CN117860792A - Use of composition containing active ingredient of ganoderma lucidum - Google Patents
Use of composition containing active ingredient of ganoderma lucidum Download PDFInfo
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- CN117860792A CN117860792A CN202410044272.5A CN202410044272A CN117860792A CN 117860792 A CN117860792 A CN 117860792A CN 202410044272 A CN202410044272 A CN 202410044272A CN 117860792 A CN117860792 A CN 117860792A
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- ganoderma lucidum
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- ganoderma
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Abstract
The invention discloses an application of a composition containing ganoderma lucidum active ingredients. The composition can inhibit radioactive lung injury, alleviate inflammatory response of lung tissues caused by radiotherapy, reduce inflammatory factor level, improve oxidative stress level, lower fibrosis-related protein level and reduce tumor metastasis nodules of lung for the first time, and has no side effect. The compositions are useful in the adjuvant therapy of radiation lung injury and prognosis of radiation therapy patients.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of a composition containing ganoderma lucidum active ingredients.
Background
Malignant tumors are the first leading cause of mortality in various diseases in China, and the incidence rate of malignant tumors is still rising. For patients with advanced localized tumors, radiotherapy in combination with concurrent chemotherapy is listed as standard therapy. Wherein >50% of breast cancer or other breast malignancy patients receive radiation therapy. The data indicate that the incidence of radiation lung injury (radiation induced lung injury, RILI) caused by lung cancer radiation therapy is highest (5-25%), followed by mediastinal lymphoma (5-10%) and breast cancer (1-5%). RILI can cause a reduction in patient lung function, impair the quality of life of cancer patients, and even increase mortality, thus becoming a bottleneck factor in limiting radiation dose and reducing the effectiveness of radiation therapy.
RILI manifests as acute phase radiation pneumonitis and chronic phase radiation pulmonary fibrosis. RILI is a complex pathological process that is multifactorial, multicellular, and interactive, where oxidative stress is thought to be the core mechanism of radiation-related injury. Ionizing radiation produces a large amount of reactive oxygen radicals (reactive oxygen species, ROS), which can cause oxidative damage to DNA, lipids, proteins, and cause injury or apoptosis of lung tissue cells, thereby causing a series of inflammatory reactions such as cytokine release, inflammatory cell infiltration, etc. Also, oxidative stress of the tissue persists after irradiation is completed, such as altered mitochondrial oxidative respiratory chain function, producing more ROS; alveolar macrophages activate, secrete ROS, and the like. ROS are very active but unstable, indirectly reflecting oxidative stress through the enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the levels of Malondialdehyde (MDA) and NO. When inflammatory lesions persist, excessive fibroblast activation results in excessive, disordered repair, matrix accumulation, and eventually lung fibrosis. Studies have shown that the radical scavenger amifostine, as well as other compounds, has an effect of alleviating RILI.
Furthermore, the cytokine network is an important driving force for the progression of inflammation-fibrosis. Studies have shown that after irradiation, damage-associated molecular pattern (DAMP) molecules are released from cells, contributing to the recruitment of neutrophils, macrophages, leukocytes and lymphocytes. Numerous cytokine levels in lung tissue are up-regulated after irradiation and change over time. Early after irradiation, pro-inflammatory factors such as TNF-alpha, IL-6, IL-1 beta and chemokines such as MCP-1, MIP-2, CXCL-6 are significantly increased, and the development of radiation pneumonitis is dominated by increasing the permeability of capillaries in the lung, chemotactic neutrophils and the like. In addition, TGF- β1, PDGF and other growth factors secreted by activated alveolar macrophages and the like are significantly increased, wherein TGF- β1 is a classical pro-fibrotic factor, promotes fibroblast proliferation and activation, and further synthesizes a large amount of collagen, resulting in alveolar space thickening and matrix accumulation, and promotes the progress of fibrosis. Compounds directed against IL-6, IL-1. Beta. Can alleviate RILI, whereas targeting TGF-beta.1, inhibiting its pro-fibrosis is a hotspot in anti-pulmonary fibrosis studies.
RILI presents a broad range of invasive inflammation, with the clinical use of glucocorticoids to alleviate inflammation, or with the instillation of amifostine immediately prior to radiation therapy to reduce morbidity, but both have significant side effects, with lower patient compliance; the radioactive pulmonary fibrosis is represented by matrix structure reconstruction and gas exchange function decline, no approved therapeutic drugs exist at present, and the curative effects of drugs for the radioactive pulmonary fibrosis (idopathic pulmonary fibrosis) such as pirfenidone, nindaanib and the like on the radioactive pulmonary fibrosis are yet to be determined, and the side effects are unknown. Compared with chemical synthesized medicines, the traditional Chinese medicine has relatively small side effect, and if the traditional Chinese medicine-based therapeutic medicine for RILI is developed through strict experiments, the defect of serious side effect of the traditional western medicines can be effectively avoided, and the popularization and application of the traditional Chinese medicine are facilitated. Therefore, there is a need in the art to find traditional Chinese medicinal materials or Chinese patent medicines capable of treating RILI.
Disclosure of Invention
The invention aims at providing the application of a composition containing ganoderma lucidum active ingredients.
It is another object of the present invention to provide a method of treating radiation lung injury and complications thereof.
To solve the above technical problems, according to a first aspect of the present invention, there is provided a use of a composition containing an active ingredient of ganoderma lucidum, for:
(i) Preventing and/or treating radiation lung injury and complications thereof;
(ii) Preparing a medicament for preventing and/or treating radiation lung injury and complications thereof;
(iii) Inhibit/alleviate pulmonary inflammation caused by radiation lung injury;
(iv) Reducing the number of metastatic nodules in lung tissue caused by radiation lung injury;
(v) Down-regulating the expression level of fibrosis-associated protein in lung tissue; and/or
(vi) Modulating the level of an oxidative stress-related factor in lung tissue;
wherein the composition comprises ganoderma lucidum spore powder and ganoderma lucidum extract, and the ganoderma lucidum extract comprises ganoderma lucidum triterpene.
In some preferred embodiments, the ganoderma lucidum extract further comprises ganoderma lucidum polysaccharide.
In some preferred embodiments, the composition comprises no less than 8% by mass of the ganoderma lucidum triterpene, more preferably no less than 10%, and even more preferably from 8% to 20%.
In some preferred embodiments, the ganoderma lucidum triterpenes include acidic ganoderma lucidum triterpenes and neutral ganoderma lucidum triterpenes.
In some preferred embodiments, the composition comprises not less than 10% by mass of the acidic ganoderma lucidum triterpene and not less than 10% by mass of the neutral ganoderma lucidum triterpene.
In some preferred embodiments, the composition comprises not less than 10% by mass of ganoderan, more preferably not less than 12% by mass, and even more preferably 10% -20% by mass.
In some preferred embodiments, the ganoderma lucidum spore powder is a wall-broken ganoderma lucidum spore powder.
In some preferred embodiments, the composition containing the active ingredient of ganoderma lucidum comprises ganoderma lucidum extract and wall-broken ganoderma lucidum spore powder.
In some preferred embodiments, the composition comprises 60% -90% by mass of the ganoderma lucidum extract, for example 60%,65%,70%,75%,80% or 85%.
In some preferred embodiments, the radiation lung injury is lung injury resulting from radiation treatment of a malignancy.
In some preferred embodiments, the malignancy is a breast malignancy; more preferably, the malignancy is selected from at least one of lung cancer, breast cancer, esophageal cancer, mediastinal malignancy (e.g., thymoma, lymphoma, lipoma, and teratoma), pleural mesothelioma, chest wall malignancy, and melanoma.
In some preferred embodiments, the complications of radiation lung injury include radiation pneumonitis and radiation pulmonary fibrosis.
In some preferred embodiments, the fibrosis-associated protein includes alpha-SMA, collagen I, collagen III, and TGF-beta 1.
In some preferred embodiments, the preparation of the wall-broken ganoderma lucidum spore powder comprises the steps of: sequentially sieving and cleaning Ganoderma spore powder, sterilizing, drying, and breaking cell wall. In some preferred embodiments, the sterilization process is a high pressure steam sterilization process.
In some preferred embodiments, the wall breaking treatment is a low temperature physical wall breaking treatment.
In some preferred embodiments, the wall breaking rate of the low-temperature physical wall breaking treatment is not less than 99.0%.
In some preferred embodiments, the method for preparing the ganoderma lucidum extract comprises the steps of:
s1, crushing ganoderma lucidum into coarse particles, extracting the particles with 70% -95% ethanol, and filtering to obtain filter residues and filtrate;
s2, concentrating the filtrate obtained in the step S1 to obtain a first concentrated solution, and adding water into the first concentrated solution to obtain a precipitate;
s3, extracting filter residues obtained in the step S1 by using water, filtering, and concentrating filtrate to obtain a second concentrated solution;
s4, mixing the precipitate obtained in the step S2 with the second concentrated solution obtained in the step S3, and drying to obtain the ganoderma lucidum extract.
In some preferred embodiments, in step S2, 0.8 to 1.5 volumes of water are added to the first concentrate for precipitation treatment to obtain a precipitate.
In some preferred embodiments, in step S3, the filter residue obtained in step S1 is extracted with 8-12 volumes of water, filtered and the filtrate is concentrated to obtain a second concentrate.
In some preferred schemes, the composition containing ganoderma lucidum spores is Kang Aizhi Baozhu ganoderma lucidum spore powder ganoderma lucidum capsules China).
In a third aspect of the invention, there is provided a method of treating radiation lung injury and complications thereof, the method comprising the steps of: administering to a subject a therapeutically effective amount of a composition comprising ganoderma lucidum active ingredient, the composition comprising ganoderma lucidum spore powder and a ganoderma lucidum extract, the ganoderma lucidum extract comprising ganoderma lucidum triterpenes, the mass percent of the ganoderma lucidum triterpenes being not less than 8%.
In some preferred embodiments, the ganoderma lucidum extract further comprises ganoderma lucidum polysaccharide, wherein the mass percentage of the ganoderma lucidum polysaccharide is not less than 10%.
In some preferred embodiments, the therapeutically effective amount is 0.6 g/day, more preferably 0.9 g/day; more preferably 1.5 g/day.
The invention has at least the following advantages over the prior art:
the composition can inhibit radioactive lung injury, alleviate inflammatory response of lung tissues caused by radiotherapy, reduce inflammatory factor level, improve oxidative stress level, lower fibrosis-related protein level and reduce tumor metastasis nodules of lung for the first time, and has no side effect. The compositions are useful in the adjuvant therapy of radiation lung injury and prognosis of radiation therapy patients.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings.
FIG. 1A is a schematic illustration of a experimental protocol for chest irradiation in a tumor-bearing mouse according to an embodiment of the invention;
fig. 1B is a block diagram of chest vaccination of groups of tumor-bearing mice according to an example of the invention (n=4-5, 1 in group No-IR mice dying from chest tumor size, P <0.01vs No-IR group);
FIG. 1C is a graph showing comparison of tumor weights of groups of tumor-bearing mice according to an embodiment of the present invention;
fig. 1D is a plot of tumor volume growth (n=5) for the example according to the invention, P <0.01vs No-IR group;
FIG. 1E is a graph of HE staining of lung tissue (scale = 500 μm,50 μm; normal group is non-tumor bearing non-irradiated mice) according to an embodiment of the invention;
fig. 1F is a graph of the change in body weight of mice in each group (n=5) according to the example of the present invention;
FIG. 2A is a schematic illustration of an experimental plan of the effect of GanoExtra administration on B16F10 tumor lung metastasis nodules following irradiation in accordance with an embodiment of the invention;
fig. 2B is a plot of the tumor mass of each group of experimental mice chest vaccinated according to an embodiment of the present invention (n=6, wherein one mouse in the No-IR group died due to tumor mass exceeding 16 days post-vaccinated, and No tumor mass was found in one mouse in the IR group at the termination of the experiment);
fig. 2C is a graph of comparison of tumor weights for groups according to an embodiment of the present invention, P <0.01vs No-IR group;
fig. 2D is a graph of tumor volume growth (n=6) in an embodiment according to the invention;
fig. 2E is a plot of HE staining (arrows indicate melanoma metastasis nodules, scale = 500 μm,50 μm) according to an embodiment of the invention;
fig. 2F is a graph of lung metastasis nodule counts (n=3-5 slices) for groups according to an embodiment of the invention, P<The 0.01vs No-IR group, ## P<0.01vs IR group;
fig. 3A is a graph of HE staining observing lung inflammatory responses of groups (scale = 200 μm,20 μm) according to an embodiment of the invention;
figure 3B is a graph of the results of blood cell analysis of groups of mice (here showing inflammatory cell analysis associated with pneumonia) according to an embodiment of the invention (n=5 to 6), * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group, WBC representing white blood cell count; LYM, # of LYM represents the percentage of lymphocytes and the lymphocyte count, respectively; GRAN, # GRAN represents percent neutrophils and neutrophil counts, respectively; MID, mid# represent the percentage of intermediate cells and intermediate cell count, respectively, as follows;
FIG. 4A is an RT-PCR assay of IL-1. Beta., IL-6 and TNF-alpha. MRNA expression (n=5-6) in lung tissue of various groups of mice according to an embodiment of the invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
figure 4B is a graph of antioxidant enzyme SOD, GSH-Px and oxidation factors MDA and NO levels (n=5-6) in various groups of lung tissue according to an embodiment of the invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
fig. 5A is a result of Masson staining of lung tissue of each group of 4 montahs after irradiation (scale=500 μm,50 μm) in an embodiment according to the present invention;
figure 5B is an IOD value (n=3) of blue (collagen) in a Masson staining chart using ImageJ analysis in accordance with an embodiment of the present invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
figure 5C is a blood cell analysis (n=6) of groups of mice 4 montahs after irradiation in an example according to the invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
FIG. 6A is a graph showing the mRNA expression level (n=6) of alpha-SMA, collagens, TGF-. Beta.1 in lung tissue of mice of each group of 4 montants after irradiation according to the RT-PCR assay of the present invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
FIG. 6B is a graph showing the expression levels of alpha-SMA (n=3) in lung tissue of mice of each group of 4 montants after irradiation by Western Blot detection in an embodiment of the invention, * P<0.05， ** P<0.01vs Normal group; # P<0.05, ## P<0.01vs IR group;
FIG. 7 shows SOD, GSH-Px, MDA and NO levels in lung tissue of 4 molts mice groups after irradiation, P <0.05, P <0.01vs Normal groups, according to an embodiment of the invention; #P <0.05, #P <0.01vs IR group.
Detailed Description
The incidence rate of radioactive lung injury (RILI) caused after chest malignant tumor radiotherapy is about 16-28%, and the probability of acute radiation pneumonia caused by RILI evolving into pulmonary fibrosis is about 50.3%, and the respiratory function of patients is seriously affected by extensive pulmonary fibrosis. However, to date, drugs for treating RILI are limited and mostly chemical drugs, and have strong side effects. The present inventors have conducted extensive and intensive studies and as a result, they have found that a composition containing an active ingredient of ganoderma lucidum is capable of effectively inhibiting RILI, has a therapeutic effect superior to that of a chemical drug in inhibiting RILI complications, and has no side effects, and at the same time, a composition containing an active ingredient of ganoderma lucidum is capable of reducing tumor lung metastasis nodules, thus being useful for the treatment of RILI and its complications and as an adjuvant therapy for improving the prognosis of radiotherapy.
Use of composition containing active ingredient of ganoderma lucidum
The invention relates to the use of a composition containing ganoderma lucidum active ingredients for: (i) Preventing and/or treating radiation lung injury and complications thereof; (ii) Preparing a medicament for preventing and/or treating radiation lung injury and complications thereof; (iii) Inhibit/alleviate pulmonary inflammation caused by radiation lung injury; (iv) Reducing the number of metastatic nodules in lung tissue caused by radiation lung injury; (v) Down-regulating the expression level of fibrosis-associated protein in lung tissue; and/or (vi) modulating the level of an oxidative stress-related factor in lung tissue.
In the invention, the composition containing the active ingredients of the lucid ganoderma comprises lucid ganoderma spore powder and lucid ganoderma extract, wherein the lucid ganoderma extract accounts for not less than 60% w.t%. In a more preferred embodiment, the mass percentage of the ganoderma lucidum extract is 60% -90%, such as 60%,65%,70%,75%,80% or 85%. The Ganoderma extract comprises Ganoderma triterpene. The Ganoderma triterpene comprises Ganoderma acid triterpene and Ganoderma neutral triterpene. The Ganoderma extract is also rich in Ganoderma polysaccharides such as beta-glucan. The ganoderma acid triterpene, ganoderma neutral triterpene and ganoderma beta-glucan in the ganoderma extract are synergistic with the components of triolein, ergosterol and the like in the wall-broken ganoderma lucidum spore powder in the composition, so that the radioactive lung injury and complications thereof are obviously inhibited or relieved. In a preferred embodiment of the invention, the content of the ganoderma lucidum triterpene in the composition is not less than 8 percent by mass. More preferably not less than 10%; more preferably 8% -20%. In a preferred embodiment of the present invention, the composition further comprises ganoderan, wherein the ganoderan is not less than 10% by mass, more preferably not less than 12% by mass, and even more preferably 10% -20% by mass.
When the composition contains only trace ganoderma lucidum triterpene compounds, the effect of resisting inflammation or pulmonary fibrosis caused by radioactive lung injury is not obvious, and when the content of ganoderma lucidum triterpene compounds is not less than 8% of the mass of the composition and the content of ganoderma lucidum polysaccharide is not less than 10% of the mass of the composition, the expression level of pulmonary fibrosis protein can be well inhibited and the level of pulmonary oxidative stress factor can be reduced.
When the composition contains both ganoderma triterpene and ganoderan, the immunity of the organism is stronger. The ganoderan can promote immunity and pulmonary fibrosis to a certain extent.
In the present invention, the term "ganoderma lucidum" is a dried fruiting body of the fungus ganoderma lucidum Ganoderma lucidum (Leys. Ex Fr.) karst. Of Polyporaceae, which is recorded in the pharmacopoeia 2020 edition of the people's republic of China.
In the invention, the term "broken-wall ganoderma lucidum spore powder" is powder obtained by treating spores generated by ganoderma lucidum fruiting bodies, and the term "ganoderma lucidum spores" refers to tiny oval germ cells ejected from fruiting bodies of ganoderma lucidum in the growth and maturation period, namely seeds of ganoderma lucidum, which are brown, oval, truncated at one end and have double walls. The invention discovers that although the ganoderma lucidum spores have therapeutic effect, the wall-broken ganoderma lucidum spore powder obtained through the processes of cleaning, sterilizing, drying and wall breaking has a significantly better effect on the treatment of the radioactive lung injury than the untreated ganoderma lucidum spores.
In the present invention, the terms "ganoderic acid triterpene" or "acidic ganoderic acid triterpene" are used interchangeably and are ganoderic acid C, ganoderic acid C2, ganoderic acid G, ganoderic acid B, ganoderic acid a, ganoderic acid H, ganoderic acid D and ganoderic acid F. The acidic triterpene of Ganoderma can be extracted from Ganoderma by extracting with organic solvent, ultrasonic wave, microwave, and supercritical CO 2 Extraction method, etc.
In the present invention, the terms "ganoderma lucidum neutral triterpene" or "neutral ganoderma lucidum triterpene" are used interchangeably and are ganoderic acid triol, ganoderic alcohol a, ganoderic aldehyde a and ergosterol. The Ganoderma neutral triterpene can be extracted from Ganoderma by extracting with organic solvent, ultrasonic wave, microwave, and supercritical CO 2 Extraction method, etc.
In the present invention, the term "ganoderma lucidum beta-glucan" refers to a macromolecular compound extracted from ganoderma lucidum and broken spore powder, the structure of the macromolecular compound is mainly beta-pyrane glucan connected by glycosidic bonds, the main monosaccharide component is glucose, and the macromolecular compound contains other small amounts of monosaccharide components of D-arabinose, D-xylose, D-mannose and D-galactose, and the molecular weight is mainly distributed in 8 multiplied by 10 4 ～2×10 5 The molecular mass is mainly 2×10 5 Is a biological macromolecule of (a). The extraction process includes, but is not limited to, water extraction, high temperature and high pressure extraction, subcritical extraction, ultrasonic extraction, microwave extraction, and the like.
As the ganoderma lucidum spore powder in the composition, the preparation method of the ganoderma lucidum spore powder in the invention comprises the following steps: sequentially cleaning Ganoderma spore powder, sterilizing, drying, and breaking cell wall.
The mode of the sterilization treatment in the present invention is not limited, and in a preferred embodiment, the sterilization treatment is a high-pressure steam sterilization treatment.
In the preferred embodiment, the wall breaking treatment is a low-temperature physical wall breaking treatment. In a more preferred embodiment, the wall breaking rate of the low-temperature physical wall breaking treatment is not less than 99.0%, and the obtained ganoderma lucidum spore powder has good drug effect.
In the preferred embodiment of the invention, the composition containing the active ingredients of the ganoderma lucidum is Kang Aizhi Baozhu ganoderma lucidum spore powder ganoderma lucidum capsulesChina). Ganoderma lucidum spore powder and Ganoderma lucidum Capsule (Fu Ling) of Kang Aizhi Bao brand>China) is mainly composed of ganoderma lucidum extract and ganoderma lucidum spore powder,
in the present invention, the term "radiation lung injury (RILI)" refers to injury of different degrees caused by exposure of lung tissue to a dose of radiation, and major complications include radiation pneumonitis and radiation pulmonary fibrosis, which can seriously lead to impaired respiratory function and respiratory failure.
In the present invention, the term "radiation pneumonitis" refers to an inflammatory reaction caused by injury of normal lung tissues in a radiation field after the lung tissues are irradiated with a certain dose.
In the present invention, the term "radioactive pulmonary fibrosis" refers to a broad range of pulmonary fibrosis formed by radioactive damage to normal pulmonary tissue in a radiation field after the pulmonary tissue is irradiated with a certain dose.
Therapeutic method
The invention also relates to a method for preventing and/or treating radiation lung injury and complications thereof, comprising the steps of: administering a therapeutically effective amount of a composition containing an active ingredient of ganoderma lucidum to a subject, wherein the composition comprises ganoderma lucidum spore powder and ganoderma lucidum extract, wherein the ganoderma lucidum extract comprises ganoderma lucidum triterpenes, and the mass percentage of the ganoderma lucidum triterpenes is not less than 8%.
In a preferred embodiment of the present invention, the composition further comprises a ganoderan content of not less than 10%.
As used herein, the term "subject" is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a particular embodiment, the subject is a human. In a particular embodiment, the subject is a mouse.
As used herein, the term "preventing" refers to preventing the onset, recurrence or spread of a disease or disorder, or one or more symptoms associated with the disease or disorder. In one embodiment, the symptoms are known to those of skill in the art to be associated with the disease or condition to be prevented. In certain embodiments, the term refers to administration of a drug provided herein with or without other additional active agents prior to onset of symptoms, for a patient at risk of suffering from a disease or disorder described herein. The term includes inhibition and reduction of symptoms of a particular disease. In particular embodiments, patients with a family history of a disease are particularly candidates. In addition, patients with a history of recurrent symptoms are also potential preventive candidates. In this regard, the term "preventing" may be used interchangeably with the term "prophylactic treatment".
As used herein, a "therapeutically effective amount" refers to an amount of a drug sufficient to provide a therapeutic effect in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a drug refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic effect in the treatment or management of a disease or disorder. The term "therapeutically effective amount" may include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. In a preferred embodiment of the invention, the therapeutically effective amount for mice is 0.1-2gPreferably 0.15-1g/kg; more preferably 0.25-0.5g/kg. According to the health food function test and evaluation method (2023 edition), the therapeutically effective amount for human is 0.6-12g/kg, more preferably 0.9-6g/kg; more preferably 1.5-3g/kg. The composition containing the ganoderma lucidum active ingredient in the invention is preferably orally administered. In a more preferred embodiment, kang Aizhi Baozhu ganoderma lucidum spore powder ganoderma lucidum capsules are applied to the subjectChina).
The frequency of administration of the composition containing the ganoderma lucidum active ingredient in the present invention can be adjusted according to the symptoms of the subject. In a preferred embodiment of the invention, the dosing frequency is 1-3 times daily. In the preferred embodiment of the invention, reference is made to Kang Aizhi Baozhu ganoderma lucidum spore powder ganoderma lucidum capsulesChina) instructions in the kit.
The present invention will be further described with reference to specific embodiments in order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated. The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs, it is to be noted that the terms used herein are used merely to describe specific embodiments and are not intended to limit the exemplary embodiments of this application.
The term "or" means and is used interchangeably with the term "and/or" unless otherwise indicated.
As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.
Chemicals, reagents and laboratory animals
The composition (GanoExtra) containing Ganoderma active ingredient used in the following examples is obtained from Kang Aizhi Baozhen Ganoderma spore powder Ganoderma capsuleChina). Kang Aizhi the main ingredient of Ganoderma spore powder Ganoderma capsule is Ganoderma extract and Ganoderma spore powder, and the triterpene content is not less than 8% and Ganoderma polysaccharide content is not less than 10% by detection. The main components of the Kang Aizhi Baozhu ganoderma lucidum spore powder ganoderma lucidum capsule are produced by the following processes:
the production process of the ganoderma lucidum extract comprises the following steps: pulverizing Ganoderma into coarse granule, extracting with 10 times of 95% ethanol for 2 hr for 2 times, filtering after extraction, concentrating to obtain suspension with a ratio of suspension volume to crude drug weight of 1:1, and centrifuging or filtering the concentrate with 1 times of water for precipitation to separate precipitate; extracting the residue with 10 times of water for 2 hr, filtering, concentrating, mixing the water concentrate with the precipitate, and drying to obtain Ganoderma extract powder.
The production process of the ganoderma lucidum spore powder comprises the following steps: cleaning Ganoderma spore powder with drinking water, removing larger impurities with 180 μm sieve, removing fine impurities with 50 μm sieve, sterilizing with high pressure steam, drying to water content less than 6%, and breaking cell wall with low temperature physical wall breaking technology to obtain wall breaking rate not less than 99.0%. The superoxide dismutase (SOD) assay kit (CAT: A001-3), glutathione peroxidase (GSH-Px) assay kit (CAT: A005-1), malondialdehyde (MDA) assay kit (CAT: A003-1) and Nitric Oxide (NO) assay kit (CAT: A012-1) used herein are all purchased from Nanjing's institute of biological engineering.
Glycyrrhetinic acid (Enoxolone, en, CAS: 471-53-4), amifostine (Amifostine, am, CAS: 20537-88-6) as used herein were all purchased from GLPBIO corporation, USA.
Sodium carboxymethylcellulose (CMC-Na) as used herein was purchased from Albumin Biochemical technologies Co., ltd (CAS: 9004-32-4, china).
The preparation method of the ganoderma lucidum suspension used in the present invention is as follows: accurately weighing a proper amount of ganoderma lucidum spore powder, adding the ganoderma lucidum spore powder into 0.1 percent CMC-Na solution (the solvent is ultrapure water), mixing uniformly by vortex, and carrying out ultrasonic treatment at the constant temperature of 37 ℃ for 30min to prepare ganoderma lucidum spore powder suspension with concentration gradients of 0.042, 0.084 and 0.168 g/mL.
The B16F10 cells used herein were purchased from the chinese academy of sciences stem cell bank and cultured as follows: cultured in complete RPMI 1640 complete medium (Semerle Feishmania technologies Co., USA) containing 10% fetal bovine serum, 100IU/mL penicillin and 100. Mu.g/mL streptomycin, routinely cultured and passaged in 5% CO2 incubator at 37 ℃.
The experimental animals used herein were 60C 57BL/6J male mice (SPF grade, body weight 18-22 g), which were kept in the laboratory animal center of the university of medical sciences of Fujian, kept at about 22.+ -. 1 ℃ at room temperature, set for 12 hours for light and dark circulation, and provided sufficient food and water.
Experimental method
1. Model of radiation pneumonitis of tumor-bearing mice and ganoderma lucidum preventive administration
To establish a model of tumor-bearing in the chest of the mice, B16F10 melanoma cells (7X 10) were seeded in the chest of the mice at a position close to the right forelimb 1week before irradiation 5 cells/cell), black spots grow from 3 to 5 days, tumors around 1week, and the size of soybeans is about. Tumor-bearing mice are randomly grouped, 6 mice in each group are fixed in a special device after being inoculated and anesthetized by intraperitoneal injection of 70mg/kg of 3% pentobarbital sodium on day 7, and the lung of the mice is singly irradiated with 6MV-X rays by a linear accelerator (Clinac 600C/D) to be about 1.5cm wide, the dose rate is 500cGy/min, the total dose is 18Gy, and the absorbed dose is 15Gy, so that a RILI model is formed. The experiment was ended 12-15 d after irradiation (19-22 d after tumor inoculation), and was an acute pneumonia stage. Normal group (Normal) is tumor-free, non-irradiated mice.
The dosing scheme is as follows: on day 5 before irradiation, 0.5g/kg, 1.0g/kg GanoExtra (fromKang Aizhi Ganoderma lucidum spore powder and Ganoderma lucidum capsuleIntragastric administration (about 0.15-0.3 ml/dose) once a day, for a period of time up to day 12 after irradiation; the IR+En 30mg/kg group was administered by gavage for 2 days before irradiation, en 30mg/kg, once a day, and 7 consecutive days, followed by once every other day to day 12 after irradiation. Meanwhile, normal group, no-IR group, IR group mice were given an equivalent amount of 0.1% cmc-Na, and were given by gavage once a day. The experiment was terminated synchronously on day 13 after irradiation.
2. Radioactive pulmonary fibrosis model and ganoderma lucidum preventive administration
C57BL/6 mice were anesthetized and fixed in a special device, and chest irradiated as described above to form a RILI model, which was terminated 4months after irradiation for the chronic fibrosis stage. Mice were randomly divided into 6 groups: pseudo-irradiation group (Control), IR group, IR+GanoExtra 0.25g/kg, IR+GanoExtra 0.5g/kg group, IR+GanoExtra 0.25 g/kg+En30 mg/kg group, IR+En30 mg/kg group, 6 each. The dosing scheme is as follows: ganoExtra administration groups were administered by gavage at a dose of 0.25g/kg and 0.5g/kg beginning 5 days before irradiation, once a day, and once every other day after 1 month; the IR+En 30mg/kg group was administered with En 30mg/kg by intragastric administration 2 days before irradiation, once a day, and once every other day after 7 consecutive days; the combination group (IR+GanoExtra 0.25g/kg+En 30 mg/kg) was given GanoExtra 0.25g/kg and En 30mg/kg; control and IR mice were given equal amounts of CMC-Na at the time of gavage. Dosing was stopped 3 months after irradiation and the experiment was terminated 4months after irradiation.
3. Routine detection of mouse blood
Blood routine testing was performed on the blood of each group of mice at 13d post-irradiation and at 4 montas post-irradiation termination. The mice were harvested from their eyeballs and whole blood was placed in a 1.5mL anticoagulation centrifuge tube, after which the mice were immediately sacrificed by cervical dislocation. And (5) timely sending out the blood after blood sampling within 2 hours, and detecting blood routine by using a URIT-2900VetPLUS full-automatic animal blood cell analyzer.
4、Western blot
The protein concentration was measured by selecting 20mg of right lung tissue, extracting protein with RIPA lysate (bio-technology limited of beijing tripod, china) and using BCA protein assay kit (bio-technology limited of beijing tripod, china). Protein samples were separated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and proteins were transferred to PVDF membranes. 5% nonfat milk powder shaker blocked for 2h, and after incubation overnight at 4℃using a-SMA rabbit primary antibody (# 19245,Cell Signaling Technology Co., USA), secondary antibody (# 7074P2,Cell Signaling Technology Co., USA) was incubated for 1h. Finally, chemiluminescent development was performed using ECL reagent (SAB company, usa).
5. Real-time fluorescent quantitative PCR
Left lung tissue 10mg was selected, extracted using Trizol reagent according to manufacturer's instructions using Total RNAIII 1st Stand cDNA Synthesis SuperMix for qPCR (YEASEN Co., china) suspension reverse transcription of mRNA into cDNA, use +.>qPCR SYB Green Master Mix (YEASEN Co., china) performing real-time fluorescent quantitative PCR (RT-PCR) to obtain C t Values. By 2 -ΔΔCt The method resulted in relative expression levels of each set of mRNAs. Primers (Table 1) were purchased from the Shang Ya organism (China).
TABLE 1 primer sequence listing
6. H & E and Masson staining
Taking a lung tissue sample, embedding paraffin, slicing and dewaxing, sequentially carrying out hematoxylin staining and eosin staining, removing water from the slices, shooting by a microscope, carrying out HE staining image analysis, observing a lung slice scanning image on a SlideViewer software, and counting the number of melanoma lung metastasis nodules on each lung slice. The Masson dyeing is to carry out aniline blue dyeing after eosin dyeing, finally, removing the water seal slice, and carrying out image acquisition and analysis by a microscope.
7. Detection of oxidative stress index (SOD, GSH-Px, MDA, NO)
Right lung tissue of the mouse is taken to be 20mg, and physiological saline is added to prepare 10% lung tissue homogenate. The protein concentration in 1% of the tissue homogenate was determined using BCA protein assay kit (bejing ding biotechnology limited, china); according to the manufacturer's instructions, the WST-1 method was used to determine the activity of SOD; measuring the activity of GSH-Px by adopting an enzymatic reaction method; measuring the MDA content by adopting a TBA method; the content of NO was determined by nitrate reductase.
8. Data statistics
The above experimental results were analyzed for group differences by One-Way ANOVA using GraphPad Prism8 software. The measurement data adopts mean ± standard deviationOr median and quarter bit spacing. The difference is at p<0.05 was considered significant.
2. Experimental results
Examples 1-4 below demonstrate that prophylactic administration of GanoExtra of the present invention reduces lung inflammation following chest subcutaneous tumor combined with chest irradiation.
EXAMPLE 1 GanoExtra 1g/kg did not affect inhibition of B16F10 subcutaneous inoculum by chest irradiation while reducing pulmonary inflammation
The C57BL/6 mice were subcutaneously chest vaccinated with B16F10 melanoma in combination with chest irradiation, and the results showed a significant decrease in tumor volume and tumor weight in the irradiated group (IR) compared to the non-irradiated group (No-IR) (fig. 1B,1C,1 d), indicating that B16F10 tumors were sensitive to radiation treatment. Amifostine has a radical scavenging effect and is often clinically injected prior to radiation therapy to protect normal cells. The tumor volume and tumor weight of amifostine group (ir+am) were not significantly different from those of No-IR group, showing that amifostine also reduced the killing effect of irradiation on tumors when scavenging free radicals caused by irradiation. GanoExtra 1g/kg (tumor volume and tumor weight significantly reduced compared to No-IR group, no difference from IR (FIGS. 1B,1C, 1D) showed that GanoExtra is different from amifostine and that GanoExtra did not affect the inhibition of B16F10 subcutaneous inoculation tumors by chest irradiation.
In the B16F10 tumor-bearing mice of this example, the development of lung inflammation was multiply affected by systemic inflammatory response caused by breast tumors, tumor lung metastasis, and lung radiotherapy. HE staining shows that obvious lung texture thickening and inflammatory cell infiltration exist in both No-IR and IR groups, the lung tissue textures of the IR+GanoExtra 1g/kg group and the IR+Am group are clearer, and inflammatory reactions are not obvious, so that GanoExtra and amifostine have the effect of reducing lung inflammation. However, the effect of the GanoExtra 2g/kg group (IR+GanoExtra 2 g/kg) was rather weaker than that of the IR+GanoExtra 1g/kg group, and the finding of the reasons revealed that the IR+GanoExtra 2g/kg group of mice contained a large amount of undigested ganoderma lucidum drug in the intestines, suggesting that the dosage of GanoExtra 2g/kg was too large. There was no significant difference in body weight among the mice in each experimental group (fig. 1F).
Example 2 administration of GanoExtra can further reduce pulmonary metastasis nodules of B16F10 tumors after chest irradiation
Pulmonary metastasis is a dangerous clinical step in melanoma lesions and treatment at this stage is limited. In this example, the inventors analyzed the effect of irradiation and GanoExtra administration on pulmonary metastasis nodules of B16F10 melanoma in mice. The results show (FIGS. 2B,2C, 2D) that chest irradiation significantly inhibited the growth of B16F10 vaccinated tumors (P < 0.05) compared to the No-IR group; compared with the IR group, the GanoExtra0.5g/kg and GanoExtra 1g/kg treatment groups have no obvious difference between tumor weight and tumor volume, and the GanoExtra does not show the radiosensitization effect due to the high sensitivity of B16F10 to radiotherapy; HE staining observed and counted for melanoma metastasis nodules in lung tissue (FIGS. 2E, 2F), and found that the presence of large amounts of micro-melanoma (16.3.+ -. 1.5/slice) in lung tissue in group No-IR, chest irradiation significantly reduced the metastasis nodules (4.4.+ -. 2.5/slice) in lung tissue; the GanoExtra administration further reduced the number of tumor metastasis nodules in lung tissue compared to the IR group (GanoExtra 1g/kg group 1.8±1.1/slice) (fig. 2e,2 f).
Glycyrrhetinic acid (En) was reported to have an effect of resisting radiation-induced lung injury, and in this example, it was observed that the antitumor effect of IR+En 30mg/kg and the pulmonary metastasis nodule inhibiting effect were comparable to GanoExtra (FIGS. 2B to 2F).
Example 3 inhibition of lung inflammation in tumor-bearing mice after chest irradiation by GanoExtra
In this example, chest-irradiated tumor-bearing mice were treated with GanoExtra and control drugs. HE staining and blood routine tests showed (fig. 3a,3 b) that both tumor-bearing No-IR group and irradiated IR group exhibited significant inflammation, alveolar wall thickening, inflammatory cell infiltration, while WBC numbers in blood were significantly increased, compared to non-tumor-bearing, non-irradiated Normal group, indicating the presence of lung inflammation associated with lung metastasis nodules and irradiation, respectively, in No-IR group and IR group; ganoExtra and En administered groups reduced inflammatory cell infiltration, and lung tissue structure was nearly Normal, while significantly down-regulating WBC numbers and was similar to Normal groups.
Further analysis of various cells in WBC (FIG. 3B) revealed that neutrophils and macrophages (the major component of MID) were significantly elevated in the No-IR and IR groups, with the No-IR group elevating neutrophils more strongly and the IR group elevating macrophages more strongly, than in the Normal group. GanoExtra and En have a decreasing effect on the number of WBC and subset neutrophils, macrophages in the blood of tumor bearing mice during the radiation pneumonitis period (P < 0.05). The above results indicate that GanoExtra has an inhibitory effect on pulmonary inflammatory response both in association with pulmonary metastasis nodules and in association with chest radiotherapy.
Example 4 modulation of inflammatory and oxidative stress factors in tumor-bearing mice during radiation pneumonitis
The RT-PCR method is adopted to detect the expression condition of inflammatory factors in lung tissues after chest irradiation of tumor-bearing mice (figure 4A), and the result shows that compared with Normal groups, the expression level of mRNA of IL-1 beta and IL-6 in the No-IR and IR groups is obviously up-regulated, and the mRNA of TNF-alpha in the IR group is also up-regulated; ganoExtra was able to significantly reduce IL-1β, IL-6 and TNF- α levels (P < 0.05) in lung tissue of tumor-bearing mice after irradiation compared to IR group. Meanwhile, the contents of oxidative stress products NO, MDA, and antioxidant enzymes SOD, GSH-Px in lung tissues were examined, and the results showed (FIG. 4B) that the SOD (and GSH-Px) contents of the No-IR and IR groups were decreased compared with the Normal group. Compared with the IR group, the content of the antioxidant enzyme SOD and GSH-Px of the GanoExtra and En administration groups is obviously increased (P is less than 0.05), but the content of NO and MDA is not reduced; these results indicate that GanoExtra is effective at alleviating the pulmonary inflammatory response in B16F10 tumor-bearing mice at lower doses, and against lung metastasis nodules and irradiation-induced oxidative stress by increasing antioxidant stress kinase. Notably, however, the high dose group (1 g/kg) of GanoExtra did not show a stronger potency than the low dose (0.5 g/kg) group, suggesting that GanoExtra can exert a stronger anti-radiation pneumonitis effect at lower doses.
Examples 5-7 below demonstrate that prophylactic administration of GanoExtra can alleviate radiation pulmonary fibrosis
Example 5 GanoExtra reduces pathological changes in radiation-induced pulmonary fibrosis and changes in blood inflammatory cells
Based on the remission of GanoExtra on radiation pneumonitis, in this example, the invention further investigated its effect on radiation pulmonary fibrosis. Masson staining (fig. 5A) of each group of lung tissue at 4 montahs (pulmonary fibrosis stage) after irradiation, significant collagen deposition was found in the IR group; reduced infiltration of cells and collagen deposition in lung tissue and reduced lung fibrosis in the GanoExtra, en and combination groups compared to the IR group; the conventional results in mouse blood showed (fig. 5B) that IR group WBCs and sub-lymphocytes and neutrophils were significantly elevated during the 4months radioactive pulmonary fibrosis period after irradiation. Compared to the IR group, there was a significant decrease in WBC counts for each treatment group; for lymphocyte numbers, each of the other administration groups, except the combination administration group, can be decreased; there was a significant decrease in neutrophil and macrophage numbers in the GanoExtra0.5g/kg group alone. The above results indicate that GanoExtra, en have a remission effect on pulmonary fibrosis and systemic inflammatory response caused by irradiation, wherein GanoExtra0.5g/kg is stronger than GanoExtra 0.25g/kg, but the combined administration does not show a more pronounced efficacy than administration alone.
EXAMPLE 6 GanoExtra down-regulates the expression level of fibrosis-related proteins such as alpha-SMA, collagen, TGF-beta 1 in radioactive pulmonary fibrosis tissues
In this example, RT-PCR was used to detect mRNA expression levels of fibrosis markers α -SMA, collagen I, collagen III and TGF- β1. The results showed (fig. 6A) that the IR group was significantly upregulated compared to the Normal group for the 4 fibrosis-associated proteins; the fibrosis-associated proteins were down-regulated in each treatment group compared to the IR group, and there was no significant synergy in the combination group relative to the GanoExtra and En-dosed groups. WB results showed (fig. 6B) that the expression level of α -SMA was down-regulated in each treatment group compared to the IR group, indicating that GanoExtra could effectively alleviate the extent of radiation lung fibrosis by down-regulating the expression of fibrosis-related proteins such as α -SMA, collagens, TGF- β1.
EXAMPLE 7 GanoExtra modulation of oxidative stress-related factors in radiofibrotic tissue
We examined the expression levels of oxidative stress-related factors in 4 montahs lung fibrosis tissues after irradiation (FIG. 7), and found that oxidative factors MDA and NO in lung tissues of IR group were significantly increased compared with Normal group; the GanoExtra dosed groups showed significantly reduced MDA and NO levels compared to the IR group, and the SOD and GSH-Px also had a tendency to decrease but not significantly. The combination group had no significant difference from the En-administered group. The above results indicate that the behavior of GanoExtra on antioxidant stress of lung tissue compared to the radiation pneumonitis stage is mainly increased antioxidant stress kinase content in the initial acute radiation pneumonitis stage, and is converted into reduction of oxidative stress factor in the later chronic pulmonary fibrosis development stage.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples of carrying out the invention and that various changes in form and details may be made therein without departing from the spirit and scope of the invention.
Claims (10)
1. Use of a composition comprising an active ingredient of ganoderma lucidum, characterized in that it is used for:
(i) Preventing and/or treating radiation lung injury and complications thereof;
(ii) Preparing a medicament for preventing and/or treating radiation lung injury and complications thereof;
(iii) Inhibit/alleviate pulmonary inflammation caused by radiation lung injury;
(iv) Inhibit/alleviate pulmonary fibrosis caused by radiation lung injury;
(v) Reducing the number of lung metastasis nodules following radiation treatment;
(vi) Down-regulating the expression level of fibrosis-associated protein in lung tissue; and/or
(vii) Modulating the level of an oxidative stress-related factor in lung tissue;
wherein the composition comprises ganoderma lucidum spore powder and ganoderma lucidum extract, and the ganoderma lucidum extract comprises ganoderma lucidum triterpene.
2. The use according to claim 1, wherein the ganoderma lucidum spore powder is a wall-broken ganoderma lucidum spore powder.
3. The use according to claim 1, wherein the ganoderma lucidum extract further comprises ganoderma lucidum polysaccharide.
4. The use according to claim 3, wherein the mass percentage of the ganoderma lucidum triterpenes in the composition is not less than 8%;
and/or, in the composition, the ganoderan is not less than 10%.
5. The use according to claim 4, wherein the complications of radiation lung injury include radiation pneumonitis and radiation pulmonary fibrosis.
6. The use according to claim 4, wherein the radiation lung injury is a lung injury caused by radiation treatment of a malignancy, which is a breast malignancy; more preferably, the malignancy is selected from at least one of lung cancer, breast cancer, esophageal cancer, mediastinal malignancy, pleural mesothelioma, chest wall malignancy, and melanoma.
7. The use according to claim 4, wherein the preparation method of the ganoderma lucidum extract comprises the steps of:
s1, crushing ganoderma lucidum into coarse particles, extracting the particles with 70% -95% ethanol, and filtering to obtain filter residues and filtrate;
s2, concentrating the filtrate obtained in the step S1 to obtain a first concentrated solution, and adding water into the first concentrated solution to obtain a precipitate;
s3, extracting filter residues obtained in the step S1 by using water, filtering, and concentrating filtrate to obtain a second concentrated solution;
s4, mixing the precipitate obtained in the step S2 with the second concentrated solution obtained in the step S3, and drying to obtain the ganoderma lucidum extract.
8. The use according to claim 4, wherein the preparation of the wall-broken ganoderma lucidum spore powder comprises the steps of: sequentially cleaning Ganoderma spore powder, sterilizing, drying, and breaking cell wall.
9. The use according to any one of claims 1 to 8, wherein the composition is Kang Aizhi baozhen ganoderma lucidum spore powder ganoderma lucidum capsule.
10. A method of treating radiation lung injury and complications thereof, the method comprising the steps of: administering to a subject a therapeutically effective amount of a composition comprising ganoderma lucidum active ingredient, the composition comprising ganoderma lucidum spore powder and a ganoderma lucidum extract, the ganoderma lucidum extract comprising ganoderma lucidum triterpenes, the mass percent of the ganoderma lucidum triterpenes being not less than 8%.
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