Penicillium verrucosum fungal strain, used for making agent with immunomodulating properties, and immunomodulator agent based on said strain

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology and design of agents with immunomodulating properties. A new fungal strain Penicillium verrucosum VKPM F-984 and a new immunomodulating agent based on the strain are proposed. The strain is extracted from microflora of ginseng roots and is kept in a medium which contains mineral salts, glucose and asparagine. Fungus mycelium is extracted with a water-alcohol solution (70% ethanol solution). The advantage of this agent is its natural occurrence and effecient stimulation of adaptive capabilities of the body.

EFFECT: obtaining an extract which has stimulating action on cell and humoral immunity, improves immune status of the body.

3 cl, 2 ex


The invention relates to biotechnology, in particular to the development of new sources of biologically active substances and immunomodulating drugs for effects on a living organism.

Currently great interest in drugs of natural origin, their advantage is their physiology to the body and environmentally friendly.

Known biologically active preparations immunostimulating action, obtained from natural sources (based on Symbiotropin fungi)that live in natural conditions on the roots of plants, such as drugs Emistim C, agreementin-Extra [1, 2]. These dyes contain optimal for stimulation of plant life set of growth substances (hormones), vitamins, amino acids, fatty acids, trace elements. Multiple trials of these drugs have shown that they are improving the germination of seeds of plants, resistance to diseases and stress factors, increase yield and improve the quality of crop production, reduce the nitrate content [3]. This is due to the activation of the fundamental life processes of plants - photosynthesis, respiration, nutrition of cells, activation of enzyme systems. These drugs are made from natural materials, obtained the mushroom-epiphytes root system of medicinal plants, certified and certified for environmental safety.

It is also known biologically active agent (Biocorrector) "Floravit e" on the basis of the extract of the fungus Fusarium sambusinum, which is an effective immunomodulator and adaptogen [4]. This tool is widely used in clinical medicine as in the treatment of various diseases (diabetes, trophic disorders, diseases of the joints), and in the fight against viral infections. Clinically shown its hepatoprotective action, efficacy of gastroenterology, obstetrics-gynecology and for healing and rejuvenation in rehabilitation medicine and cosmetics [5]. Therapeutic possibilities of preparation "Floravit e" connected, primarily, with its natural origin of the fungus Fusarium sambusinum and unique set of biologically active components in its composition.

However, finding natural sources to search for and create a highly biologically active agents, with a unique set of constituent components and its influence on the organism of man and animals, is a difficult task. The selection of a biologically active substance from a source of natural origin must also ensure maximum preservation of useful properties, UTS is DTIE toxicity and side effects.

The solution to this problem is possible using the new tools of natural origin, have immunomodulatory properties, that can be used in a variety of therapeutic effects.

This is achieved by using as the source of natural raw materials of a new strain of the fungus Penicillium verrucosum VKPM F-984 and the allocation of a drug with immunomodulatory properties.

A new strain of the fungus Penicillium verrucosum VKPM F-984 used to obtain funds, have immunomodulatory properties, and the means obtained on the basis of the strain Penicillium verrucosa VKPM F-984, have immunomodulatory properties. This tool is obtained, in particular, the extraction of the mycelium of the specified strain and is a water-alcohol extract.

The technical result of the claimed group of inventions is finding new natural sources of biologically active substances and expanding range of high-performance tools-immunomodulators natural origin, designed to impact on a living organism in the field of medicine, veterinary medicine or holistic health events. Use them to more effectively carry out the treatment and prevention of diseases by improving immunity and overall impact on the body.

is received from a strain of the fungus Penicillium verrucosum VKPM F-984 immunomodulatory agent possesses adaptogenic action, increases the nonspecific resistance of the organism and its adaptive capacity. To obtain usually carry out the extraction of the mycelium of the fungus in an aqueous solution of alcohol.

The strain of the fungus Penicillium verrucosum VKPM F-984 isolated from the microflora of ginseng roots as follows.

The method of strain isolation: ginseng roots washed under running water, dried on filter paper and taken roots 4-5 procedure, 5 g of dry roots treated with 60% H2SO4, crushed and transferred to flasks with culture medium (nutrient medium composition: glucose - 8.0 g, K2HPO4- 0.5 g, KH2PO4- 1.0 g, MgSO4- 0.2 g, K2SO40.1 g l - asparagine-20 mg, water water up to 1 litre).

For storage and reproduction of endophytic micromycete Penicillium verrucosum VKPM F-984 use apparitional environment: glucose - 8.0 g, K2HPO4- 0.5 g, KH2PO4- 1.0 g, MgSO4- 0.2 g, K2SO40.1 g l - asparagine-20 mg tap water to 1 liter, agar-agar - 15,0,

The culture is plated on Petri dishes, incubated in thermostat and used for preparation of inoculum.

The selected strain was deposited in the collection of the Depositary PMBC, he assigned a registration number F-984.

Kulturalna-morphological properties of the strain.

Micromorphologically signs: when planting a shot on medium with agar on day 5 of growth at +24°C develops warty colony rounded grey-green, on the periphery of the weak striation, the size of the colony diameter of 35-40 mm, aerial mycelium-reverse white, surface sporulation, the color of the reverse side of the colony brownish-yellowish. Mycelium colorless septate, a large number of small round greenish conidia, conidiophores onomatopoeia monoarticular, spores spherical shape, transparent, smooth shell.

Physiological and biochemical properties of the strain.

The strain grows in a temperature range from 24 to 27°C, the temperature optimum of 25-27°C.

When growth on nutrient media preferred slightly acidic pH values, the pH optimum of 6.5.

Can be grown in simple environments using glucose as a carbon source, preferably the content in environments potassium and magnesium.

The method of obtaining funds from the strain of Penicillium verrucosum VKPM F-984 includes the following operations.

The culture fluid with mycelium with stirring, treated with activated charcoal (5 g/l liquid), incubated for 25 hours and filtered. Solid fraction at intensive stirring and extracted with an aqueous solution of alcohol (70%) during the day. The extract is filtered.

The obtained filtered alcohol extract is described by means of having immunomodulatory properties.

Example 1. Receiving immunomodulator is C strain Penicillium verrucosum VKPM F-984.

In fermentors under sterile conditions, add seeds at a dose of 3% of the volume of the fermentation medium. Fermentation environment includes: glucose - 8.0 g, K2HPO4- 0.5 g, KH2PO4- 1.0 g, MgSO4- 0.2 g, K2SO40.1 g l - asparagine-20 mg tap water to 1 liter fermentation is finished for the maturation of the mycelium of the fungus and on the achievement of the maximum accumulation in the culture fluid of metabolic products of the fungus-micromycete.

The obtained culture liquid with mycelium under intensive stirring, treated with activated charcoal at a rate of 5 g per 1 l of the liquid is maintained at a temperature of 25°C for 24 hours and filtered. The solid fraction is placed in a separate container and with vigorous stirring extracted the estimated amount of 75%aqueous ethanol solution for 24 hours. Upon completion of the extraction are filtering and receive the filtered extract.

Example 2. The study of the properties of the obtained immunomodulator.

To study the effect of the drug on hematological, biochemical and immunological parameters of the body was an experiment with a duration of 6 months in rats male WISTAR rats with an initial weight of 125-130, Rats were divided into 2 groups: the control group animals received obsessively diet, experience the Naya group animals on the background obseving daily diet along with food received drug-immunomodulator dose of 0.25 ml/kg weight of the animal. Conducted 2 slaughter animals: after 3 and 6 months from the beginning of the experiment.

The influence of the drug-immunomodulator on morphological characteristics of the organism.

The General condition of the animals of all groups was satisfactory throughout the experiment.

Conducted microscopically studies 10 bodies from each rat: liver, kidneys, lungs, testes, lymphoid organs (mesenteric lymph node, spleen and thymus gland, thymus) digestive tract (thin and thick intestine, stomach). After 3 months from the beginning of the experiment there was a slight degenerative changes in the liver in the experimental group compared with the control. In the spleen and the mesenteric lymph node in some cases it was noted lymphoid proliferation in the experimental group compared with the control. After 6 months from the beginning of the experiment was not found significant morphological changes of the internal organs in the experimental group compared to control.

The effect of the drug on the biochemical and hematological parameters of blood and urine.

In the study of biochemical parameters take into account the total protein content, glucose content in the blood serum, the activity of some enzymes in the blood serum and liver slid the, the content of creatinine in the urine.

The content of total protein in the serum of rats, the enzyme activity of blood serum and liver of rats when their diet immunomodulatory agent obtained in example 1, did not differ from controls throughout the experiment (after 3 and 6 months).

Not identified differences between the experimental group and the control on such parameters as the concentration of hemoglobin, the total number of erythrocytes, hematocrit, CCO, sste throughout the experiment. Leukocyte formula in rats when their diet study drug did not significantly differ from the control.

Immunotoxic properties of the drug.

Immunotoxic properties of the drug were studied in the experiment on white mice-males weighing 18-20 g

On the influence of the drug on cellular immunity was assessed by the severity of hypersensitivity reactions of the delayed type and autologous rosette cells (autologous ROCK).

Determination of severity of hypersensitivity reactions of the delayed type (GTT) was performed in 40 mice CBA. The first group of animals were administered the study drug at a dose of 0.25 ml/kg, 2-nd group - at a dose of 0.5 ml/kg, 3rd group - 1 ml/kg for 5 days oral, all experimental groups on day 5 in parallel with conducting drug was administered suspension of sheep erythrocytes (EB) nutriplus the NGOs (10% suspension) at a dose of 0.3 ml/kg Animals of the control group was injected only 10% suspension of DL. 5 days after sensitization all experimental animals were injected with a resolving dose of 2% suspension of DL in the amount of 0.02 ml in the right foot, and left in the saline solution and 0.02 ml of the Control animals were injected only 2% suspension of EB and took into account the stimulation index. When the stimulation index was established that the study drug has immunostimulating properties in all tested doses (of 0.25; 0.5; 1.0 ml/kg body weight) and stimulation index (IP) was 9,8±0,7; 10,1±0,2; 9,45±0,4 accordingly, groups of experimental animals in the control IP=4,5.

Changes in the dynamics of auto-ROCK animals on the background of the introduction of the drug was studied on 75 mice CBA. Group 1 mice received the drug at a dose of 0.25 ml/kg, 2-I in a dose of 0.5 ml/kg orally for 5 days, group 3 served as a control. Studies were performed at 5, 10, 15, 20 days after the last injection of the drug. Kinetics of auto-ROCK was characterized by an increase in both absolute and relative number of rosette cells in the blood of mice.

Changes in the dynamics of indicators of autologous rosette cells in mice provides insight into the impact of the drug on cellular immunity, resulting in increased functional activity of T-lymphocytes. Evaluation of In-cell component of the immune system was carried out according to definition number is the number of antibody productive cells in the spleen and the kinetics of b-lymphocytes.

Determination of antibody productive cells (AFC) in the spleen was performed in the experience of 30 mice CBA. The first group of animals, the drug was administered at a dose of 0.25 ml/kg, 2 to 0.5 ml/kg, intraperitoneally simultaneously introduced the EB. The number of KLA believed in one sample among 200 lymphocytes. The drug induces the transformation of b-lymphocytes in the AFC in the spleen, the stimulation index (IP) is equal to 1.4 in the control group IP amounted to 0.9.

The kinetics of b-lymphocytes was determined in the experience of 60 mice CBA. Contents EAC-rosette cells in the blood of the mice of the control group did not significantly differ from the experimental group during the whole research period and amounted to 19,4±2,6-20,9±1,4.

In the dynamics of the relative amount of b-lymphocytes after drug maintenance dose of 0.25 ml/kg was observed the significant increase in the EAC-ROCK on the 10th and 15th days of the study, while in the 2nd group of animals (dose 0.5 ml/kg) on 5-th, 10 th, 15 th days of observations the contents of the EAC-ROCK amounted to 23.6±1,18-22,6±1,13. The data obtained allow to conclude that the investigational drug in a dose of 0.5 ml/kg, administered orally for 5 days increases cellular immune response.

Determination of hemagglutinin titers in the serum of animals after administration of the drug was carried out on 30 mice CBA (2 experimental groups, 1 control group). On day 7 after immunization all belly is s were scored and determined the titers of total antibodies and antibody classes M and O. The content of immunoglobulins M and O in the experimental groups was higher than in the control.

Immunological studies in rats.

Determination of immune status was assessed by the competence of the cellular and humoral immune response in rats male WISTAR rats with an initial weight of 125-130 g in chronic Toxicological experiment with a duration of 6 months. Rats were divided into 2 groups: the control group animals received obsessively diet, experimental group of animals on the background obseving diet along with food received study drug at a dose of 0.25 ml / kg of body weight of the rat.

The competence of cellular immunity was assessed by induced phytohemaglutinin (PHA) and specific antigen prepared from the investigational drug reactions stimulation of peripheral blood lymphocytes, the expression of response inhibition of leukocytes in the presence of PHA and specific antigens and the degree T-dependent cellular cytotoxicity. Mitogenic response of peripheral lymphocytes of rats to PHA and specific antigen (CA) were evaluated for the percentage of transformed cells. A study of the influence of the drug on the mitogenic stimulation of peripheral lymphocytes of rats, it was found that it can increase the proliferative activity of T cells. The value of the Indus the KSA cytotoxicity in rats of the experimental group after 3 months amounted to 0.35±0.02 and after 6 months of 0.32±0.03 in, and in the control group, respectively, and 0.28±0.04 to 0.24±0,01.

These findings indicate immunostimulirutuyu role of the investigational product in relation to thymusdependent lymphocytes.

Competence humoral immunity was assessed by the content in the serum of rats the major classes of immunoglobulins. Research the content of immunoglobulins in the blood serum of rats when their diet drug has allowed to establish the General orientation to the stimulation of humoral immunogenesis. After 3 months, the concentration of immunoglobulin O, a, M, E was in control 743±37,2; 138±6,8; 8±3,9; 0,45±0,01; in the experimental group 861±43,05; 132±6,6; 87±4,5; 0,42±0,03 respectively. 6 months after the beginning of the experiment in the control- 723±36,14; 131±6,5; 80±3,5; 0,45±0,01; in the experimental group- 836±41,8; 136±6,8; 86±4,3; 0,46±0,02 accordingly, by classes of immunoglobulins.

Nonspecific protective indicators studied the content in the serum of some components of the complement and the level of the individual whey proteins acute phase of inflammation. The content of the components of complement NW, C4, C5, C9 in the control was 551+27,5; 239+12,0; 107+5,35: 38±1,9; in the experimental group 567±28,35; 269±13,45; 116±5,8; 46±2,3 respectively.

As a result of the experiments revealed the modulating effect of study drug on cellular immunodeficiency, the major reactions (increased proliferative response of peripheral lymphocytes to mitogens (PHA), the intensity of cytotoxicity). Marked stimulating effect on the synthesis of immunoglobulins (1^0 1^M), components of complement (C4 and C9), proteins of acute phase of inflammation (transferrin, C-reactive protein).

During the research it was revealed that the study drug has not immunotoxic effect in relation to the functional activity of T - and b-cells.

The drug is used in poultry farms to optimize metabolism, enhance immunity and increase productivity. When the feeding of the drug with water, the bird was observed due to the rapid expansion of the mass of broiler chickens, improving the livability of Chicks. The drug activates specific antitelomerase against Newcastle disease in birds, revealed no adverse effects on the clinical status of broiler chickens. Protein quality of meat increased by 3.7%. Thus the use of immunomodulating drug improves zootechnical performance of poultry.

Conducted production tests of the studied drug in animal husbandry has shown its high efficiency as a therapeutic and prophylactic agent in the dyspepsia of newborn calves, diarrhea infectious etiology, bronchopneumonia.

The feeding newborn calves solution is Reparata within 3-10 days at a dose of 0.17-0.25 ml/kg reduced the number of diseased calves 1.6-4.5 times and duration of the disease is 2-4 times. The increase in live weight in the experimental groups outperformed the control animals 3.2-6.2 kg at 30 days of age, at 60 days of age 4.4-8,1 kg the oral application of the drug at a dose of 1 ml per day newborn calf is effective against diarrhea in animals. Livestock safety in experimental groups reached 90-100%.

Thus, the described immunomodulator is not toxic, has a therapeutic effect on a living organism, can be effectively applied in animal husbandry and veterinary medicine for effects on the immune system of animals, increasing the gain and improve the safety of the animals.

Sources of information

1. The biostimulant Emistim STU AT 88.264.021-95.

2. The Biostimulator Of Agreementin-Extra. TU 24.2-31168762-001-2004.

3. Pokrovskaya ST Ways to reduce the nitrate content in vegetables. M: Agropromizdat, 1990, s.

4. Catalog-Handbook of Diagnostic and treatment technologies of regenerative medicine, Ministry of health of the Russian Federation, 2004, vol. 1, s, 229, 264.

5. "Dietary Supplement Floravit e in gastroenterology, guidelines / edited by academician of the Russian Academy of natural Sciences, Dr. SC Mahurangi, publishing house of the Russian medical Academy of postgraduate education, 2002.

1. The strain of the fungus Penicillium verrucosum VKPM F-984 used to obtain funds, have immunomodulatory his is Tami.

2. The agent with immunomodulatory properties, characterized by the fact that it is derived from a strain of the fungus Penicillium verrucosum VKPM F-984.

3. The tool according to claim 2, characterized in that it is a hydroalcoholic extract of the mycelium of the strain of the fungus Penicillium verrucosum VKPM F-984.


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FIELD: chemistry, biochemistry.

SUBSTANCE: invention refers to biotechnology and agriculture, specifically to fungi growing. Interstrain hybridisation method is applied to produce somatic strain of macroscopic oyster fungus Pleurotus ostreatus (Fr.) Kumm "ВИК" F - 6 being a producer for carposomes of pileate fly edible fungi of carposome productivity 60-70% of dry weight of substratum and high commercial properties. Strain is deposited in "ВКМ" under number F - 3889 D.

EFFECT: higher productivity and improved carposome habitus.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method of obtaining laccase enzyme medicine involves sustaining cultivation parametres depending on dissolved oxygen concentration in medium. Temperature of 25-27°C and pH within 3.0-7.0 are maintained from the start of cultivation until dissolved oxygen concentration falls to 50%. After further decrease of dissolved oxygen concentration to 5% temperature is increased to 27-29°C and uncompensated pH range is narrowed to 4.0-5.0. At reduction of dissolved oxygen concentration to minimum level and its further increase, temperature of 30-33°C and pH of 4.0-6.0 are maintained.

EFFECT: enhanced activity of culture fluid containing laccase.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: in formulas (I) and (Ia) . A is 1-cyclopentene-1,2-diyl; Z1 and Z2 are O; E is phenyl substituted with 1-4 substituting groups selected from halogen, Y is phenyl substituted with 1-2 substituting groups selected from halogen, C1-C6alcoxy, halogen C1-C6alcoxy; the meaning of other radicals are indicated in the formula of the invention. The invention refers also to the pharmaceutical composition including the compound of the invention, to the application of the said compound at preparation of the medicinal agent and to the application for DHODH inhibition.

EFFECT: compound of the present invention can find application as medicinal agent inhibiting dehydroorotate dehydrogenase.

9 cl, 18 ex