mixture is filled into capsules or prepared into a tablet form to obtain a single preparation. The term "acceptable carrier" in the context of orally administrable compositions (e.g., tablets and capsules) also includes carriers such as conventional excipients, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose and starch; lubricants such as magnesium stearate, sodium stearate and other stearates, glyceryl stearate, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring and the like may also be used. It may be desirable to add coloring agents to differentiate dosage forms. Tablets may also be coated by methods well known in the art. The tablets may be compressed or molded, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the free-flowing form of the active ingredient, such as a powder or granules, optionally mixed with one or more binders, lubricants, inert diluents, preservatives, surfactants or dispersants.
In summary, the Cordyceps sinensis fermented composition of the invention is not only the first Cordyceps sinensis fermented product with ergothioneine, but also the fermented composition obtained in the range has very excellent antioxidant effect due to the research on the content of ergothioneine and adenosine, so that the Cordyceps sinensis fermented composition of the invention has more excellent technical effects on the whole than the prior art.
Accordingly, the present invention also provides a pharmaceutical composition comprising a combination of ergothioneine and adenosine, wherein the combination ratio of ergothioneine to adenosine is 1:1-1:20.
further, the ratio of ergothioneine to adenosine content is preferably 1:1-1: 15. preferably 1:1-1: 10. preferably 1:1-1: 8. preferably 1:1-1: 7. preferably 1:1-1: 6. preferably 1:1-1: 5. preferably 1:1-1: 4. preferably 1:1-1: 3. preferably 1:1-1:2.
the invention also provides a pharmaceutical composition comprising a combination of ergothioneine and erythritol, wherein the combination ratio of ergothioneine to erythritol is 1:1-1:600, preferably 1:1-1: 500. preferably 1:1-1: 400. preferably 1:1-1: 300. preferably 1:1-1: 200. preferably 1:1-1:100.
the pharmaceutical composition of the present invention can be directly prepared into various dosage forms including powder, granule, tablet, pill, capsule, or a mixture of the parts and encapsulating the mixture or preparing the mixture into a tablet form to obtain a single preparation. Can also be prepared into various dosage forms by using acceptable carriers.
The pharmaceutical composition provided by the invention has excellent antioxidation and has a synergistic technical effect.
Drawings
FIG. 1 is an HPLC profile of ergothioneine standard
FIG. 2 is a HPLC chromatogram of ergothioneine from sample B-5
FIG. 3 is a HPLC chromatogram of ergothioneine from sample B-7
FIG. 4 is an adenosine HPLC profile of example 4 CNC101096641A sample
FIG. 5 is an adenosine HPLC profile of example 4B-2 sample
FIG. 6 is an HPLC chromatogram of erythritol of B-2 sample
FIG. 7 is a standard curve of polysaccharide
Detailed Description
1. Ergothioneine detection method
The measurement is carried out by high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 0.2% of heptafluorobutyric acid is taken as a mobile phase A, and methanol is taken as a mobile phase B; the detection wavelength was 255nm. The theoretical plate number is not less than 3000 calculated according to the ergothioneine peak.
Preparation of reference solution ergothioneine reference appropriate amount, precisely weighing, and adding 0.5% phosphoric acid solution to obtain solution containing μg per 1 ml. Gradient elution was performed as follows:
preparing a sample solution, namely taking 0.5g of fermented cordyceps sinensis bacterial powder, precisely weighing, placing the sample solution into a conical bottle with a plug, adding 20ml of diethyl ether, sealing, soaking for 30 minutes, filtering, discarding diethyl ether, volatilizing diethyl ether from residues, placing the residue together with filter paper into the conical bottle with the plug, precisely adding 50ml of 0.5% phosphoric acid solution, sealing, weighing, performing ultrasonic treatment for 30 minutes, performing power of 250W, frequency of 33kHz, cooling, shaking uniformly, centrifuging, and taking supernatant.
Respectively precisely sucking 10 μl of the reference solution and the sample solution, and injecting into a liquid chromatograph for measurement.
2. Method for detecting erythritol
Preparation of reference substance solution
Taking an appropriate amount of erythritol reference substance, precisely weighing, and adding deionized water to prepare a solution containing 1000 mug per 1 ml.
Preparation of test sample solution
And (3) taking 0.5g of fermented cordyceps sinensis bacterial powder, precisely weighing, precisely adding 10ml of deionized water into a conical bottle with a plug, sealing, weighing, performing ultrasonic treatment (with the power of 250W and the frequency of 40 kHz) for 60min, cooling, weighing again, supplementing the lost weight with deionized water, shaking uniformly, filtering, and taking a subsequent filtrate.
Detection method
A detector: a RID differential detector;
chromatographic column: model Agilent Hi-Plex Ca, 300X 7.7mm,8um;
mobile phase: deionized water;
chromatographic column flow rate: 0.6ml/min; column temperature: 80 ℃; sample injection volume: 10ul; the detection time is 50min;
flow cell temperature: 35 ℃.
3. Method for detecting anthrone-sulfuric acid of polysaccharide
Solution preparation
Anthrone sulfate solution: precisely weighing anthrone 0.1 g, adding sulfuric acid solution 100 mL to dissolve, shaking, and placing in brown bottle.
Preparation of a Standard Curve
Preparation of control solution
Taking proper amount of anhydrous glucose reference substance, precisely weighing and adding water to obtain solution containing 0.1 mg per 1. 1 mL.
Standard curve drawing
Precisely measuring reference solutions 0, 0.2, 0.4, 0.8, 1.2, 1.6 and 2.0mL, respectively placing in test tubes with plugs of 20 mL, respectively adding water to 2.0mL, rapidly and precisely adding anthrone sulfate solution 6 mL, shaking uniformly immediately, standing for 15 min, immediately cooling in ice water bath for 15 min, standing at room temperature for 10min after taking out, taking the corresponding reagent as a blank, measuring absorbance at 625 nm, taking absorbance as an ordinate, and drawing a standard curve, see FIG. 7.
Preparation of test solutions
Taking fermented Cordyceps sinensis bacterial powder about 2 g, precisely weighing, placing into a round bottom flask, adding water 60 mL, standing for 30 min, heating and refluxing for 3 h, transferring to a centrifuge tube while the materials are hot, washing a filter and filter residues with a small amount of hot water, centrifuging at 5000rpm for 10min, taking supernatant, transferring the precipitate to the round bottom flask with a small amount of hot water, adding water 60 mL, heating and refluxing for 2 h, transferring the heat to the centrifuge tube while the materials are still hot, centrifuging again, merging the supernatant, evaporating the supernatant to dryness on a water bath, dissolving the residues with water 5 mL, slowly adding ethanol 75 mL while stirring, shaking, placing 12 h at 4 ℃, centrifuging, discarding the supernatant, dissolving the precipitate with hot water and transferring to 50 mL, cooling, adding water to a scale, shaking to take a proper amount of solution, centrifuging, precisely weighing supernatant 1 mL, placing 25 mL measuring flask, adding water to a scale, shaking, and obtaining the product.
Measurement
Precisely measuring the sample solution 2 mL, placing the sample solution 2 mL into a 10 mL test tube with a plug, and calculating the content of anhydrous glucose in the sample solution from the process of rapidly and precisely adding the anthrone sulfate solution 6 mL according to the standard curve.
Result calculation
Wherein:
W-polysaccharide content,%;
c-polysaccharide concentration, mg/mL, of the sample examined from the standard curve;
m-sample mass, mg;
8/2, 25/2 represents dilution factors;
50-volume value of the precipitate obtained after water extraction and alcohol precipitation through dissolution and volume fixation by hot water.
4. Hydroxy radical clearance detection (Fenton colorimetric method)
Principle of detection
H 2 O 2 /Fe 2+ Generates hydroxyl free radical through Fenton reaction and adds Fe 2+ Oxidation to Fe 3+ phenanthroline-Fe resulting in red color 2+ Oxidation to colorless phenanthrene-Fe in ortho-bi-atmosphere 3+ To make phenanthroline-Fe 2+ The maximum absorption peak at 536 nm disappears, and the change of absorbance at 530-540 nm can be measured by a spectrophotometer, so that the content change of the hydroxyl radical can be calculated, and the hydroxyl radical scavenging rate or scavenging capacity of the sample can be calculated.
Solution preparation
1. Weighing 0.2. 0.2 g fungus powder, adding 2 ml purified water, mixing, standing at room temperature for 4 h, centrifuging at 10000 rpm for 10 min, and collecting supernatant.
2. The other samples were control solutions.
The spectrophotometer was turned on and preheated for 30 min, wavelength was adjusted to 536, nm, and purified water was zeroed.
Sample addition
The blank tube, the undamaged tube, the damaged tube, the control tube and the measuring tube were set according to the following table, and the solutions were sequentially added and mixed uniformly in a water bath 1 h at 37 ℃.
And (3) calculating: test sample OH clearance (%) = [ (A3-A3') - (A2-A0) ]/(A1-A2) ×100%
5. The detection method of adenosine, mannitol, total amino acid content and water content is detected according to the detection method of the fermented Cordyceps sinensis powder under the national drug standard.
EXAMPLE 1 different mycelium Ergothioneine (EGT), erythritol content
The research of the inventor shows that no ergothioneine is detected in the culture soil, larva and silkworm pupa of the natural cordyceps sinensis, and only 0.008 percent of ergothioneine is detected in part of fresh worm bodies and dry worm bodies, so that the ergothioneine is difficult to detect from the mycelium of the natural cordyceps sinensis:
although the fungus separated from the natural Cordyceps sinensis is used for fermentation in theory, the content of nutrient substances in mycelium and the medicinal effect of the fungus are similar to those of the natural Cordyceps sinensis, the components of the Cordyceps sinensis fermentation product still have differences from those of the natural Cordyceps sinensis, especially the metabolites and secondary metabolites in the fermentation process are different from those of the natural Cordyceps sinensis, and the differences between different Cordyceps sinensis fermentation products are larger. Based on the research of natural Cordyceps, the inventor stores hirsutella sinensis in multiple collections Hirsutella sinensis) Such as hirsutella sinensis (CCTCC) of China Center for Type Culture Collection (CCTCC)Hirsutella sinensis) The preservation number is CCTCC No: m2011278 and hirsutella sinensis purchased from China general microbiological culture collection center (CGMCC)Hirsutella sinensis) CGMCC 3.14240 and hirsutella sinensisHirsutella sinensis) CGMCC3.14243 the Paecilomyces hepialid is purchased from China general microbiological culture collection center (CGMCC)Paecilomyces hepiali) 3.15540 Paecilomyces hepialidPaecilomyces hepiali) CGMCC3.7845 and Paecilomyces hepialidPaecilomyces hepiali) With further reference to the prior art and CGMCC3.7908, on the basis of eliminating the possible interference of exogenous ergothioneine (for example, the ergothioneine is not detected by silkworm chrysalis powder used as a culture medium), the fermentation filtrate and mycelium dry powder in the existing fermentation process of the Cordyceps sinensis are researched, and the amounts of the ergothioneine are lower than those of the natural Cordyceps sinensisMost of them were not detected, but the inventors have unexpectedly found that hirsutella sinensis fermented mycelium is capable of obtaining a trace amount of ergothioneine.
Note that: ∓ the content of the Cordyceps is 3-10% of that of the natural Cordyceps.
As shown in the table above, the ginseng of the invention is fermented according to the method disclosed by the prior art, and the fermentation filtrate and mycelium in the fermentation process do not obtain meaningful ergothioneine.
Further, the inventors made a study on commercially available hirsutella sinensis strains in addition to the strains available from the above-mentioned collectionsHirsutella sinensis) For example, cordyceps sinensis (hirsutella hepiali Chen et Shen, hirsutella sinensis) purchased from the China industry microbiological culture Collection center (CICC)Ophiocordyceps sinensisStandard strains CICC 14092, CICC 14095, CICC 14097, CICC 14099, cordyceps sinensis (hirsutella hepiali Chen et Shen, hirsutella sinensis) purchased from Tex Tu organismsOphiocordyceps sinensisThe goods number is TS326189, TS326199 and hirsutella sinensisHirsutella sinensis) Strains with the product numbers TS361737 and TS392986 are fermented according to the prior art, and ergothioneine is not obtained from the obtained fermentation filtrate and mycelium.
Similarly, the inventor performs the following steps on a plurality of strains of the paecilomyces hepiali which are sold in the marketPaecilomyces hepiali) For example, the preservation numbers are CGMCC 3.15421, CGMCC 3.14870, CGMCC 3.12108, CGMCC 3.10157, CCTCC NF 20081231, CCTCC NF 20081239, CCTCC NF 20081244 and CCTCC NF 20081250, and the ergothioneine is not obtained from the obtained fermentation filtrate and mycelium by referring to the prior art.
As shown in the above table, the inventive ginseng was fermented according to the method disclosed in the prior art, and neither the fermentation filtrate nor the mycelium during the fermentation process obtained erythritol with a stable and meaningful content.
Further, the inventors made a study on commercially available hirsutella sinensis strains in addition to the strains available from the above-mentioned collectionsHirsutella sinensis) For example, cordyceps sinensis (hirsutella hepiali Chen et Shen, hirsutella sinensis) purchased from the China industry microbiological culture Collection center (CICC)Ophiocordyceps sinensisStandard strains CICC 14092, CICC 14095, CICC 14097, CICC 14099, cordyceps sinensis (hirsutella hepiali Chen et Shen, hirsutella sinensis) purchased from Tex Tu organismsOphiocordyceps sinensisThe goods number is TS326189, TS326199 and hirsutella sinensisHirsutella sinensis) Strains with the product numbers TS361737 and TS392986 are fermented by referring to the prior art, and erythritol with stable and meaningful content is not obtained in the obtained fermentation filtrate and mycelium.
Similarly, the inventor performs the following steps on a plurality of strains of the paecilomyces hepiali which are sold in the marketPaecilomyces hepiali) For example, the preservation numbers are CGMCC 3.15421, CGMCC 3.14870, CGMCC 3.12108, CGMCC 3.10157, CCTCC NF 20081231, CCTCC NF 20081239, CCTCC NF 20081244 and CCTCC NF 20081250, and the obtained fermentation filtrate and mycelium do not obtain erythritol with stable and meaningful content by referring to the prior art for fermentation.
Example 2 has the stabilization of fermented products containing 0.004% or more of Ergothioneine (EGT)
Hirsutella sinensis (China center for type culture collection (CCTCC)) obtained from China Center for Type Culture Collection (CCTCC)Hirsutella sinensis) The preservation number is CCTCC No: m2011278, inoculating hirsutella sinensis strain on the inclined plane, and performing inclined plane culture, shake flask/seed flask culture and fermentation culture by the following method:
1. slant culture
1.1 formulation of slant solid Medium: silkworm chrysalis meal 1.8%, corn meal 1.5%, glucose 2.0%, mgSO 4 0.01%，KH 2 PO 4 0.02 percent of oatmeal 1.0-3.0g/60ml, 0.65 percent of agar powder, pH of 6.8-7.2, water preparation, sterilization (30+/-1) min at the temperature of (118-122).
1.2 under aseptic condition, bacterial blocks of about 2 x 2cm are dug out by an inoculating shovel, hyphae are uniformly coated on a blank solid culture medium, and the blank solid culture medium is placed in a biochemical incubator and cultured for 30 days at 15 ℃.
1.3 And (3) placing the cultured inclined plane in a refrigerator at 0-8 ℃ for low-temperature preservation, slowly growing hypha during the period, and taking out the inclined plane after the inclined plane hypha grows fully for standby.
2. Shake flask culture
2.1 Shake flask medium formulation: silkworm chrysalis meal 2.0%, corn meal 2.5%, bran 2.5%, fish peptone 0.25%, peptone 0.75%, KH 2 PO 4 0.02%, glucose 3.0%, mgSO 4 0.01%，pH6.8-7.2；
2.2 Liquefying: weighing silkworm chrysalis powder, corn flour and bran according to the preparation volume of the liquefied material, adding water, liquefying for 30min at the temperature of 118-122 ℃, taking out the liquefied material, standing, layering up and down, and filtering by a filter screen with 6 layers of gauze to obtain filtrate.
2.3 Preparing a culture medium: weighing the corresponding materials, dissolving with liquefied filtrate, fixing volume, shaking, packaging with 1500ml/5000ml liquid, sterilizing at (118-122) deg.C for 30+ -1 min.
2.4 Digging: cutting the slant into about 1.5X2.0 cm pieces, raking the cut pieces into prepared culture medium of digging block/seed bottle with sterile rake, (13-16deg.C, (120-140) rpm, and shake culturing for 9-14 days.
3. Fermentation culture:
3.1 The basic fermentation medium formula comprises: glucose 2.8%, yeast extract 1%, KH 2 PO 4 0.02%，MgSO 4 0.01%，pH7.0。
3.2 Preparing a culture medium: the liquid filling amount of the shake flask is 1000ml/5000ml, (118-122) DEG C, and sterilization (30+ -1) min.
3.3 Fermentation: the inoculation amount is 10 percent, the temperature is (13-16) DEG C, (120-140) rpm, and the flask is placed after shaking culture for 7 days.
3.4 And measuring a proper volume of fermentation liquor, vacuum filtering to obtain wet bacterial slices, and drying to obtain a bacterial powder sample.
In the above basic fermentation medium (glucose 2.8%, yeast extract 1%, KH) 2 PO 4 0.02%，MgSO 4 0.01% (% weight-volume ratio of each)The mycelium test number samples of A-1 to A-8 and B-1 to B-8 are obtained by fermenting different components, and the results of the ergothioneine and erythritol detection are shown in the following table:
further, the inventors made a study on commercially available hirsutella sinensis strains other than the strains disclosed in the above-mentioned patents Hirsutella sinensis) For example, hirsutella sinensis purchased from China general microbiological culture collection center (CGMCC)Hirsutella sinensis) CGMCC 3.14240 and hirsutella sinensisHirsutella sinensis) CGMCC3.14243, cordyceps sinensis (hirsutella hepiali, hirsutella sinensis) purchased from China industry microbiological culture collection center (CICC)Ophiocordyceps sinensisStandard strains CICC 14092, CICC 14095, CICC 14097, CICC 14099, cordyceps sinensis (hirsutella hepiali Chen et Shen, hirsutella sinensis) purchased from Tex Tu organismsOphiocordyceps sinensisThe goods number is TS326189, TS326199 and hirsutella sinensisHirsutella sinensis) The strains with the goods numbers TS361737 and TS392986 are hirsutella sinensis prepared according to the method of example 2Hirsutella sinensis) The preservation number is CCTCC No: the fermentation method of M2011278 is to repeat experiments under the conditions of different culture mediums shown in the table above for fermentation, and different hirsutella sinensis are preparedHirsutella sinensis) The EGT content, the adenosine content% and the mannitol content% of the bacterial powder sample obtained by fermentation are the same as those of the bacterial powder sample obtained by fermentation under the same conditions, and the preservation number is CCTCC No: the content of each component in the bacterial powder prepared by M2011278 has no obvious difference.
EXAMPLE 3 study of the Effect of the effective amount of ergothioneine or erythritol on the Mortierella bainieri fermentation cylinder powder
1. Synergistic experimental result of ergothioneine and adenosine hydroxyl radical clearance
2. Experimental results of the synergistic effects of the hydroxyl radical scavenger of ergothioneine and erythritol
3. Synergistic experimental result of erythritol and adenosine hydroxyl radical clearance
The theoretical values in the table are simple superposition of the two-component hydroxyl radical scavengers;
from the above data, it can be seen that erythritol itself does not have a hydroxyl radical scavenging effect, but produces a significant synergistic effect with the composition of adenosine, the two components having at least a 4.76 fold improvement in hydroxyl radical scavenging effect over theory.
EXAMPLE 4 results of the hydroxyl radical scavenger test of the fermentation powder obtained by the present invention
Experimental samples:
b-2, B-5 and B-7 mycelium samples are prepared as before;
sample preparation of CN108384726a, example 5:
2.0% of sorbose, 0.1% of sea cucumber extract and 0.15% of angelica extract were added to the basal medium described in example 1, and mycelia were fermented using the medium.
Sample preparation of CN101096641a, example 1:
inoculating strain on inclined plane, culturing with culture medium comprising glucose 1.5%, corn flour 1.0%, dextrin 0.5%, bran 1.5%, yeast powder 0.5%, pupa Bombycis powder 1.5%, peptone 1.0%, magnesium sulfate 0.01%, potassium dihydrogen phosphate 0.02%, agar powder 0.8% and water for 25 days at 12deg.C; then inoculating the strain into a fermentation culture medium, wherein the formula of the culture medium comprises 1.0% of glucose, 1.0% of molasses, 0.5% of silkworm chrysalis meal, 1.0% of soybean cake meal, 0.5% of yeast extract, 0.01% of magnesium sulfate, 0.02% of potassium dihydrogen phosphate and the balance of water, and placing the mixture on a shaking table for culturing for 8 days at the temperature of 14 ℃; then inoculating the strain into a primary fermentation tank, culturing for 8 days at the temperature of 14 ℃, expanding the strain by 10 times of the culture medium amount, and fermenting step by step until reaching a 30-ton tank. And (3) separating solid from liquid after discharging from the tank, and drying and crushing the solid.
It will be appreciated by those skilled in the art that the above-described specific embodiments are merely illustrative of the present invention and are not to be construed as limiting the invention, and that various embodiments can be implemented to achieve the same technical effects, which are encompassed within the scope of the present invention, as will be understood by those skilled in the art in light of the spirit of the present invention.
Claims (7)
1. A fermented composition of Cordyceps sinensis, wherein the fermented composition comprises erythritol, adenosine and ergothioneine, wherein the erythritol content is more than 1wt%, the adenosine content is more than 0.02wt%, and the ergothioneine content is more than 0.004 wt%; the fermentation composition is mycelium dry bacterial powder; the fermentation composition is prepared from hirsutella sinensisHirsutellasinensis) Fermenting to obtain the final product.
2. The fermentation composition of claim 1, wherein the erythritol content is 1wt% -6 wt%.
3. The fermentation composition of claim 2, wherein the erythritol is present in an amount of 2.5wt% to 4wt%.
4. The fermentation composition of claim 1, wherein the adenosine content is 0.03wt% to 1.0wt%.
5. A fermentation composition according to claim 1, wherein the ergothioneine content is 0.01 wt% or more.
6. The fermentation composition of claim 1, wherein the fermentation composition comprises one or more of mannitol, amino acids, and polysaccharides.
7. Use of a fermented composition according to any one of claims 1-6 for the preparation of a medicament or a health food.
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