CN115381886B - Traditional Chinese medicine extract, preparation method thereof and application thereof in preventing and treating hepatic ischemia reperfusion injury - Google Patents
Traditional Chinese medicine extract, preparation method thereof and application thereof in preventing and treating hepatic ischemia reperfusion injury Download PDFInfo
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- CN115381886B CN115381886B CN202210581871.1A CN202210581871A CN115381886B CN 115381886 B CN115381886 B CN 115381886B CN 202210581871 A CN202210581871 A CN 202210581871A CN 115381886 B CN115381886 B CN 115381886B
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Classifications
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- 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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/80—Scrophulariaceae (Figwort family)
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application belongs to the technical field of medicines, and particularly relates to a traditional Chinese medicine extract, a preparation method thereof and application thereof in preventing and treating hepatic ischemia reperfusion injury. The medicinal effect experiment shows that the traditional Chinese medicine extract, namely the prepared rehmannia root water extract, has obvious effects of resisting inflammation, oxidation injury and liver cell group apoptosis, reducing serum glutamic pyruvic transaminase and glutamic oxalacetic transaminase levels and liver tissue malondialdehyde, lactic dehydrogenase and nitric oxide levels, increasing superoxide dismutase activity, and improving liver blood sinus microenvironment pathological conditions so as to relieve liver ischemia reperfusion injury. Compared with the prior HIRI pretreatment means or experimental positive drug N-acetylcysteine which is clinically used at present, the prepared rehmannia root aqueous extract has wide sources, low cost and obvious curative effect, provides a new method for preventing and treating the hepatic ischemia reperfusion injury, and has great clinical significance.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a traditional Chinese medicine extract, a preparation method thereof and application thereof in preventing and treating hepatic ischemia reperfusion injury.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Liver ischemia reperfusion injury (Hepatic ischemia reperfusion injury, HIRI), which is commonly found in the end-stage treatment of clinical acute and severe liver diseases, and liver injury diseases such as liver trauma, hemorrhagic shock, and the like, involves a plurality of pathological links such as oxidative stress, inflammatory reaction, apoptosis, and the like, and is directly related to postoperative complications of a liver part, such as liver fibrosis, liver dysfunction, multi-organ injury, even acute rejection, liver failure, and the like. These complications not only seriously threaten the survival of the receptor and increase the possibility of transplantation failure in the perioperative period, but also have a certain influence on the long-term prognosis of the patient, while the HIRI is lack of effective therapeutic drugs at present, and the alleviation of the HIRI is always a problem to be explored in the clinical practice of liver transplantation.
Treatment of HIRI is currently mainly dependent on reducing liver ischemia time, improving microcirculation, increasing liver blood flow, and performing HIRI pre-adaptation, but the above methods have extremely high operation difficulty or strict operation time window requirements. Many pretreatment methods such as short-time temporary ischemia pretreatment (ischemia preconditioning, IPC) and post-reperfusion pretreatment (IPO) are commonly used, and short-time repeated ischemia-reperfusion pretreatment is respectively carried out before operation and before long-time post-ischemia reperfusion in operation, and the drug pretreatment adopts a calcium channel blocker, an oxygen free radical scavenger ribozyme inhibitor and the like to achieve the protection effect similar to IPC, so that the method has a certain effect, but the treatment defect is obvious and the cost is higher. Among them, N-acetylcysteine (NAC), a classical antioxidant, can act on oxidative radicals and as a cysteine precursor for glutathione synthesis to limit oxidative stress in the HIRI, and is increasingly used to alleviate liver injury during clinical liver transplantation and improve prognosis, but it still has limitations on inflammation in the HIRI and even changes in liver function enzyme levels, etc. Therefore, the method searches and researches the safe, effective, simple, convenient and easily available medicines with definite action mechanism for relieving the HIRI in the traditional Chinese medicine range have profound significance, and can make an important contribution to the clinical HIRI prevention and treatment.
Disclosure of Invention
Based on the defects of the prior art, the application provides a traditional Chinese medicine extract, a preparation method thereof and application thereof in preventing and treating hepatic ischemia reperfusion injury. According to the application, researches show that the radix rehmanniae preparata aqueous extract of the figwort family plant can obviously improve pathological structural disorder of liver tissues caused by hepatic ischemia reperfusion injury, and the levels of glutamic-oxaloacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), lactic Dehydrogenase (LDH), nitric Oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA) and serum Hyaluronic Acid (HA) in the blood serum and liver tissues are further analyzed, so that a foundation is laid for the practical application of the radix rehmanniae preparata in preventing and treating hepatic ischemia reperfusion injury.
In order to achieve the technical purpose, the application adopts the following technical scheme:
in a first aspect of the present application, a traditional Chinese medicine extract is provided, wherein the traditional Chinese medicine extract is an aqueous extract of radix rehmanniae Preparata, and specifically can be obtained by decocting radix rehmanniae Preparata yellow with water.
The active components of the application are analyzed and identified, and the main active components at least comprise catalpol, rehmannia glycoside D, acteoside, hesperidin, 5-hydroxymethylfurfural and the like.
Proved by researches, the prepared rehmannia root water extract has obvious effects of resisting inflammation, resisting oxidative damage and resisting hepatic cell apoptosis, reducing serum AST (human serum, administration of a drug) and ALT (ALT) levels and liver tissue MDA (MDA, LDH and NO) levels, increasing SOD (superoxide dismutase) activity, and improving pathological conditions of liver blood sinus microenvironment so as to relieve liver ischemia reperfusion injury, thereby being capable of being used for preparing medicines for treating or/and preventing the liver ischemia reperfusion injury.
In a second aspect of the present application, a preparation method of the above traditional Chinese medicine extract is provided, wherein the traditional Chinese medicine extract is an aqueous extract of radix rehmanniae Preparata, and the specific preparation method comprises:
soaking radix rehmanniae Preparata in water, decocting, filtering to obtain supernatant I0.5-1.5 hr (preferably 1 hr) after boiling, decocting the residue with water again, filtering to obtain supernatant II 0.5-1.5 hr (preferably 1 hr) after boiling, mixing the supernatants, and concentrating.
In a third aspect, the application provides an application of the prepared rehmannia root aqueous extract in preparing a medicament for preventing and/or treating hepatic ischemia reperfusion injury.
In particular, the prevention and/or treatment of hepatic ischemia reperfusion injury is manifested by at least any one or more of the following uses:
(a) Anti-inflammatory, anti-oxidative damage, and anti-apoptotic to a population of hepatocytes;
(b) Reducing serum AST and ALT levels and liver tissue MDA, LDH and NO levels, and increasing SOD activity;
(c) Improving the pathological state of liver blood sinus microenvironment.
In a fourth aspect of the present application, there is provided a pharmaceutical composition for preventing and/or treating hepatic ischemia reperfusion injury, which comprises the above-mentioned Chinese medicinal extract and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.
The beneficial effects of one or more of the technical schemes are as follows:
the technical scheme provides the medicinal application of the prepared rehmannia root aqueous extract in preventing and treating liver ischemia reperfusion injury. The drug effect experiment shows that the prepared rehmannia root water extract has obvious functions of resisting inflammation, resisting oxidation injury and resisting liver cell apoptosis, reducing serum AST and ALT levels and liver tissue MDA, LDH and NO levels, increasing SOD activity, improving pathological conditions of liver blood sinus microenvironment and further relieving liver ischemia reperfusion injury. Compared with the prior HIRI pretreatment means or experiment positive drug NAC which is commonly used clinically, the prepared rehmannia root water extract has wide sources, low price and obvious curative effect, provides a new method for preventing and treating the hepatic ischemia reperfusion injury, and has great clinical significance.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application.
Fig. 1 is a flow chart of the preparation of the aqueous extract of traditional Chinese medicine in the embodiment of the application.
Fig. 2 is a schematic diagram of model creation of ischemia reperfusion injury of mouse liver in an embodiment of the present application, wherein the left diagram is the model creation operation ischemia period mouse liver, and the right diagram is the model creation operation reperfusion period mouse liver.
Fig. 3 is a graph showing the results of HE staining for pathological structural changes in the liver of mice in the examples of the present application, notes: mouse liver HE results.
FIG. 4 is a graph of mouse serum/liver tissue AST, ALT, LDH and HA levels in the examples of the present application, as follows: p < 0.5, P < 0.1, P < 0.01 compared to sham group; in contrast to the set of models, # P＜0.5。
FIG. 5 shows the levels of NO, SOD and MDA in mouse serum/liver tissue, according to the examples of the present application, as follows: p < 0.5, P < 0.1, P < 0.01 compared to sham group; in contrast to the set of models, # P＜0.5。
FIG. 6 is a graph showing HPLC results of an aqueous extract of radix rehmanniae Preparata in the example of the present application, notes: 1. catalpol; 2.5-hydroxymethylfurfural; 3. rehmannia root glycoside D;4. acteoside; 5. hesperidin.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. It is to be understood that the scope of the application is not limited to the specific embodiments described below; it is also to be understood that the terminology used in the examples of the application is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the application. Experimental methods in the following embodiments, unless specific conditions are noted, are generally according to conventional methods and conditions within the skill of the art, and are fully explained in the literature.
As mentioned above, the treatment of the existing HIRI is currently mainly dependent on reducing liver ischemia time, improving microcirculation, increasing liver blood flow, and performing HIRI pre-adaptation, etc., but the above manner has extremely high operation difficulty or strict operation time window requirements. The pretreatment of the medicine adopts a calcium channel blocker, an oxygen free radical scavenger nucleoprotein inhibitor and the like to achieve the protection effect similar to IPC, has a certain effect, but has obvious treatment defect and higher cost.
In view of the above, in an exemplary embodiment of the present application, a traditional Chinese medicine extract is provided, and the traditional Chinese medicine extract is an aqueous extract of radix rehmanniae Preparata, specifically may be obtained by decocting radix rehmanniae Preparata yellow with water.
The active components of the application are analyzed and identified, and the main active components at least comprise catalpol, rehmannia glycoside D, acteoside, hesperidin, 5-hydroxymethylfurfural and the like.
Proved by researches, the prepared rehmannia root water extract has obvious effects of resisting inflammation, resisting oxidative damage and resisting liver cell apoptosis, reduces the serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase level and the liver tissue malondialdehyde, lactic dehydrogenase and nitric oxide level, improves the activity of superoxide dismutase, improves the pathological state of liver blood sinus microenvironment so as to relieve liver ischemia reperfusion injury, and can be used for preparing medicines for treating or/and preventing the liver ischemia reperfusion injury.
In still another embodiment of the present application, a preparation method of the above traditional Chinese medicine extract is provided, wherein the traditional Chinese medicine extract is an aqueous extract of radix rehmanniae Preparata, and the specific preparation method includes:
soaking radix rehmanniae Preparata in water, decocting, filtering to obtain supernatant I0.5-1.5 hr (preferably 1 hr) after boiling, decocting the residue with water again, filtering to obtain supernatant II 0.5-1.5 hr (preferably 1 hr) after boiling, mixing the supernatants, and concentrating.
Wherein the mass ratio of the prepared rehmannia root to the water is 1:6-10, preferably 1:8, and the mass ratio of the residue to the water is 1:5-8, preferably 1:6.
The concentration can be carried out by adopting a rotary evaporation mode, and the concentration is 1/6-1/2 of the original volume, preferably 1/5.
The application further analyzes, identifies and researches main active ingredients of the traditional Chinese medicine extract, which comprises catalpol, rehmannia glycoside D, acteoside, hesperidin, 5-hydroxymethylfurfural and the like, and constructs an identification and analysis method for the active ingredients, wherein the identification and analysis method for the active ingredients comprises the step of adopting an HPLC method to identify and analyze the active ingredients.
In yet another embodiment of the present application, an identification analysis method includes:
diluting the prepared radix rehmanniae Preparata water extract with water, filtering to obtain a sample solution, and analyzing catalpol, rehmannioside D, acteoside, hesperidin and 5-hydroxymethylfurfural in the sample solution based on HPLC.
Wherein the liquid chromatography conditions include: the chromatographic column is C18 column, preferably Welch Ultimate TM C18, 250mm by 4.6mm i.d.;5 μm; the method is carried out by adopting a gradient elution mode, wherein the mobile phase is acetonitrile (phase A) and 0.1% phosphoric acid water (phase B);
the specific gradient elution procedure is as follows: 0.01-2min,3% -3.2% A;2-10min,3.2% -3.3% A;10-14min,3.3% -3.6% A;14-18min,3.6% A;18-22min,3.6% -9%A;22-30min,9% -20% of A;30-50min,20% A;50-53min,20% -25% A;53-60min,25% A.
The flow rate is 0.5-5mL/min, preferably 1mL/min, the detection wavelength is 203nm, the sample injection amount is 1-5 mu L, preferably 2 mu L, and the column temperature is 30-40 ℃, preferably 35 ℃.
In still another embodiment of the present application, there is provided an application of the aqueous extract of prepared rehmannia root in preparing a medicament for preventing and/or treating hepatic ischemia reperfusion injury.
According to the present application, the concept of "prevention and/or treatment" means any measure suitable for the treatment of diseases associated with hepatic ischemia reperfusion injury, or for the prophylactic treatment of such a represented disease or of a represented symptom, or for the avoidance of recurrence of such a disease, for example, after the end of a treatment period or for the treatment of symptoms of a disease that has already been developed, or for the pre-interventional prevention or inhibition or reduction of the occurrence of such a disease or symptom.
In particular, the prevention and/or treatment of hepatic ischemia reperfusion injury is manifested by at least any one or more of the following uses:
(a) Anti-inflammatory, anti-oxidative damage, and anti-apoptotic to a population of hepatocytes;
(b) Reducing serum AST and ALT levels and liver tissue MDA, LDH and NO levels, and increasing SOD activity;
(c) Improving the pathological state of liver blood sinus microenvironment.
In yet another embodiment of the present application, a pharmaceutical composition for preventing and/or treating hepatic ischemia reperfusion injury is provided, which is composed of the above-mentioned Chinese medicinal extract with at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.
The pharmaceutically inactive ingredients may be carriers, excipients, etc. which are generally used in pharmacy. The non-pharmaceutically active ingredients, such as carriers, excipients, etc., that may be included are well known in the art and one of ordinary skill in the art will be able to ascertain that they meet the clinical criteria.
The administration form of the medicine can be liquid form or solid form. The liquid dosage form can be true solution, colloid, microparticle, emulsion, and mixed rotation. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc.
The medicament of the application contains common carriers, and pharmaceutically acceptable carriers include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, buffer substances such as phosphates, glycerol, sorbitol, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, etc. The carrier may be present in the pharmaceutical composition in an amount of from 1% to 98% by weight, typically about 80% by weight. For convenience, preservatives, buffers and the like may be directly dissolved in the carrier.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers, for example lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine, lubricants, for example magnesium stearate, talc, polyethylene glycol, silica, disintegrants, for example potato starch, or acceptable wetting agents, for example sodium lauryl sulfate. The tablets may be coated by methods known in the pharmaceutical arts.
The oral liquid can be made into water and oil suspension, solution, emulsion, syrup, or dry product, and can be supplemented with water or other suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or a non-aqueous carrier (possibly containing edible oils) such as almond oil, fats and oils such as glycerin, ethylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl parahydroxybenzoate, sorbic acid. Flavoring or coloring agents may be added as desired.
For parenteral administration, liquid dosage forms are typically made of the compound and a sterile carrier. The carrier is water. Depending on the carrier and drug concentration selected, the compound may be dissolved in either the carrier or in suspension, and when preparing an injectable solution, the compound is first dissolved in water, filtered and sterilized, and filled into sealed bottles or ampoules.
In yet another embodiment of the application, the medicament of the application may be administered to the body in a known manner. For example, by intravenous systemic delivery or local injection into the tissue of interest. Alternatively via intravenous, transdermal, intranasal, mucosal or other delivery methods. Such administration may be via single or multiple doses. It will be appreciated by those skilled in the art that the actual dosage to be administered in the present application may vary greatly depending on a variety of factors, such as the target cell, the type of organism or tissue thereof, the general condition of the subject to be treated, the route of administration, the mode of administration, and the like.
In yet another embodiment of the present application, the subject to which the pharmaceutical composition is administered may be a human or a non-human mammal, such as a mouse, rat, guinea pig, rabbit, dog, monkey, gorilla, more preferably a human.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present application, the technical scheme of the present application will be described in detail with reference to specific embodiments.
Examples
1. Preparation of Chinese medicinal water extract
1.1 Chinese herbal medicine
The traditional Chinese medicine prepared rehmannia root is provided by a Tongren Tang pharmacy in Beijing city.
1.2 preparation flow of aqueous extract of Chinese medicinal materials (see FIG. 1)
1) Preparation of medicines and consumables: taking the traditional Chinese medicine and the filter bag which are prepared in advance.
2) 20g of Chinese medicinal materials are ground into powder after cleaning.
3) 20g of the Chinese medicinal materials are soaked in 160ml of ultrapure water for one hour.
4) Decocting the Chinese medicinal materials, maintaining micro-boiling state for 1 hr, and preventing bumping.
5) Collecting the liquid medicine.
6) Then adding 120ml of ultrapure water into the residue for secondary decoction, keeping micro-boiling state for 1 hr, and preventing bumping.
7) Collecting the twice decocted Chinese medicinal liquid to obtain 100ml of mixed liquid.
8) Performing rotary steaming of the liquid medicine, and treating the waste liquid during the rotary steaming.
9) Obtaining 20ml of concentrated Chinese medicine water extract.
10 Warehousing the Chinese medicinal water extract for later use.
2. Liver ischemia reperfusion mouse model preparation (see figure 2)
2.1 laboratory animals SPF grade C57BL/6 mice, male, 6w-8w for week, 22 g-24 g body weight, offered by Si Bei Fu (Beijing) Biotechnology Co., ltd.
2.2 experimental grouping: mice were randomly divided into 5 groups: sham operation group, model group, low dose group of aqueous extract of prepared rehmannia root (SDH, 2.5 g/kg), medium dose group of aqueous extract of prepared rehmannia root (SDH, 5 g/kg), high dose group of aqueous extract of prepared rehmannia root (SDH, 10 g/kg) and positive drug control group (NAC, 0.1 g/kg), each mouse was pretreated for 7d in a 1mL/100g body mass intragastric administration mode, and the sham operation group and model group were administered with an equal volume of physiological saline.
2.3 HIRI mouse model
1) Mice were fasted 2h before surgery and were free to drink water.
2) Inhalation anesthesia is induced by isoflurane through a small animal gas anesthesia instrument, after the anesthesia is successful, the mice are laid on an operation table, limbs are fixed by using an adhesive tape, the abdomen of the mice is unhairing, and the operation area is disinfected by iodine and 75% ethanol.
3) The left and middle lobes of the liver (the portal vein and hepatic artery supplying blood to the left and middle lobes of the liver) were carefully isolated from the abdominal cavity of the mice at 1cm incision, and the portal vein and hepatic artery of the middle and left lobes were clamped with a non-invasive vascular clamp to cause about 70% of the liver to be ischemic to prevent severe mesenteric venous stasis. After 0.5min, the blocking leaves were visibly whiter compared to the non-blocking right leaves, indicating successful blocking, temporarily closing the abdominal cavity by clamping the skin incision with a hemostat, while placing the mice on a constant temperature heating pad at 37 ℃.
4) After the continuous ischemia is completed for 60min, the abdominal cavity is opened again, the vascular clamp is taken out rapidly, the blood flow of the ischemic liver is restored, the liver in the ischemic area is gradually restored to bright red from white about 0.5min, the reperfusion is successful, the abdominal cavity muscle and skin are sutured layer by layer, and the abdominal cavity is closed, so that the operation is completed. After the mice are awake, the mice are put back into a feeding room for feeding, and the states and the survival conditions of the mice are closely concerned and recorded.
5) After the operation, the mice are anesthetized for 6 hours after reperfusion, blood is taken from abdominal aorta, after standing for 2 hours at room temperature, serum is extracted by centrifugation at 4 ℃/3000r for 10 minutes, and the mice are put into a-80 refrigerator for freezing, and meanwhile, left lobe tissues of the liver are uniformly taken, and pathological specimens and meristematic specimens are reserved.
3. Pretreatment of the aqueous extract of radix rehmanniae Preparata can relieve damage of liver tissue pathological structure of HIRI mice
After the HIRI model is prepared, the liver left She Weizhi of the mouse is fixed, and the tissue is dehydrated: 80% ethanol 40min, 90% ethanol 400min, 95% ethanol I50min, 95% ethanol II 50min, absolute ethanol I50min, and absolute ethanol II 45min. Then, transparent treatment is carried out: xylene I20 min xylene II 20min xylene III 30min. And (5) wax dipping is carried out immediately: placing the transparent tissue block into melted paraffin at 58-60 ℃ in an incubator, adding three cups of the paraffin, wherein the first cup of the paraffin is 1h, the second cup of the paraffin is 1h and 20min, and the third cup of the paraffin is 1h and 30min. Embedding: the filtered fresh wax is poured into the embedder and the tissue mass saturated with wax is placed inside as soon as possible. Slicing: paraffin blocks were cut into 5 μm thick sections using a paraffin microtome. And (3) sticking: the cut paraffin tissue pieces are firstly put into 40% alcohol and then transferred into warm water with the temperature of about 40 ℃. Finally, the tissue slice is fished out by the glass slide which is coated by polylysine and is attached to the glass slide. Baking slices: the paraffin-sectioned slides were placed on slide racks and baked overnight at 60 ℃. Dyeing: washing with distilled water for 5min, hematoxylin staining for 16min, washing off floating color with tap water, differentiating with 1% hydrochloric acid alcohol for 2s, returning tap water to blue, staining with eosin at room temperature for 15s, terminating color development with tap water, gradient alcohol dehydration, 75% → 80% → 85% → 90% → 100% → 100%. Each of the films was transparent to xylene for 10min, transparent to xylene for 30min, sealed with neutral resin, and the color development results were observed under a common optical microscope and photographed.
The results are shown in FIG. 3. The experimental results show that: compared with the liver cells of the mice in the sham operation group which are in radioactive regular arrangement with the central vein as the center; the peripheral of hepatic tissue vein of the mice in the liver ischemia reperfusion injury group starts to necrose, the vacuolated degeneration of liver cells, infiltration of inflammatory cells and obvious tissue ischemia; compared with a model group, each administration group of the prepared rehmannia root aqueous extract can relieve pathological changes of liver tissue pathological structures of mice damaged by liver ischemia reperfusion, wherein a low-dose group (SDH 2.5 g/kg) of the prepared rehmannia root aqueous extract shows a slight relieving effect, a dose group (SDH 5 g/kg) of the prepared rehmannia root aqueous extract and a high-dose group (SDH 10 g/kg) of the prepared rehmannia root aqueous extract show a remarkable improving effect on the damaged liver tissue structures, and a positive medicine control group (NAC 0.1 g/kg) of the liver tissue pathological structures of the mice are close to the low-dose group of the prepared rehmannia root aqueous extract. In conclusion, the dose group (5 g/kg) and the high dose group (10 g/kg) of the SDH water extract can obviously improve the pathological structure of damaged liver tissues of the model mice.
4. Pretreatment of radix rehmanniae Preparata water extract can relieve liver function injury of HIRI mice
After the model is prepared and the materials are taken, blood collection is carried out by adopting a blood collection mode of the abdominal aorta of the mice, the blood collection is carried out after the blood collection is carried out for 2 hours at room temperature, the centrifugation is carried out for 10 minutes at a rotating speed of 3000r/min, and the supernatant is taken and stored at the temperature of minus 20 ℃ for detection. Rapidly taking out liver tissue under low temperature condition, drying surface water by filter paper, weighing, cutting into small pieces, placing into 10mL precooled centrifuge tube, homogenizing in ice bath, adding 1mL 1 XPBS (phosphate buffer solution) per 100mg tissue, homogenizing, centrifuging at 4deg.C 5000r/min for 5min to obtain supernatant, measuring protein content in each group of serum and liver tissue homogenate according to BCA protein measurement kit requirement, and measuring content according to AST, ALT, LDH measurement kit requirement; and detecting HA activity in serum according to the ELISA kit requirement of Hyaluronic Acid (HA).
The results are shown in FIG. 4. The experimental results show that: compared with the sham operation group, ALT, AST, HA in the serum of mice in the liver ischemia reperfusion injury group is obviously increased, liver tissue LDH is increased, the liver function injury is serious, the ALT, AST, LDH and HA levels of each dosage group (2.5 g/kg,5g/kg and 10 g/kg) of the prepared rehmannia root aqueous extract are reduced, the protection of the liver function in HIRI by the prepared rehmannia root aqueous extract is indicated, and the liver function index level can be improved by a positive medicine control group (NAC 0.1 g/kg), wherein the reduction effect of NAC on AST is general.
5. Pretreatment of radix rehmanniae Preparata water extract can relieve liver oxidative stress injury of HIRI mice
The mice were sampled and treated as described above, and serum and liver tissue were taken for detection. And calculating the protein content of the serum and liver tissue homogenate of the mice according to the quantitative BCA protein result, and respectively detecting the NO level of the serum and the NO, SOD and MDA level of the liver tissue homogenate according to the requirements of NO, SOD and MDA detection kits.
The results are shown in FIG. 5. The experimental results show that: compared with the sham operation group, the liver ischemia reperfusion injury group has the advantages that the NO level of mice is reduced, the SOD activity of liver tissues is reduced, the MDA of the liver tissues is increased, the oxidative stress injury of the liver after molding is shown, each dosage group (2.5 g/kg,5g/kg and 10 g/kg) of the prepared rehmannia root aqueous extract has the advantages that the NO level and the SOD activity are protectively increased, the MDA level is reduced, the prepared rehmannia root aqueous extract can relieve the oxidative stress injury of the liver in HIRI, and the positive medicine control group (NAC 0.1 g/kg) does not show the protection effect on the liver oxidative stress injury related indexes.
6. Identification of major active components of aqueous extract of prepared rehmannia root
6.1 laboratory apparatus
A high performance liquid chromatograph of Shimadzu LC-20A type; chromatographic column Welch Ultimate TM C18, 250mm by 4.6mm i.d.;5 μm; an electronic analytical balance; ultrasonic cleaning instrument and the like
6.2 medicine and Standard substance
5-hydroxymethylfurfural control, lot number: b21832, source leaf; calycosin control, lot number: s31661, source leaves; catalpol reference, lot number: b21678-20mg, source leaf; ou haha water; acetonitrile, chromatographic grade, purity >99.9%, beijing forward organisms; anhydrous methanol with purity >99.9%. The Chinese medicinal materials are purchased from Tongren Tang drug store.
6.3 preparation method
1) Chromatographic conditions: the mobile phase is acetonitrile (phase A) and 0.1% phosphoric acid water (phase B); gradient elution, gradient elution procedure is: 0.01-2min,3% -3.2% A;2-10min,3.2% -3.3% A;10-14min,3.3% -3.6% A;14-18min,3.6% A;18-22min,3.6% -9%A;22-30min,9% -20% of A;30-50min,20%
A, A is as follows; 50-53min,20% -25% A;53-60min,25% A. The flow rate is 1mL/min, the detection wavelengths are 203nm and 285nm, and the peaks of all the standard substances can be shown at 203nm after debugging, so that the final liquid phase diagram shows the result at 203nm and the concentration is calculated subsequently. The sample injection amount was 2uL and the column temperature was 35 ℃.
2) Preparation of a standard: taking catalpol, rehmannia glycoside D, acteoside, hesperidin and 5-hydroxymethylfurfural (5-HMF) standard substance powder with a proper amount of about 1mg, precisely weighing by a ten-thousandth electronic balance, adding anhydrous methanol for dissolving, preparing mother solutions with different solubilities of 100mg/mL, 50mg/mL and 20mg/mL, preserving at low temperature and in a dark place, then sucking the mother solution, adding the anhydrous methanol into the mother solution to prepare a working solution with the concentration of 0.2mg/mL, and filtering for later use.
3) Preparation of test solution: 4g of traditional Chinese medicine radix rehmanniae Preparata is pulverized and then packaged, and put into a flask according to the following weight ratio of 1: 832 ml of dH was added thereto 2 O, soaking for 60min, heating to boiling, decocting for 60min, pouring out medicinal liquid, and adding 32ml dH into residue 2 O is also decocted for 60min, concentrated and supplemented with dH 2 O is fixed to 64ml, 5ml is taken out, and the equal volume dH is added 2 O dilution 1:16, an aqueous extract solution of radix rehmanniae Preparata; filtering with 8 layers of gauze, and filtering with 0.22 μm filter membrane; placing the liquid phase bottle for low-temperature preservation.
And continuously sampling for 8 times according to the chromatographic conditions, sampling for 2 mu L, respectively measuring the retention time, peak height and peak area of 5-HMF, catalpol, rehmannia glycoside D, calycosin and hesperidin, and calculating the concentration of 5 standard substances in the yellow seeds of the prepared rehmannia according to the area difference. The results were as follows: catalpol 0.17mg/mL,5-HMF 0.09mg/mL, rehmannia glycoside D0.14 mg/mL, acteoside 0.01mg/mL, hesperidin 0.06mg/mL. The results are shown in FIG. 6.
While the foregoing description of the embodiments of the present application has been presented in conjunction with the drawings, it should be understood that it is not intended to limit the scope of the application, but rather, it is intended to cover all modifications or variations within the scope of the application as defined by the claims of the present application.
Claims (1)
1. Application of a Chinese medicinal extract in preparing medicine for preventing and/or treating hepatic ischemia reperfusion injury is provided; the prevention and/or treatment of hepatic ischemia reperfusion injury is at least manifested by the following uses:
(a) Anti-inflammatory, anti-oxidative damage, and anti-apoptotic to a population of hepatocytes;
(b) Reducing serum AST and ALT levels and liver tissue MDA, LDH and NO levels, and increasing SOD activity;
(c) Improving the pathological state of liver blood sinus microenvironment;
the main active components of the traditional Chinese medicine extract at least comprise catalpol, rehmannioside D, acteoside, hesperidin and 5-hydroxymethylfurfural;
the traditional Chinese medicine extract is prepared rehmannia root water extract, and the specific preparation method comprises the following steps:
soaking radix rehmanniae Preparata in water, decocting, filtering for 1 hr after boiling to obtain supernatant I, decocting the residue with water again, filtering for 1 hr after boiling to obtain supernatant II, mixing the supernatants, and concentrating;
the mass ratio of the prepared rehmannia root to the water is 1:6-10, and the mass ratio of the residue to the water is 1:6;
the concentration is carried out by adopting a rotary steaming mode, and the concentration is carried out to 1/5 of the original volume.
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| 孔晓妮.熟地黄抗Ⅰ型变态反应活性部位研究.中国优秀硕士学位论文全文数据库医药卫生科技辑》.2010,(第6期),E057-164. * |
| 熟地黄抗Ⅰ型变态反应活性部位研究;孔晓妮;中国优秀硕士学位论文全文数据库医药卫生科技辑》(第6期);E057-164 * |
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