CN113730418A - Application of physalilactone B in preparation of medicine for treating diseases associated with cytokine storm - Google Patents
Application of physalilactone B in preparation of medicine for treating diseases associated with cytokine storm Download PDFInfo
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- CN113730418A CN113730418A CN202111133046.7A CN202111133046A CN113730418A CN 113730418 A CN113730418 A CN 113730418A CN 202111133046 A CN202111133046 A CN 202111133046A CN 113730418 A CN113730418 A CN 113730418A
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- Prior art keywords
- physalilactone
- inflammatory bowel
- bowel disease
- disease
- cytokine storm
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention discloses an application of physalis pubescens lactone B in preparing a medicine for treating diseases associated with cytokine storm, wherein the structural formula of the physalis pubescens lactone B is shown as follows. The invention also discloses an anti-inflammatory bowel disease medicament, which comprises the physalis pubescens lactone B, wherein the inflammatory bowel disease is acute colon injury. The invention discloses the application of the physalis pubescens lactone B in preparing the medicine for treating diseases associated with the cytokine storm for the first time, further expands the application range of the physalis pubescens lactone B, belongs to natural active compounds, is safe, reliable and free from toxic and side effects, and has potential development value in the field of preparing the medicine for treating the diseases associated with the cytokine storm.
Description
Technical Field
The invention belongs to the application field of physalis pubescens lactone B, and particularly relates to an application of physalis pubescens lactone B in preparation of a medicine for treating diseases associated with cytokine storm and an anti-inflammatory bowel disease medicine.
Background
"cytokine storm" is used to describe abnormally elevated levels of cytokines and chemokines and the accompanying immunopathological processes. For example, cytokine and chemokine levels are closely associated with morbidity and mortality from inflammatory bowel disease, graft versus host disease, sepsis, respiratory viral infection, hemorrhagic viral infection, and the like. At this stage, no safe and effective method has been developed for treating cytokine storm-related pathological processes.
Inflammatory Bowel Disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic nonspecific inflammation of the intestine with unknown etiology, including Ulcerative Colitis (UC) and Crohn's Disease (CD). The incidence and prevalence of these diseases have increased dramatically in recent years. The chronic colitis and ulcerative colitis have the pathological parts affecting rectum and colon, and have repeated attacks, mainly manifested as diarrhea, abdominal pain and mucopurulent bloody stool in clinic. Inflammatory bowel disease not only seriously affects the quality of life of patients, but also is liable to induce colorectal cancer.
The current drug treatment of inflammatory bowel diseases is mainly realized by controlling the inflammatory reaction of intestinal tracts and regulating immune disorder. There are four main types of drugs that are clinically used for treating inflammatory bowel disease: aminosalicylic acids, glucocorticoids, immune preparations and biological preparations, but have the problems of undesirable curative effect, serious side effect, high price and the like. Because of the advantages of rich resources, small side effects and the like, the development of novel anti-inflammatory drugs from natural drugs gradually becomes a research hotspot. Many natural pharmaceutical active ingredients exhibit varying degrees of anti-inflammatory effects on a variety of models of inflammation. The classes of anti-inflammatory natural product active ingredients that are currently found mainly include: phenylpropanoids, anthraquinones, monoterpenes and diterpenes, flavones and their glycosides, alkaloids, and polysaccharides.
Nuclear transcription factor (NF-kB) is an important transcription regulator in cells and plays an important role in maintaining normal physiological functions of organisms. The classical NF-kB signal path is related to the autoimmunity of the body, and the inflammatory response of vertebrates is an important expression form of autoimmunity. The inflammatory reaction is a complex process comprising many steps, which not only maintains the normal physiological functions of the body, but also has an influence on the long-term performance of the body. Many molecules involved in the early stages of the immune response and inflammatory response are regulated by NF- κ B, including: TNF-alpha, IL-1 beta, IL-2, IL-6, IL-8, etc. NF-kB participates in chronic inflammatory reaction of the body through molecular regulation and generates certain physiological change. The NF-. kappa.B signaling pathway thus plays an important regulatory role in various physiological processes of the body. In recent years, the relationship between the NF-kappa B signal channel and human diseases is more and more emphasized, and the NF-kappa B signal channel is closely related to inflammatory bowel diseases, if stronger targeting and lower toxicity can be developed, the NF-kappa B activation can be more effectively prevented, so that the symptoms of inflammatory bowel disease patients can be more effectively relieved, the adverse reaction of medicaments can be greatly reduced, and the life quality of the patients can be further improved.
Physalis pubescens, also known as cherry or sea girl, contains 18 amino acids required by the human body. The book Shen nong Ben Cao Jing was recorded at the earliest time and listed as a Chinese medicine. The hair Chinese lantern cherry has the effects of clearing away dysphoria with smothery sensation, clearing throat and the like, is commonly used for treating acute pharyngitis in folk, and has obvious effect. Modern pharmacological research shows that the physalis pubescens has the effects of resisting inflammation, resisting cancer, reducing blood sugar, reducing blood fat, regulating immunity, resisting allergy and the like.
Chen Fang et al (Chen Fang, Wang Yu Chen, Guanxuewa, colongen, et, anti-inflammatory action and mechanism research of ethanol extract of physalis pubescens. drug evaluation research, 2016,39(5): 747-752) research anti-inflammatory action and mechanism of ethanol extract of physalis pubescens. fruits, which uses physalis pubescens with persistent calyx as raw material, soaks 3 times of 80% ethanol by 10 times of volume at room temperature, then combines the extractive solutions, and obtains powder (recorded as AEFPP) through vacuum drying and crushing. Research results show that AEFPP can inhibit the expression of p65 protein, reduce the release of LPS-induced RAW264.7 cell inflammatory factors TNF-alpha and IL-6, and further play an anti-inflammatory role. First, however, the AEFPP is a complex mixture of components, the exact anti-inflammatory active ingredient is not clear, and quality control is not possible in industrial protocols; secondly, analysis of the anti-inflammatory data shows that the action concentration of mg/mL cannot be really realized in animal models or clinical human body tests.
Physapidus calyciferin B (PB) is an active compound obtained by extracting dried calyx of Physappan hirsutum with solvent, extracting, concentrating, eluting, and recrystallizing. However, the application of physalilactone B is less researched at present, and only the application of physalilactone B in tumor resistance is found. For example, as shown in the application publication No. CN 103961362 a, chinese patent document discloses an application of physalilactone B in the preparation of anticancer drugs, and test results show that physalilactone B can be used as a novel STAT3 inhibitor and a chemotherapeutic synergist, and can produce a synergistic effect when used in combination with cisplatin, thereby greatly improving anticancer activity, and having high anticancer activity on lung cancer, gastric cancer, breast cancer, colon cancer, ovarian cancer, liver cancer, and prostate cancer.
At present, no application report of the physalilactone B in anti-inflammatory drugs exists.
Disclosure of Invention
Aiming at the problems in the prior art, the invention discloses the application of the Physalilactone B (PB) in the preparation of the medicine for treating diseases associated with the cytokine storm for the first time, in particular the application in the preparation of the medicine for resisting inflammatory bowel diseases, and further expands the application range of the Physalilactone B (PB).
The specific technical scheme is as follows:
use of physalilactone B in the manufacture of a medicament for the treatment of a disease associated with a cytokine storm, said physalilactone B having the formula:
preferably, the disease associated with cytokine storm comprises: inflammatory bowel disease, graft versus host disease, sepsis, respiratory or hemorrhagic viral infection.
Further preferably, the disease associated with a cytokine storm is selected from inflammatory bowel disease, more preferably acute colon injury.
Preferably, the inflammatory bowel disease comprises ulcerative colitis or crohn's disease.
Through research, the PB disclosed by the invention can realize an anti-inflammatory effect by inhibiting a STAT1 signal pathway and/or an NF-kB signal pathway. The results of the detection of the cytokine expression level by the ELISA method are shown in the following table 1: the PB can remarkably reduce the transcription expression of inflammatory cytokines, chemokines and related proteins such as IL-6, TNF alpha, IL-1 beta and the like when treating RAW264.7 cells for 16 hours at 15 mu M, and the conclusion is also verified.
TABLE 1PB Effect on transcriptional expression of inflammatory cytokines, chemokines and related proteins (_ x + -s, n ═ 3)
FPKM (fragments per library of exon per fragments mapped): the number of reads per 1K bases of map to exon in reads per 1 million maps. FPKM reflects the expression level of the gene.
The in vitro cell experiment research shows that:
the physalidroside B disclosed by the invention can cause the average of phosphorylation levels of P-IKB alpha, P-P65 and P-IKK alpha/beta in upstream regulation and control channels STAT1 and NF-kappa B classical signal channels of cell factor storm related factors to be remarkably reduced, so that the activation of STAT1 and NF-kappa B classical signal channels is remarkably inhibited; can also obviously reduce the release of inflammatory cytokines TNF-alpha and IL-1 beta from RAW264.7 cells.
The in vivo anti-inflammatory research shows that:
proved by Lipopolysaccharide (LPS) induced zebra fish inflammation model research, the physalilactone B disclosed by the invention can obviously reduce the number of neutrophils and has a good anti-inflammatory effect. And experimental results in mouse animal models of dextran sulfate (DSS) -induced inflammatory bowel disease indicate: the intraperitoneal injection administration can effectively improve the clinical symptoms of colitis such as weight loss, diarrhea, hematochezia and the like of experimental animals, relieve the pathological damage of colon tissues and reduce the level of related proinflammatory cytokines.
The invention also discloses an anti-inflammatory bowel disease medicament, which comprises the physalis pubescens lactone B. The anti-inflammatory bowel disease drug has excellent anti-inflammatory activity against inflammatory bowel diseases caused by acute colon injury, particularly ulcerative colitis and Crohn's disease.
Preferably, the administration mode of the anti-inflammatory bowel disease drug is intraperitoneal injection, and the adopted dosage form is injection.
Further preferably, the injection dose of the physalilactone B in the anti-inflammatory bowel disease medicine is 5-40 mg/kg once a day.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses the application of physalilactone B in preparing a medicament for treating diseases associated with cytokine storm for the first time, and the physalilactone B has excellent anti-inflammatory activity particularly aiming at inflammatory bowel diseases including ulcerative colitis or Crohn's disease. The physalis pubescens lactone B belongs to a natural active compound, is safe, reliable and free of toxic and side effects, and has potential development value in the field.
Drawings
FIG. 1 is a graph of inhibition of RAW264.7 cell STAT1 signaling pathway activation by physcolide B;
FIG. 2 is a graph of inhibition of NF- κ B signaling pathway activation in RAW264.7 cells by physcolide B;
FIG. 3 shows the effect of physcolide B on the release of inflammatory cytokine IL-1. beta. from RAW264.7 cells, and the effect of physcolide B on the release of inflammatory cytokine TNF-. alpha. from RAW264.7 cells;
in FIG. 4, (A) is a graph showing the anti-inflammatory effect of physalilactone B on a zebra fish inflammation model; (B) the figure is a comparison graph of the number of the zebra fish neutrophils in each experimental group and the model group; (C) the figure is a graph comparing the inflammation resolution effect of the zebra fish of each experimental group with that of a model group;
FIG. 5 is a graph showing disease activity index scores of groups of mice during the experiment;
in FIG. 6, (A) is a diagram showing colon tissue patterns of various groups of mice at the end point of the experiment; (B) the figure shows a colon tissue intestinal weight coefficient graph of each group of mice at the experimental end point;
FIG. 7 is a diagram of pathological sections prepared by sectioning the colon of each group of mouse colon tissues, fixing the cut distal colon in formalin, and performing paraffin-embedded section and HE staining;
in FIG. 8, (A) is a graph showing the results of measurement of the levels of inflammatory cytokines TNF-. alpha.in colon tissues of each group of mice, (B) is a graph showing the results of measurement of the levels of inflammatory cytokines IL-1. beta. in colon tissues of each group of mice, and (C) is a graph showing the results of measurement of the levels of inflammatory cytokines IL-6 in colon tissues of each group of mice.
Detailed Description
The use of physcolide B as claimed in the present invention in the manufacture of a medicament for the treatment of diseases associated with cytokine storm is described in further detail below in conjunction with the activity assay and the accompanying figures. The following activity tests are intended to illustrate the invention, but are not intended to limit the scope of the invention.
Activity test:
firstly, the physalilactone B inhibits the activation of the RAW264.7 cell STAT1 signal pathway
The concentration of RAW264.7 cells was adjusted to 3X 105Cell suspension was seeded onto 6-well cell culture plates at cell/mL density, and added per well1mL of cell suspension, incubate for 24h, carefully aspirate the supernatant. Treating RAW264.7 cells with different concentrations of physalolide B (0 μ M, 2.5 μ M, 5 μ M, 10 μ M, 15 μ M) for 4h, extracting total cell protein, observing phosphorylation level of each member in STAT1 classical signal pathway by immunoblotting, and using beta-actin as reference protein.
The experimental result shows that the mean value of STAT1 phosphorylation is remarkably reduced, and the level of STAT1 protein is unchanged, so that the STAT1 signal pathway activation is remarkably inhibited by physalidroside B.
Secondly, the physalilactone B inhibits the activation of NF-kB signal channel of RAW264.7 cells
The concentration of RAW264.7 cells was adjusted to 3X 105Cell suspensions were plated at density of one/mL onto 6-well cell culture plates, 1mL of cell suspension was added per well, incubated for 24h, and the supernatant carefully aspirated. Treating RAW264.7 cells with different concentrations of physalolide B (0 μ M, 2.5 μ M, 5 μ M, 10 μ M, 15 μ M) for 4h, extracting total cell protein, observing phosphorylation level of each member in NF- κ B classical signal pathway by immunoblotting, and using β -actin as reference protein.
The experimental result shows that the phosphorylation levels of P-P65, P-IKK alpha/beta and P-IKB alpha in the NF-kB classical signal pathway are reduced when the action concentration of the physcolide B is 5 mu M, the phosphorylation levels of P-P65, P-IKK alpha/beta and P-IKB alpha are obviously reduced when the action concentration of the physcolide B is 10 mu M, and the phosphorylation levels of P-IKK alpha, P-P65 and P-IKK alpha/beta are averagely and obviously reduced when the action concentration of the PB is 15 mu M (see figure 2). Therefore, in RAW264.7 cells, when the action concentration of the physalactone B is 15 mu M, the activation of the NF-kappa B classical signal pathway can be obviously inhibited, and the concentration dependence is presented.
Thirdly, the influence of the physalilactone B on the release of inflammatory cytokines of an LPS-induced RAW264.7 cell inflammation model
The concentration of RAW264.7 cells was adjusted to 1X 105Cell suspensions were plated at 24-well cell culture plates at individual/mL, 1mL of cell suspension was added per well, incubated for 24h, and the supernatant carefully aspirated. Adding 1mL of DMEM solution into the blank group; LPS group was added to 1mL of DMEM solution containing LPS (1. mu.g/mL); LPS + physalis pubescens lactone group BLPS (10. mu.g/mL) and 1mL of DMEM solution containing the physcolide B at different concentrations (5, 10 and 15. mu.M) were placed in a cell incubator and cultured for 16 hours, and the supernatant was collected and measured by ELISA to calculate the inflammatory factor release level.
The experimental results show that the release of inflammatory factors of RAW264.7 cells can be reduced when the action concentration is 5 mu M after the RAW264.7 cells are treated by the physalactone B for 16 hours, and the release of inflammatory factors of RAW264.7 cells can be obviously inhibited when the action concentration is 10 mu M and 15 mu M (see (A) diagram and (B) diagram in figure 3).
Fourth, zebra fish inflammation model establishment and pharmacodynamics evaluation
Randomly selecting transgenic neutrophilic granulocyte fluorescent zebra fish 3 days after fertilization into a six-hole plate, injecting 30 zebra fish per hole (namely per dose group) with the volume of 3mL, respectively injecting 2.1, 6.7 and 20 ng/tail phycite B intravenously, dissolving in water to give 100 mu M concentration of indomethacin as a positive control drug, setting a normal control group and a model group, placing the normal control group and the model group in an incubator at 28 ℃ for pretreatment for 1 hour, and then treating by LPS in an injection mode to establish a zebra fish inflammation model. After the physalis pubescens lactone B is continuously treated for 2 hours, 10 zebra fishes are randomly selected from each experimental group and placed under a fluorescence microscope for observation, photographing and picture storage; carrying out image analysis by Nikon NIS-Elements D3.10 advanced image processing software, analyzing and counting the number (N) of local neutrophils of the zebra fish, and evaluating the anti-inflammatory effect of the physalilactone B on the inflammation of the zebra fish according to the statistical analysis result.
The experimental result shows that the number of the zebra fish local neutrophils in the model control group is 31, and compared with the normal control group (4), p is less than 0.001, which prompts the successful establishment of the model; the number of local neutrophilic granulocytes of the zebra fish in the positive control drug indometacin group with the concentration of 100 mu M is 21, compared with the p <0.001 of the model control group, the inflammation regression effect is 32.3 percent, and the 100 mu M indometacin is suggested to have the anti-inflammatory effect on the inflammation of the zebra fish; the number of local neutrophilic granulocytes of the zebra fish in the physcolide B2.1, 6.7 and 20 ng/tail dose groups is 20, 21 and 13 respectively, the inflammation regression effect is 35.5%, 32.3% and 58.1% respectively, and p is less than 0.001 compared with a model control group, which indicates that the physcolide B has obvious anti-inflammatory effect on the inflammation of the zebra fish under the condition of the experimental dose (see (A) diagram, (B) diagram and (C) diagram in figure 4).
Fifth, DSS induces ulcerative colitis mouse model establishment and pharmacodynamics evaluation
40 BALB/c mice, male, 18-22g, were randomly divided into 4 groups, namely a normal control group, a model group, a positive drug treatment group (mesalazine, 250mg/kg), and a physapubescin B treatment group (35mg/kg), and 8 mice in each group. Except for the mice of the normal control group, 5% DSS was added to the drinking water of the model group, the positive drug treatment group and the physapubescin B treatment group for 7 consecutive days to perform induction modeling of the intestinal inflammation model.
On the first day after the model building, mesalazine (250mg/kg, once a day) and physapubescin b (35mg/kg, once a day) were administered intraperitoneally for therapeutic intervention in each treatment group.
Disease activity index evaluation:
disease Activity Index (DAI) mice were observed for body weight, stool quality, and occult blood from the first day of molding to day 10 of dosing and scored according to the Disease Activity Index (DAI) scale, standard in table 2.
TABLE 2
Table 2 weight loss was graded as 5 (0, no weight loss or gain; 1, 1-5% loss; 2, 5-10% loss; 3, 10-20% loss; 4, more than 20% loss); the hardness of the feces is classified into 3 grades (0, normal; 2, soft feces; 4, loose feces); fecal occult blood was classified into 5 grades (0, negative; 1, +; 2, + +; 3, + + +; 4, perianal bleeding).
Gross and microscopic pathological changes in colon tissue in mice:
and taking a mouse colon tissue at an experimental end point, measuring the length, cutting a distal colon, fixing the distal colon in formalin, and preparing a pathological section by paraffin embedded section and HE (high-intensity electrophoresis) staining.
Detection of proinflammatory cytokine levels in colon tissue:
and homogenizing colon tissues of the same segment of each group of mice, centrifuging, and performing protein quantification on homogenized supernatant of the BCA kit.
The content of proinflammatory cytokines in the supernatant was measured by ELISA and is shown as the amount of cytokines in units of total protein.
The results in FIG. 5 show that the body weight of the rats in the model group is significantly reduced, and loose stools are generated with hematochezia or occult blood. The Physapubescin group B can obviously inhibit the weight reduction of rats and improve the stool character and the hematochezia condition of the rats.
In fig. 6, (a) graph results show that physapbeccinb treatment can significantly inhibit colon length shortening due to DSS-induced inflammation, and in the graph, the normal control group, the model group, the physapbeccinb group, and the mesalamine group are sequentially corresponded from left to right. (B) The results of the graphs show that the colonic edema, ulcer in the severe case, and the intestinal weight coefficient are significantly increased in the model group mice, while the Physapubescin group B can improve the intestinal weight coefficient.
The colon histopathological detection results of different administration groups show that the colon local gland structural disorder, mucosal local erosion and partial crypt destruction of the model group mice can be obviously relieved, and the change of the treatment group mice is shown in figure 7.
The inflammatory cytokine plays a key role in regulating intestinal inflammatory immune response and participates in the occurrence and development process of inflammatory bowel disease. Figure 8 experimental results show that administration of physapubescin b treatment reduced the level of proinflammatory cytokines in colon tissue.
Therefore, the research of the representative compounds in vitro cell experiments shows that the release of inflammatory cytokines from RAW264.7 cells is reduced by inhibiting the activation of signal pathways STAT1 and NF-kappa B. Meanwhile, the LPS-induced zebra fish inflammation model research shows that the number of neutrophils can be obviously reduced, and the anti-inflammatory effect is good. And experimental results in mouse animal models of dextran sulfate (DSS) -induced inflammatory bowel disease indicate: the intraperitoneal injection administration can effectively improve the clinical symptoms of colitis such as weight loss, diarrhea, hematochezia and the like of experimental animals, relieve the pathological damage of colon tissues and reduce the level of related proinflammatory cytokines.
Claims (9)
1. The application of physalilactone B in preparing a medicament for treating diseases associated with cytokine storm is characterized in that the physalilactone B has the following structural formula:
2. the use of physalilactone B according to claim 1 in the manufacture of a medicament for the treatment of a disease associated with a cytokine storm, wherein said disease associated with a cytokine storm comprises inflammatory bowel disease, graft versus host disease, sepsis, respiratory or hemorrhagic viral infection.
3. The use of physalilactone B according to claim 2 in the manufacture of a medicament for the treatment of a disease associated with a cytokine storm, wherein the inflammatory bowel disease is acute colon injury.
4. The use of physalilactone B according to claim 2, in the preparation of a medicament for the treatment of a disease associated with a cytokine storm, wherein the inflammatory bowel disease comprises ulcerative colitis or crohn's disease.
5. The use of physalilactone B in the manufacture of a medicament for the treatment of a disease associated with a cytokine storm according to claim 1, wherein the physalilactone B achieves an anti-inflammatory effect by inhibiting the STAT1 signaling pathway and/or the NF- κ B signaling pathway.
6. An anti-inflammatory bowel disease drug, characterized by comprising physalilactone B, wherein the inflammatory bowel disease is acute colon injury.
7. The anti-inflammatory bowel disease agent of claim 6, wherein said inflammatory bowel disease comprises ulcerative colitis or Crohn's disease.
8. The anti-inflammatory bowel disease drug according to claim 6, wherein said anti-inflammatory bowel disease drug is administered by intraperitoneal injection.
9. The anti-inflammatory bowel disease drug according to claim 6, wherein the injection dose of the physalilactone B in the anti-inflammatory bowel disease drug is 5 to 40mg/kg once a day.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103961362A (en) * | 2014-05-16 | 2014-08-06 | 富阳科兴生物化工有限公司 | Application of physalis pubescens lactone B in preparing anti-cancer drugs |
| CN111377994A (en) * | 2018-12-28 | 2020-07-07 | 南开大学 | Seven withanolides compounds from cape gooseberry and preparation method and application thereof |
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| CN103961362A (en) * | 2014-05-16 | 2014-08-06 | 富阳科兴生物化工有限公司 | Application of physalis pubescens lactone B in preparing anti-cancer drugs |
| CN111377994A (en) * | 2018-12-28 | 2020-07-07 | 南开大学 | Seven withanolides compounds from cape gooseberry and preparation method and application thereof |
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