An anti-aging composition for replenishing vitality and spirit and its application

Abstract

The present invention provides an anti-aging composition for replenishing the spirit, energy and spirit, a preparation method and application thereof, and also provides health products, cosmetics and medicines containing the composition. The composition of the present invention has strong free radical scavenging activity and cell anti-aging activity, and can replenish the spirit, energy and spirit. In animal experiments, the learning and memory abilities of aged mice can be significantly improved.

Description

Technical Field

[0001] The invention relates to the field of medicine and plant extracts, and in particular to an anti-aging composition for replenishing vital energy and spirit and an application thereof. Background Art

[0002] Aging is a gradual biological process that affects the normal functioning of cells and tissues, leading to diseases that endanger human health and even death. Both internal and external factors play an integral role in aging. Internal factors include the regular biological processes of cells, while external factors include long-term sun exposure, hormonal imbalances, nutritional deficiencies, UV exposure and other factors such as pollution and smoking. The clinical manifestations of intrinsic aging can be determined by evaluating the regenerative capacity of damaged tissues or organs. All dividing and differentiating cells are susceptible to damage, leading to intrinsic aging. The external characteristics of aging begin to appear in the early 40s. Most cells, tissues and organs steadily age and become less functional. Aging has a noticeable impact on the skin, learning ability, and memory. The skin becomes loose, wrinkled and inelastic. Facial fat also decreases, resulting in sunken eye sockets and cheeks. In addition, hair begins to thin from the armpits and scalp. As the melanin content decreases, the hair becomes thinner and grayer, and the nails also become thinner. Over the age of 80, more obvious visual changes can be observed, such as compression of the intervertebral discs, vertebrae and joints. Hearing also decreases depending on the severity of the aging phenomenon. Apart from this, the elderly population suffers from presbyopia and may need to wear reading glasses. Compared to healthy adults, they lack deep sleep and are unable to get enough rest as required by the body at this stage. Bone density decreases and becomes weaker, increasing the risk of fractures. Due to slow metabolism and hormonal changes, muscle mass decreases and body fat increases. Apart from this, the elderly also suffer from memory loss and blurriness, making them unable to recall names and unable to recall memories. Over time, the efficiency of the heart and lungs decreases, and kidney function weakens. The accumulated harmful metabolic waste later manifests as dangerous diseases and allergies, causing severe discomfort to the elderly. In addition, menopausal women produce a reduced amount of estrogen, so they experience various changes such as vaginal dryness, hot flashes, chills, night sweats, sleep problems, mood swings, weight gain, and slowed metabolism. Apart from this, unhealthy diet and lazy lifestyle further increase the risk of chronic diseases such as cancer, osteoarthritis, type 2 diabetes, obesity, coronary artery disease osteoporosis, and hypertension in the elderly.

[0003] There is currently an urgent need for drugs or health products that can resist or slow down aging.

[0004] People around the world are living longer and their expectations are increasing. Aging is a biophysiological process of continuous change. The mechanisms of aging are mainly due to increased cellular senescence, genetic instability, oxidative stress, and inflammatory cytokines. One of the most practical anti-aging strategies is intervention with herbal and bioactive therapies. Consumption of antioxidant-rich supplements, a balanced diet, and pharmacological treatments can inhibit the harmful effects caused by free radicals and slow down aging. Summary of the invention

[0005] In one aspect of the present invention, a composition is provided, comprising cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum.

[0006] In some embodiments of the present invention, the cordyceps powder is a medicinal powder made from cordyceps. In some embodiments of the present invention, the propolis is a resinous substance collected by worker bees from the terminal buds and exudates of plants, and mixed with beeswax and bees' maxillary gland secretions to form a sticky solid with an aromatic odor. In some embodiments of the present invention, the frankincense is a resin exuded from the bark of Boswellia carterii Birdw., a plant of the olive family. In some embodiments of the present invention, the clove is its dried flower buds.

[0007] In some embodiments of the present invention, the mass proportion of each medicinal material in the composition is 1 / 12.

[0008] In some embodiments of the present invention, the weight proportion of each medicinal material in the composition is the same.

[0009] In some embodiments of the invention, the composition comprises ≥ 1.50% (w / w) of compound ExVASP09C1:

[0010]

[0011] In some embodiments of the invention, the composition comprises 1.50%-1.60% (w / w) of compound ExVASP09C1.

[0012] In some embodiments of the invention, the composition comprises 1.56% (w / w) of compound ExVASP09C1:

[0013]

[0014] In some embodiments of the present invention, the composition is prepared by the following method:

[0015] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, grind and mix them evenly; add 95% ethanol, heat in a high-pressure heating autoclave in an air-tight state, cool and filter to obtain the product.

[0016] In some embodiments of the present invention, the composition is prepared by the following method:

[0017] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, crush and mix them; add 95% ethanol, heat in a high pressure heating autoclave in an airtight state, filter after cooling, and remove the solvent to obtain the product.

[0018] In some embodiments of the present invention, the composition is prepared by the following method:

[0019] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, crush and mix them evenly; add 95% ethanol, heat in an air-tight condition, and obtain the product.

[0020] In some embodiments of the present invention, the composition is prepared by the following method:

[0021] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, crush and mix them; add 95% ethanol, heat at 78-82° C. for 4-6 hours in an airtight condition, filter after cooling, and remove the solvent to obtain the product.

[0022] In some embodiments of the present invention, the composition is prepared by the following method:

[0023] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, crush and mix them; add 95% ethanol, heat in a high pressure heating autoclave in an airtight state, filter after cooling, remove the solvent, and obtain a crude extract;

[0024] The crude extract was dissolved in ethanol, loaded onto a silica gel column, the eluate with ethyl acetate-methanol 1:1 was collected, and the solvent was removed to obtain the product.

[0025] In some embodiments of the present invention, the composition is prepared by the following method:

[0026] Take 1 part by weight of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacosperma paniculatum, grind and mix them; add 120 parts by weight of 95% ethanol, heat to 80° C. in a high pressure heating autoclave under a nitrogen atmosphere of 0.2 MPa, and keep it for 5 hours; filter after cooling, and dry under reduced pressure to obtain a crude extract;

[0027] The crude extract was dissolved in ethanol and loaded onto a silica gel column. Gradient elution was performed using a mixed solvent of ethyl acetate-methanol in a volume ratio of 2:0, 2:1, 1:1, and 1:2, with each ratio of mixed solvent used for elution for 5 times the column volume. The eluate in a ratio of ethyl acetate-methanol in a ratio of 1:1 was taken and dried under reduced pressure to obtain the product.

[0028] In some embodiments of the present invention, the composition is prepared by the method described in Example 1.

[0029] The inventor unexpectedly discovered that by combining Cordyceps sinensis powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, cloves, and leaves of the African endemic plants Voacanga africana and Sacospermapaniculatum, under relatively intense extraction conditions, a new composition was obtained, which has good anti-aging and memory-improving effects. In particular, the extracts ExVASP06 and ExVASP09 are more active, have significant free radical scavenging ability and anti-aging effects. Among them, compound ExVASP09C1 is the single component with the highest content in the extract ExVASP09. Without being bound by theory, this component may be formed by degradation and condensation of flavonoid components and alkaloid components during the extraction process.

[0030] In another aspect of the present invention, a method for preparing the composition of the present invention is provided, the preparation method comprising:

[0031] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, grind and mix them evenly; add 95% ethanol, heat in a high-pressure heating autoclave in an air-tight state, cool and filter to obtain the product.

[0032] In some embodiments of the present invention, the cordyceps powder is a medicinal powder made from cordyceps. In some embodiments of the present invention, the propolis is a resinous substance collected by worker bees from the terminal buds and exudates of plants, and mixed with beeswax and bees' maxillary gland secretions to form a sticky solid with an aromatic odor. In some embodiments of the present invention, the frankincense is a resin exuded from the bark of Boswellia carterii Birdw., a plant of the olive family. In some embodiments of the present invention, the clove is its dried flower buds.

[0033] In some embodiments of the present invention, a method for preparing a composition is provided, the preparation method comprising:

[0034] Take equal weight portions of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum, crush and mix them; add 95% ethanol, heat in a high pressure heating autoclave in an airtight state, filter after cooling, remove the solvent, and obtain a crude extract;

[0035] The crude extract was dissolved in ethanol, loaded onto a silica gel column, the eluate with ethyl acetate-methanol 1:1 was collected, and the solvent was removed to obtain the product.

[0036] In some embodiments of the present invention, a method for preparing a composition is provided, the preparation method comprising:

[0037] Take 1 part by weight of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacosperma paniculatum, grind and mix them; add 120 parts by weight of 95% ethanol, heat to 80° C. in a high pressure heating autoclave under a nitrogen atmosphere of 0.2 MPa, and keep it for 5 hours; filter after cooling, and dry under reduced pressure to obtain a crude extract;

[0038] The crude extract was dissolved in ethanol and loaded onto a silica gel column. Gradient elution was performed using a mixed solvent of ethyl acetate-methanol in a volume ratio of 2:0, 2:1, 1:1, and 1:2, with each ratio of mixed solvent used for elution for 5 times the column volume. The eluate in a ratio of ethyl acetate-methanol in a ratio of 1:1 was taken and dried under reduced pressure to obtain the product.

[0039] In some embodiments of the present invention, a method for preparing a composition is provided, the preparation method comprising:

[0040] It was prepared using the method described in Example 1.

[0041] In another aspect of the present invention, there is provided use of the composition of the present invention in preparing anti-aging drugs.

[0042] In some embodiments of the present invention, a composition is provided for use in preparing an anti-aging drug, wherein the composition is prepared by the following method:

[0043] Take 1 part by weight of cordyceps powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacosperma paniculatum, grind and mix them; add 120 parts by weight of 95% ethanol, heat to 80° C. in a high pressure heating autoclave under a nitrogen atmosphere of 0.2 MPa, and keep it for 5 hours; filter after cooling, and dry under reduced pressure to obtain a crude extract;

[0044] The crude extract was dissolved in ethanol and loaded onto a silica gel column. Gradient elution was performed using a mixed solvent of ethyl acetate-methanol in a volume ratio of 2:0, 2:1, 1:1, and 1:2, with each ratio of mixed solvent used for elution for 5 times the column volume. The eluate in a ratio of ethyl acetate-methanol in a ratio of 1:1 was taken and dried under reduced pressure to obtain the product.

[0045] In another aspect of the present invention, a cosmetic is provided, comprising the composition of the present invention.

[0046] In some embodiments of the present invention, the cosmetic further comprises an auxiliary material.

[0047] In another aspect of the present invention, a medicament is provided, wherein the medicament comprises the composition of the present invention.

[0048] In some embodiments of the present invention, the medicament further comprises a pharmaceutically acceptable excipient.

[0049] In another aspect of the present invention, a health care product is provided, wherein the health care product comprises the composition of the present invention.

[0050] In some embodiments of the present invention, the health care product further comprises an auxiliary material.

[0051] The technical effect of the technical solution of the present invention: The composition of the present invention has strong free radical scavenging activity and cell anti-aging activity, and can replenish the spirit. In animal experiments, it can significantly improve the learning and memory ability of aging mice, achieving unexpected technical effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The results of Morris water maze test on mice of different extracts are shown. DETAILED DESCRIPTION

[0053] The present invention is further described below by way of specific examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

[0054] Example 1. Preparation of extract

[0055] Cordyceps sinensis powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense (Boswelliacarterii Birdw. resin), clove, Voacanga africana (leaf) and Sacospermapaniculatum (leaf) were taken and air-dried at room temperature. 100 g of each medicinal material was taken, crushed and mixed to obtain mixed powder 1.

[0056] Take half of the mixed powder 1, add 10 times the weight of 95% ethanol, and let stand at room temperature for 30 days. Filter and dry under reduced pressure to obtain a crude extract, named ExVASP01.

[0057] Add 10 times the weight of 95% ethanol to the other half of the mixed powder 1, heat to 80°C in a high pressure heating autoclave under a nitrogen atmosphere (0.2 MPa) for 5 hours, filter after cooling, and dry under reduced pressure to obtain a crude extract named ExVASP06.

[0058] The crude extract ExVASP06 was dissolved in ethanol and loaded onto a silica gel column. Gradient elution was performed using a mixed solvent of ethyl acetate-methanol with a volume ratio of 2:0, 2:1, 1:1, and 1:2, with each ratio eluting for about 5 times the column volume. The eluate with a volume ratio of ethyl acetate-methanol of 1:1 was taken and dried under reduced pressure to obtain the extract ExVASP09.

[0059] In addition, Cordyceps sinensis powder, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense (Boswellia carterii Birdw. resin), and cloves were taken and dried in the sun at room temperature. Take 100g of each medicinal material, crush it, and mix it to obtain mixed powder 2. Take mixed powder 2, add 10 times the weight of 95% ethanol, and heat it to 80°C in a nitrogen atmosphere (0.2MPa) in a high-pressure heating kettle for 5 hours. After cooling, filter, decompress and dry to obtain a crude extract. Ethanol dissolves the crude extract and loads it on a silica gel column. Use ethyl acetate-methanol mixed solvent gradient elution with a volume ratio of 2:0, 2:1, 1:1, and 1:2, and each ratio is eluted about 5 times the column volume. Take the eluent of ethyl acetate-methanol 1:1, decompress and dry to obtain the extract ExVASP10.

[0060] Example 2. Antioxidant activity test of the extract - DPPH free radical scavenging experiment

[0061] Prepare 0.1mM DPPH ethanol solution. Prepare ethanol solutions of plant extracts of different concentrations. Take 100μL of extract solution and 900μL of DPPH solution respectively, mix well, and let stand at rt for 30min. Use a UV-visible spectrophotometer to measure the absorbance of the reaction solution (λ=517nm), and ethanol is used as a blank control. Free radical scavenging rate (%) = [(DPPH solution absorbance-reaction solution absorbance) / DPPH solution absorbance]×100.

[0062] As shown in Table 1, the free radical scavenging activities of extracts ExVASP06 and ExVASP09 were significantly better than those of extracts ExVASP01 and ExVASP10.

[0063] Table 1. DPPH free radical scavenging rate of different extracts

[0064]

[0065] Example 3: Cell anti-aging experiment

[0066] Human fibroblasts WI-38 (IMMOCell, IM-H221) were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO2. The cells were exposed to low concentrations of H2O2 for 24 hours to induce cell aging caused by oxidative stress. The extract was dissolved in an equal volume of DMEM medium to obtain extract solutions of different concentrations, which were added to the induced aging cells and treated for 24 hours (the negative control group used an equal volume of DMEM medium). The activity of β-galactosidase in the cells was measured using β-galactosidase staining, and the number of senescent cells was observed and recorded under a microscope to evaluate the degree of cell aging.

[0067] The results showed that compared with normal cells, the β-galactosidase activity of cells treated with H2O2 was significantly increased, indicating that the cells had aged.

[0068] After treatment with the extract ExVASP01 at a concentration of 64 μg / mL, the number of senescent cells was not significantly different from that in the negative control group, and a decrease in the number of senescent cells was observed at a concentration of 128 μg / mL.

[0069] After treatment with the extract ExVASP09 at a concentration of 1 μg / mL, a significant decrease in the number of senescent cells was observed compared with the negative control group.

[0070] Example 4: The extract improves learning and memory function in aged mice

[0071] Male C57BL / 6 mice aged 8 weeks and weighing 19-21 g were randomly divided into a blank group, a model group, and experimental groups, with 10 mice in each group.

[0072] The aging mouse model was successfully obtained by intraperitoneal injection of 200 mg / kg of D-galactose (Sigma), and the blank group was intraperitoneally injected with an equal volume of saline. Each extract was dissolved in sterile water to obtain an aqueous solution, and the model was gavaged once a day (0.2 mL / d) for one month. The blank group and the model group were given an equal amount of sterile water. The Morris water maze test was performed on the second day after the administration. The results are shown in Table 2. Figure 1 shown.

[0073] Table 2. Morris water maze test results

[0074]

[0075] Compared with the model group, the latency of crossing the platform in the ExVASP06 (32 μg / mL) group and the ExVASP09 (2 μg / mL) group was significantly shortened (P<0.05, P<0.01). Compared with the ExVASP01 (64 μg / mL) and ExVASP10 (64 μg / mL) groups, the latency of crossing the platform in the ExVASP09 (2 μg / mL) group was also significantly shortened (P<0.01, P<0.01).

[0076] Compared with the ExVASP01 (64 μg / mL) group, the number of platform crossings in the ExVASP09 (2 μg / mL) group increased significantly (P<0.01). Compared with the ExVASP10 (64 μg / mL) group, the number of platform crossings in the ExVASP09 (2 μg / mL) group increased significantly (P<0.01).

[0077] It was demonstrated that extracts ExVASP06 and ExVASP09 can significantly improve the learning and memory abilities of aged mice.

[0078] Example 5: Extract ExVASP09 was isolated and purified to obtain compound ExVASP09C1

[0079] Using Hypersil GOLD TM The extract ExVASP09 obtained by the method of Example 1 was separated and purified by PREP C18 HPLC column, and methanol-water (1% TFA) was used as the mobile phase for gradient elution to obtain compound ExVASP09C1, which accounted for 1.56% by mass. The mass proportion of any other single component in the extract was less than 0.52%.

[0080] Extract ExVASP10 was purified using essentially the same method, and compound ExVASP09C1 was not isolated.

[0081]

[0082] ExVASP09C1: 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.95(s,1H),7.18(dd,J=9.6,2.1Hz,1H),7.05(d,J=2.3Hz,1H),6.90(d,J=9.5Hz,1H),6.54–6.20(m,2H),4.7 1(tt,J=3.1,1.5Hz,1H),4.52(s,2H),3.50(dq,J=7.0,1.2Hz,2H),3.06– 2.77(m,1H),2.44(d,J=1.5Hz,3H),2.28–2.07(m,1H),1.97–1.64(m,5H).

[0083] ExVASP09C1: 13 C NMR (100MHz, DMSO-d6) δ (ppm): 178.1,172.5,163.9,162.6,149,147.3,146.8,142.2,132.6,129.4,12 6.5,122.2,117.4,116.2,112.7,112.1,111.5,101.3,100.4,54.6,39.7,33.8,32.9,25.5,22.8,18.9.

[0084] The chirality of the compound was determined by circular dichroism spectroscopy, that is, the ECD of the compound was calculated in MeOH at the B3LYP / 6-311+G(d,P) level using the TDDFT method, which was consistent with the experimentally determined ECD curve, thus confirming that it was an S configuration.

[0085] Example 6: Compound ExVASP09C1 improves learning and memory function in aged mice

[0086] The same method as in Example 4 was used to test the aging model mice in the Morris water maze experiment. The results showed that the mice given 0.2 mL of 2 μg / mL compound ExVASP09C1 daily by oral gavage had a latency of only 30.2 seconds to cross the platform, and crossed the platform 5 times, which was significantly better than the model group mice of the same batch (P<0.01) and the extract ExVASP01 (64 μg / mL) group (P<0.01). This proves that compound ExVASP09C1 has excellent efficacy in delaying aging and improving learning and memory.

[0087] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and do not constitute limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. An anti-aging Chinese medicine composition, which is composed of equal parts by weight of Cordyceps sinensis, American ginseng, Astragalus, Safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacospermapaniculatum.

2. The Chinese medicine composition according to claim 1, comprising 1.50%-1.60% of compound ExVASP09C1:

3. The Chinese medicine composition according to claim 1, wherein the Chinese medicine composition is prepared by the following method: Take 1 part by weight of cordyceps sinensis, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacosperma paniculatum, crush and mix; add 120 parts by weight of 95% ethanol, heat to 80°C in a high-pressure heating autoclave under a nitrogen atmosphere of 0.2 MPa, and keep for 5 hours; filter after cooling, and decompress and spin-dry to obtain a crude extract; dissolve the crude extract in ethanol, load it on a silica gel column, and use ethyl acetate-methanol mixed solvents with volume ratios of 2:0, 2:1, 1:1, and 1:2 in sequence for gradient elution, and each ratio of mixed solvents is used for elution for 5 times of column volume; take the eluate with ethyl acetate-methanol in a ratio of 1:1, and decompress and spin-dry to obtain the extract.

4. A method for preparing an anti-aging Chinese medicine composition, the method comprising: Take 1 part by weight of cordyceps sinensis, American ginseng, astragalus, safflower, cinnamon, wolfberry, propolis, epimedium, frankincense, clove, leaves of Voacanga africana and leaves of Sacosperma paniculatum, crush and mix; add 120 parts by weight of 95% ethanol, heat to 80°C in a high-pressure heating autoclave under a nitrogen atmosphere of 0.2 MPa, and keep for 5 hours; filter after cooling, and decompress and spin-dry to obtain a crude extract; dissolve the crude extract in ethanol, load it on a silica gel column, and use ethyl acetate-methanol mixed solvents with volume ratios of 2:0, 2:1, 1:1, and 1:2 in sequence for gradient elution, and each ratio of mixed solvents is used for elution for 5 times of column volume; take the eluate with ethyl acetate-methanol in a ratio of 1:1, and decompress and spin-dry to obtain the extract.

5. Use of the Chinese medicine composition according to any one of claims 1 to 3 in the preparation of anti-aging drugs.

6. A cosmetic comprising the traditional Chinese medicine composition according to any one of claims 1 to 3.

7. A medicine comprising the Chinese medicine composition according to any one of claims 1 to 3.

8. A health product, comprising the Chinese medicine composition according to any one of claims 1 to 3.

9. Compound ExVASP09C1 and its salt, wherein the structure of the compound ExVASP09C1 is:

10. Use of compound ExVASP09C1 in the preparation of anti-aging drugs, wherein the structure of the compound ExVASP09C1 is:

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