CN113662977A - Application of artemisia annua extract in preparation of preparation for treating or preventing AD - Google Patents
Application of artemisia annua extract in preparation of preparation for treating or preventing AD Download PDFInfo
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- CN113662977A CN113662977A CN202010411897.2A CN202010411897A CN113662977A CN 113662977 A CN113662977 A CN 113662977A CN 202010411897 A CN202010411897 A CN 202010411897A CN 113662977 A CN113662977 A CN 113662977A
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- artemisia annua
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- extract
- zwh2880
- water extract
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Abstract
The invention discloses application of artemisia annua extract in preparing an AD treatment or prevention preparation. The artemisia annua boiling water extract can unexpectedly improve the learning and memory capacity of a mouse of a transgenic model of the Alzheimer disease, prevent nerve cell death caused by oxidative damage, promote the recovery of the transmembrane potential of mitochondria, reduce the deposition of amyloid plaques, the entanglement of nerve fibers and the loss of neurons, and provide an experimental basis for clinical research on the treatment of the Alzheimer disease.
Description
Technical Field
The invention relates to a new application of artemisia annua extract, in particular to an application of the artemisia annua extract in preventing or treating Alzheimer Disease (AD).
Background
Alzheimer's Disease (AD) is one of the most devastating diseases affecting the elderly. Amyloid beta (a β) accumulation and downstream pathological events (e.g., inflammation, oxidative stress) play a key role in the pathogenesis of AD. Including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, pose a significant economic burden and social stress. Senile dementia among the elderly, the incidence of which increases year by year with the disease (AD), is the most common form of aging of the population worldwide, causing enormous social and economic burden to the family and society.
The cause of alzheimer's disease is still unclear at present, and numerous studies indicate that β -amyloid (a β) is the main therapeutic factor. In recent years, many drugs targeting a β by immunotherapy or using secretase inhibitors have entered clinical trials, but none have been able to improve the cognitive function of patients. Alzheimer's Disease (AD) is one of the most devastating diseases affecting the elderly. A β accumulation and downstream pathological events (e.g., oxidative stress) play a key role in the pathogenesis of AD. Current clinical trials fail to teach that multiple key pathways to AD pathogenesis are necessary to arrest disease progression. Despite the significant progress made in recent years in understanding the pathogenesis of AD, no effective drug is available for the treatment of AD, and thus the study of effective treatment of AD is of great significance.
Artemisia annua L is an annual herb of Compositae, and is called Artemisia japonica, Artemisia annua, Artemisia odorifera, and Artemisia. As one of traditional Chinese medicines, the artemisia annua has the effects of heat-clearing and detoxifying, malaria-preventing and resisting bacteria and the like. The artemisia annua extract contains sesquiterpenes, flavonoids, volatile oils, coumarins and other substances which have the effects of clearing heat, relieving summer-heat, preventing malaria, invigorating stomach and the like. In addition, the artemisia annua extract has the effects of resisting oxidation, improving the immunity, sterilizing and resisting viruses (Wang hong bo, Xiao , Huahuiming, and the like, the research on chemical components of the artemisia annua advances [ J ] modern medicine and clinic, 2011, 26 (6): 430-. The extraction method of active substances of Artemisia annua comprises water extraction, traditional organic solvent extraction (ethanol extraction), etc., and mainly comprises the forms of extractive solution, powder, etc. Wherein the artemisinin and its derivatives, Artemisia annua polysaccharide and Artemisia annua essential oil are main effective components of Artemisia annua extract. The artemisinin compound is mainly fat-soluble component, and has low content in herba Artemisiae Annuae. The artemisinin compounds are generally sensitive to heat, are almost insoluble in water, are generally extracted by alcohol or organic solvents, have improper extraction methods, and are very easy to damage the structure or cannot be extracted. At present, the active action of artemisinin and derivatives thereof is mainly researched in oxidation resistance, immune anti-inflammatory capacity and the like besides antimalarial.
Recent researches show that the artemisinin and partial derivatives thereof also have certain treatment or prevention effects on neurodegenerative diseases. For example, CN107802621A discloses the use of artemisinin B in the preparation of a medicament for the treatment of neurodegenerative diseases, wherein said neurodegenerative diseases are characterized by learning and memory disorders, and wherein said neurodegenerative diseases include alzheimer's disease, parkinson's disease, huntington's disease. CN109394757A discloses the use of artemether in the prevention and treatment of Alzheimer's disease. CN105147666A discloses a compound for treating and relieving neurodegenerative diseases, which is an Artemisinin (Artemisinin) derivative, and the Artemisinin (Artemisinin) derivative comprises Artemether, Arteether, artesunate, Dihydroartemisinin and pharmaceutically acceptable adjuvants. It can be used for treating Alzheimer's disease, Parkinson's syndrome and Huntington's disease.
The artemisinin compound has low content in the artemisia annua, and is hardly soluble in water or insoluble in water. It is generally considered that the water extract (total extract) of artemisia annua does not contain artemisinin compounds. The effect research of the artemisia annua water extract is less, Guohenhan, Shenhumin, Yang sense, et al, the preliminary research of artemisia annua allelopathica mechanism on receptor oat allelopathic mechanism [ J ]. report of Ministry of agriculture university in Gansu, 2008,43(1) the influence of the artemisia annua water extract with different concentrations on the activity of several enzymes (12-60 h) in oat plants is determined, and the result shows that the artemisia annua water extract can inhibit the activity of polyphenol oxidase (PPOD), superoxide dismutase (SOD), Peroxidase (POD), Catalase (CAT) and other resistant enzymes in the oat bodies, and improve the activity of Phenylalanine Ammonia Lyase (PAL). In vitro antibacterial activity research of artemisia annua extract [ J ] Jiangsu agricultural science, 2013,041(003):291-292. in vitro antibacterial activity research of the artemisia annua extract is carried out by adopting a filter paper method and a spore germination method and taking aspergillus niger, penicillium and cotton mold as test strains by adopting an aspergillus niger, penicillium and cotton mold; the water extract has the highest bacteriostatic activity on cotton mold, the maximum bacteriostatic circle diameter reaches 28.3mm, and the maximum spore germination inhibition rate is 45.45%; the 50% ethanol crude extract has the best antibacterial effect on penicillium and aspergillus niger, the maximum antibacterial circle diameters are 15.6 mm and 14.5mm respectively, and the maximum spore germination inhibition rates are 31.58% and 27.08% respectively.
Disclosure of Invention
The invention aims to provide application of artemisia annua water extract in preparation of a preparation for treating or preventing Alzheimer's disease.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
application of herba Artemisiae Annuae water extract in preparing preparation for treating or preventing Alzheimer disease is provided.
In some examples, the aqueous extract of Artemisia annua is extracted at a temperature of not less than 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C, boiling temperature.
In some examples, the extraction time of the artemisia annua water extract is not less than 30min, 1h, 2h, 3h, 4h, 5 h.
In some examples, the preparation method of the artemisia annua water extract comprises the following steps:
1) soaking herba Artemisiae Annuae in water, boiling and extracting to obtain filtrate;
2) adding water into the residue, boiling and extracting, and collecting filtrate;
3) mixing the filtrates, concentrating, and drying to obtain herba Artemisiae Annuae water extract.
In some examples, the alzheimer's disease is caused by loss of neurons, dysfunction of neurons, or oxidative damage to neurons.
In a second aspect of the present invention, there is provided:
use of a water extract of artemisia annua as described in the first aspect of the invention in the manufacture of a formulation for improving learning memory or cognitive dysfunction.
In some examples, the cognitive dysfunction includes, but is not limited to, learning memory or cognitive dysfunction due to aging and alzheimer's disease.
In a third aspect of the present invention, there is provided:
a preparation for treating or preventing Alzheimer's disease, wherein the active ingredient of the preparation comprises the artemisia annua water extract in the first aspect of the invention.
In some examples, the formulation is selected from the group consisting of an oral agent, a functional food.
In some examples, the oral formulation is selected from granules, tablets, capsules, or suspensions; the functional food is selected from the group consisting of solid beverages, confectionery, bakery products, non-potable dairy products, livestock and poultry meats, cereals and flours, frozen fruit and vegetable products.
The invention has the beneficial effects that:
the inventor finds that after the artemisia annua extract ZWH2880 (boiling water extract) is given in a drinking water mode in an alzheimer mouse model, secondary damage caused by injection can be effectively avoided, the artemisia annua boiling water extract can improve the learning and memory capacity of the mouse, protect nerve cell loss and reduce the capacity of amyloid plaque deposition and neurofibrillary tangle of the alzheimer mouse model; meanwhile, the learning and memory capacity of the transgenic model mouse of the Alzheimer disease can be improved, the oxidative damage of the transgenic model mouse of the Alzheimer disease is improved, and in a nerve cell (PC12, SY5Y) and primary neuron cell model, the boiling water extract of artemisia annua can resist A beta-induced neurotoxicity and reduce ROS accumulation and mitochondrial transmembrane potential loss (early apoptosis/death indication) caused by A beta/oxidative emergency. The experimental result shows that the artemisia annua boiling water extract can improve the activity of MAPK/ERK-related signal pathways, improve pathological changes of Alzheimer disease through MAPK/ERK key signal pathways, and has better treatment or prevention effect on AD.
Drawings
In the figure, 3xTg mice refer to 3xTg AD mice, unless otherwise specified.
FIG. 1 shows the effect of different concentrations of Artemisia annua extract ZWH288 on improving learning and memory ability of Alzheimer's disease model mice. (A) ZWH288 effect of 288 on escape latency (learning ability) of mice; (B) ZWH288 effect of 288 on the number of times the mouse crossed the platform in the target quadrant (memory). (C) ZWH288 effect of 288 on mouse memory. The experiment was divided into a normal mouse control group (WT) (given equivalent amount of drinking water), a model group (3xTg AD mouse) (given equivalent amount of drinking water), a model group + ZWH 288020 mg/kg, a model group + ZWH28806.7mg/kg, and a model group + ZWH 28802 mg/kg. (3xTg AD mice are represented by 3xTg in the figure, the same applies below). The results show that ZWH2880 improves the learning and memory ability of the aged AD mice (3 xTg-AD). #/# P <0.05, # #/# P <0.01, # # # # #/# P <0.001(two-way or one-way ANOVA).
Figure 2 is the result of the effect of artemisia annua aqueous extract ZHW2880 on Α β deposition and Tau phosphorylation in aged 3xTg AD mice. (A) Immunofluorescence staining of a β brain hippocampal slices (β -amyloid immunofluorescence staining, 6E10 labeling amyloidosis); (B) immunoblots of beta-amyloid in each group; (C) statistical analysis of immunoblots for beta-amyloid in each group (quantitative analysis of beta-amyloid expression in each group); (D) immunofluorescent staining of p-Tau-Thr181 in each group; (E) immunoblotting of p-Tau protein in each group. The results show that Α β deposition and phosphorylation of Tau protein are significantly increased in the brains of aged 3xTg AD mice, whereas ZWH2880 treatment significantly reduced the expression of both marker proteins in the brains of 3xTg AD mice.
Fig. 3 is a graph of the effect of various concentrations of artemisia annua extract ZWH2880 on primary neurons. (A) Cellular morphological features were detected by immunofluorescence staining. (B) Neuronal cell viability was examined by MTT assay. JUJ1 are neuronal markers. The results show that beta-amyloid (Abeta 1-42) reduces the cell viability of primary neurons (causing the death of the primary neurons), while ZWH2880 treatment significantly inhibits the effect of beta-amyloid, improves the cell viability of the primary neurons, and reduces the death of the primary neuron cells.
#/*P<0.05，##/**P<0.01，###/***P<0.001(two-way or one-way ANOVA).Error bar，SEM。
FIG. 4 is a graph of the effect of various concentrations of Artemisia annua extract ZWH2880 on neuronal antioxidant function. The results show that (a) artemisia annua extract ZWH2880 reduced the level of ROS, and (B) the effect of artemisia annua extract ZWH2880 on the level of ROS was quantitatively analyzed. #/# P <0.05, # #/# P <0.01, # # # # #/# P <0.001(two-way or one-way ANOVA). ZWH2880 treatment reduces the level of neuronal ROS, reducing the death of primary neuronal cells.
FIG. 5 shows the protective effect of Artemisia annua extract ZWH2880 on nerve cell PC12 at different concentrations. (A) PC12 cells are treated with Artemisia annua extract ZWH2880 and Abeta 1-42 for 24 hours, and Artemisia annua extract ZWH2880 has obvious protective effect on A beta-induced neurotoxicity. (B) PC12 cells were treated with Artemisia annua extract ZWH2880 and A β 1-42 for 24 hr, and Artemisia annua extract ZWH2880 was not toxic to P12 cells.
FIG. 6 is a graph of the effect of various concentrations of Artemisia annua extract ZWH2880 on ROS and mitochondrial membrane potential generation within neural cells. The results show that artemisia annua extract ZWH2880 can restore the A beta 1-42-induced reduction of the mitochondrial transmembrane potential of PC12 cells and reduce the A beta 1-42-induced ROS accumulation and apoptosis. (A) Mitochondrial transmembrane potential (upper panel) and ROS (lower panel) fluorescent staining analysis; (B) analysis of the statistical results for mitochondrial transmembrane potential (upper panel) showed ZWH2880 dose-dependently reversed a β 1-42-induced decrease in mitochondrial transmembrane potential in PC12 cells; (C) analysis of statistical results for ROS (lower panel) showed ZWH2880 dose-dependently decreased ROS levels. All the results indicate that artemisia annua extract ZWH2880 can resist oxidative damage of cells by promoting mitochondrial membrane potential recovery, reducing ROS accumulation.
FIG. 7 is a graph of the effect of various concentrations of Artemisia annua on the activation of intracellular signaling. The result shows that artemisia annua extract ZWH2880 can activate MAPK/ERK signal to dredge collaterals and play a protective role.
FIG. 8 shows the protective effect of Artemisia annua extract ZWH2880 on human nerve cells and the effect of resisting oxidative damage. (A) SY5Y cell is treated with Artemisia annua extract ZWH2880 and Abeta 1-42 for 24 hr, and Artemisia annua extract ZWH2880 has obvious protective effect on A beta-induced neurotoxicity. (B) ZWH2880 shows that A beta 1-42 induced ROS accumulation and apoptosis are reduced, artemisia annua extract ZWH2880 reduces ROS level, and (C) is a statistical analysis of the ROS induced by A beta 1-42. The result shows that ZWH2880 has protective effect and antioxidation damage effect on human nerve cells.
Detailed Description
For convenience of comparison, artemisia annua extract ZWH2880 used in the following experiments was prepared as follows.
Preparation method of Artemisia annua extract ZWH2880
S1) soaking herba Artemisiae Annuae in 10 times of water for 2h, heating, timing when the water is boiling, extracting for 2h,
taking a filtrate;
s2) adding 8 times of water into the dregs of a decoction, heating, boiling and extracting for 2 hours, and taking the filtrate;
s3) concentrating: mixing the two extractive solutions, heating the concentrator to 65 deg.C, vacuum degree-0.08 MPa, and concentrating the extract to relative density of 1.12;
s4) spray drying: the air inlet temperature is controlled to be 180 ℃, the air outlet temperature is controlled to be 90 ℃, the concentrated solution to be sprayed is dried,
the obtained product is marked as artemisia annua extract ZWH 2880.
Artemisia annua extract ZWH2880 with different concentrations has effect of improving learning and memory ability of mice with Alzheimer disease model
Firstly, feeding and breeding an Alzheimer disease transgenic mouse model (3xTg AD) to 9 months of age, drinking the mouse with artemisia annua extract ZWH2880 with different concentrations every day, performing a Morris water maze experiment after 3 months of administration, and then taking materials for subsequent experiments.
40 transgenic mice with Alzheimer's disease were divided into 4 groups of 10 mice each. The body weights were weighed before administration. The artemisia annua extract ZHW2880 solution is sterilized water, is prepared into 3 different concentrations, is administrated once a day, and is subjected to Morris water maze experiments after being administrated for 3 months. The Morris water maze consists of movable platforms, four equidistant mark points are arranged on the wall of the pool and are used as the water inlet points of the mice, and the water diversion pool is provided with four quadrants. In the experimental process, the water temperature is kept constant, and the temperature is kept at 22-26 ℃.1 hour before the start of the experiment, the mice were placed in advance in a laboratory where the water maze was placed, so that they were acclimatized. The first 5 days of each water maze experiment are positioning navigation experiments (place navigation tests), and the 6 th day is space probe experiments (spatial probe tests). During the experiment of the positioning navigation, the platform is fixedly placed in the middle of one quadrant and is about 1cm away from the water surface. The experiment is carried out at a fixed morning moment every day, and the time when the mouse finds the platform is recorded, namely the incubation period of the mouse. At the beginning of each experiment, all mice were placed in water from any one of the four quadrants, facing the pool wall, and four experiments were performed per mouse, with a swimming time of 60s each. If the mouse can find the platform within 60s, the mouse can rest on the platform for 10 s; if the platform can not be found within 60s, an experimenter guides the mouse to the platform, the experimenter also takes a rest for 10s, the latency period of the mouse is 60s, and the time and the movement route of the mouse for finding the platform are recorded through the camera system and the software acquisition system. The above procedure was repeated on days 2, 3, 4 and 5. And (4) counting the average latency in the 5-day positioning navigation experiment of each group of mice as an index for judging the learning ability of the mice. And after the positioning navigation experiment is finished for 24 hours, withdrawing the platform hidden under the water, and performing a space exploration experiment.
Selecting a point far away from the platform as a water inlet point, putting the mouse into water, and recording the movement track of the mouse in 60s, the times of passing through the platform and the residence time of the mouse in the quadrant of the platform. And (4) counting the time percentage of each group of mice in the platform quadrant to measure the space positioning capability and the memory capability of the mice. All data acquisition and processing are completed by an automatic Morris water maze image monitoring and processing system.
The results are shown in FIG. 1. In fig. 1, it is shown that the average escape latency of the mice of each group gradually decreases with the extension of the training time, which indicates that the mice generate memory (learning ability) on the position of the underwater platform after training; the escape latency of 3xTg AD mice was significantly longer than WT mice, while the escape latency of mice treated with artemisia annua extract ZWH2880 was shorter than 3xTg AD mice. The space exploration experiment shows that the target quadrant crossing platform times of the 3xTg AD mice treated by the artemisia annua extract ZWH2880 are higher than that of the non-dosed 3xTg AD mice. The artemisia annua extract ZWH2880 has the function of improving the learning and memory capacity of the mice of the Alzheimer's disease model and improves the cognitive disorder of the AD mice.
Effect of different concentrations of Artemisia annua on deposition and deposition of amyloid plaques in brain of transgenic mouse model of Alzheimer's disease (3xTg AD)
40 transgenic mice with Alzheimer's disease were divided into 4 groups of 10 mice each. Before administration, the body weights are respectively weighed, and the dosage is calculated according to the body weights. The drug is administered every day, after 3 months of drug administration, the mice are killed by decapitation, half of the brain tissue is frozen and stored in a refrigerator at-80 ℃ for the subsequent Western Blot experiment, and the other half of the brain tissue is fixed, embedded and sliced for standby.
The specific implementation method comprises the following steps:
and (3) immunofluorescence staining:
1) the treated cells were aspirated off the culture medium, washed 1-2 times with PBS, and fixed with 4% paraformaldehyde (4% PFA) for 30min at room temperature;
2) washing 4% PFA with PBS, adding 0.2% Tritron membrane, and standing at room temperature for 30 min;
3) washing the membrane penetrating liquid by PBS, adding 3% BSA, and blocking for 1h at room temperature;
4) add primary antibody (primary antibody diluted by a corresponding fold with 1% BSA) and go overnight at 4 ℃;
5) the next day, washing with washing solution for 3-5 times for 10min, washing with PBS for 3-5 times for 10min, adding secondary antibody and DAPI (the secondary antibody and DAPI are diluted with 1% BSA by corresponding times), and incubating at room temperature for 60 min;
6) washing with cleaning solution for 3-5 times for 10min, washing with PBS for 3-5 times for 10min, adding appropriate amount of PBS, and storing at 4 deg.C for observation.
Western blot experiment:
s1) adding 100 mu L of PMSF into each 10mL of RIPA protein lysate, wherein the concentration is 100 mM; adding phosphatase inhibitor and protease inhibitor, mixing, and standing on ice for 20 min;
s2) killing each group of mice, dissecting and separating brain tissues, removing olfactory bulbs, and taking out the intact brain;
s3) fully shearing the brain tissue of the mouse on ice, putting the brain tissue into lysate, and fully homogenizing the brain tissue on the ice by using a grinding rod;
s4) at 12000rpm and 4 ℃, centrifuging for 15min, obtaining supernatant which is the protein extract, carrying out Western Blot test, and testing the expression condition of the beta-Amyloid protein.
The results are shown in FIG. 2. Immunofluorescence shown in fig. 2A shows Amyloid plaque deposition in the brains of each group of mice (an important indication of AD), Western blot shows Amyloid plaque deposition in the brains of each group of mice shown in fig. 2B and 2C, artemisia annua extract ZWH2880 can reduce deposition of a β (6E 10 in the figure is a specific antibody to β -Amyloid, which can specifically label the location and expression level of a β) in the hippocampus of 3xTg AD mice. And Western Blot was used to perform quantitative analysis on the related proteins (fig. 2C), which also shows that artemisia annua extract ZWH2880 can reduce the deposition of a β in 3 × tg AD mice. Fig. 2D and 2E show that artemisia annua extract ZWH2880 is able to reduce hyperphosphorylation of Tau in hippocampus of 3xTg AD mice (another important indication of AD).
The results prove that the artemisia annua extract ZWH2880 can improve cognitive impairment of AD mice, reverse various pathological changes and has better prevention and treatment effects on AD.
Effect of different concentrations of Artemisia annua extract ZWH2880 on Primary neurons
Separating and culturing primary neurons: to further test the protective effect of artemisia annua extract ZWH2880 on Α β toxicity in vitro, primary cortical neurons were isolated from neonatal WT mouse brains and cultured on poly D-lysine coated coverslips for 7D inoculation, followed by incubation with 2 μ M A β oligomers. While not co-culturing for 24 hours with ZWH2880 of different concentrations, immunofluorescent staining and MTT experiments were performed.
And (3) immunofluorescence staining:
(1) the treated cells were aspirated off the culture medium, washed 1-2 times with PBS, and fixed with 4% paraformaldehyde (4% PFA) for 30min at room temperature;
(2) washing 4% PFA with PBS, adding 0.2% Tritron membrane, and standing at room temperature for 30 min;
(3) washing the membrane penetrating liquid by PBS, adding 3% BSA, and blocking for 1h at room temperature;
(4) add primary antibody (primary antibody diluted by a corresponding fold with 1% BSA) and go overnight at 4 ℃;
(5) the next day, washing with washing solution for 3-5 times for 10min, washing with PBS for 3-5 times for 10min, adding secondary antibody and DAPI (the secondary antibody and DAPI are diluted with 1% BSA by corresponding times), and incubating at room temperature for 60 min;
(6) washing with cleaning solution for 3-5 times for 10min, washing with PBS for 3-5 times for 10min, adding appropriate amount of PBS, and storing at 4 deg.C;
(7) to be observed.
MTT test: cultured neuronal cells were incubated with 2 μ M A β oligomers. Meanwhile, after co-culturing for 24 hours without using artemisia annua extract ZWH2880 with different concentrations, adding MTT, incubating for 4 hours at 37 ℃, removing the MTT, adding 100 mu l of DMSO into each hole for color reaction, then mixing uniformly, and measuring OD in an enzyme-linked immunosorbent assay.
The results are shown in FIG. 3. The isolated primary cells are shown to have the morphological characteristics of neurons, express the neuron marker TUJI1(A), and the artemisia annua extract ZWH2880 can resist A beta toxicity and improve the vitality of primary neuron cells (B).
Effect of Artemisia annua extract ZWH2880 with different concentrations on neuron antioxidant function
Primary neuronal cells cultured for 7 days were incubated with 2 μ M A β oligo. While not co-culturing for 24 hours with ZWH2880 at different concentrations. The level of ROS was examined.
The results are shown in FIG. 4. The control group had a lower ROS level than the Α β treated group and the ROS level was significantly reduced with a different concentration of ZWH 2880. The results show that artemisia annua extract ZWH2880 can reduce the accumulation of ROS in cells, so that the (anti) ROS can be inhibited to cause apoptosis.
Artemisia annua extract ZWH2880 with different concentrations has protective effect on mouse nerve cells.
PC12 cells were cultured in DMEM (Dulbecco's Modified Eagle's) medium supplemented with 10% Fetal Bovine Serum (FBS) and 100. mu.g/ml streptomycin and maintained in a humidified environment at 37 ℃ and 5% CO 2 with 2. mu. M A. beta. oligo. While not co-culturing for 24 hours with ZWH2880 of different concentrations, immunofluorescent staining and MTT experiments were performed. In addition, ZWH2880 was examined for its cytotoxic effect on P12 by incubation with ZWH2880 alone with PC12 for 24 h.
The results are shown in FIG. 5. ZWH2880 concentration-dependently protected nerve cells, and Artemisia annua extract ZWH2880 itself was not toxic to nerve cells.
Effect of different concentrations of Artemisia annua extract ZWH2880 on ROS and mitochondrial membrane potential production in nerve cells
PC12 cells were cultured in DMEM (Dulbecco's Modified Eagle's) medium supplemented with 10% Fetal Bovine Serum (FBS) and 100. mu.g/ml streptomycin, and maintained at 37 ℃ and 5% CO2Was incubated with 2 μ M A β oligomers in a humid environment. Also after 24 hours of co-culture without using ZWH2880 at different concentrations, changes in intracellular ROS levels and cell membrane potential were examined.
The results are shown in FIG. 6. It is shown that artemisia annua ZWH2880 concentration-dependently reverses the decrease of mitochondrial transmembrane potential caused by A beta, thereby resisting the apoptosis of nerve cells caused by mitochondrial injury. The artemisia annua extract ZWH2880 reduces the intracellular ROS level in a concentration-dependent manner, and cell nerve apoptosis caused by ROS is reduced.
Effect of different concentrations of Artemisia annua on intracellular signaling through activation
PC12 cells were cultured in DMEM (Dulbecco's Modified Eagle's) medium supplemented with 10% Fetal Bovine Serum (FBS) and 100. mu.g/ml streptomycin, and maintained at 37 ℃ and 5% CO2In a humid environment. The groups of cells, which are pre-treated or not treated with artemether and induced and not induced with Abeta 1-42, are harvested, added to the lysate, and the supernatant obtained is ground on ice for Western Blot.
The specific implementation method comprises the following steps:
1) collecting cells treated or untreated with artemether, washing with cold Phosphate Buffered Saline (PBS), and lysing the cells on ice in 1X sample lysis buffer containing newly added protease and phosphatase inhibitors;
2) the lysed cells were centrifuged at 13,000 rpm for 15 minutes for protein quantification. Proteins were separated by polyacrylamide gel electrophoresis and transferred to PVDF membranes;
3) the membranes were blocked in 5% skim milk in PBST for 1 hour. Primary antibody was then added and incubated at 4 ℃ overnight;
4) the following day the membranes were washed three times with 1X TBST, then incubated with horseradish peroxidase-conjugated secondary antibody for 1 hour at room temperature and exposed using ECL detection kit. Thereby further testing the expression of the protein related to the AMPK signal pathway in vitro.
The results are shown in FIG. 7. The artemisia annua extract ZWH2880 is shown to activate MAPK/ERK signal channels in a concentration-dependent manner, and the artemisia annua extract ZWH2880 is shown to play a role in protecting nerves by activating AMPK/ERK.
Artemisia annua extract ZWH2880 with different concentrations has effect of protecting human nerve cells
Human glioblastoma cells (SY5Y cells) were cultured in DMEM (Dulbecco's Modified Eagle's) medium supplemented with 10% Fetal Bovine Serum (FBS) and 100. mu.g/ml streptomycin and incubated with 2. mu. M A. beta. oligomers maintained in a humidified environment at 37 ℃ and 5% CO 2. While not co-culturing for 24 hours with ZWH2880 of different concentrations, immunofluorescent staining and MTT experiments were performed. In addition, incubation with ZWH2880 and SY5Y cells alone for 24h examined ZWH2880 for cytotoxic effects on SY 5Y.
The results are shown in FIG. 8. ZWH2880 concentration-dependently protecting nerve cells (A); the results of FIGS. 8B-C show that ZWH2880 concentration-dependently reduces A β -induced ROS accumulation and inhibits neuronal apoptosis. The results show that artemisia annua extract ZWH2880 can reduce the accumulation of ROS in SY5Y cells and prevent ROS from causing apoptosis.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. Application of herba Artemisiae Annuae water extract in preparing preparation for treating or preventing Alzheimer disease is provided.
2. Use according to claim 1, characterized in that: the extraction temperature of the artemisia annua water extract is not lower than 50 ℃, 60 ℃, 70 ℃ and the boiling temperature.
3. Use according to claim 1 or 2, characterized in that: the extraction time of the artemisia annua water extract is not less than 30min, 1h and 2 h.
4. Use according to claim 1 or 2, characterized in that: the preparation method of the artemisia annua water extract comprises the following steps:
1) soaking herba Artemisiae Annuae in water, boiling and extracting to obtain filtrate;
2) adding water into the residue, boiling and extracting, and collecting filtrate;
3) mixing the filtrates, concentrating, and drying to obtain herba Artemisiae Annuae water extract.
5. Use according to claim 1 or 2, characterized in that: the alzheimer's disease is caused by loss of neurons, dysfunction of neurons, or oxidative damage of neurons.
6. The application of the artemisia annua water extract in preparing the preparation for improving the learning memory or cognitive dysfunction is characterized in that: the artemisia annua water extract is as claimed in any one of claims 1 to 4.
7. A formulation for treating or preventing alzheimer's disease, characterized by: the active ingredient of the preparation comprises the artemisia annua water extract as claimed in any one of claims 1 to 4.
8. The formulation of claim 7, wherein: the preparation is selected from oral preparation and functional food.
9. The formulation of claim 8, wherein: the oral preparation is selected from granules, tablets, capsules or suspension; the functional food is selected from the group consisting of solid beverages, confectionery, bakery products, non-potable dairy products, livestock and poultry meats, cereals and flours, frozen fruit and vegetable products.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150087719A (en) * | 2014-01-22 | 2015-07-30 | 경북대학교 산학협력단 | Composition containing Artemisia annua extract for preventing or treating cognitive dysfunction |
| CN107802621A (en) * | 2017-12-06 | 2018-03-16 | 中国中医科学院中药研究所 | The purposes of the anti-neuroinflamation of artemisinin B and treatment nerve degenerative diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150087719A (en) * | 2014-01-22 | 2015-07-30 | 경북대학교 산학협력단 | Composition containing Artemisia annua extract for preventing or treating cognitive dysfunction |
| CN107802621A (en) * | 2017-12-06 | 2018-03-16 | 中国中医科学院中药研究所 | The purposes of the anti-neuroinflamation of artemisinin B and treatment nerve degenerative diseases |
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