CN100998583A - Novel use of Bitai-en for protecting liver stem cell, eliminating apoptosis of said cells and protecting nepatic function - Google Patents
Novel use of Bitai-en for protecting liver stem cell, eliminating apoptosis of said cells and protecting nepatic function Download PDFInfo
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Abstract
An application of Bitaien in preparing the medicines in the form of capsule, oral liquid, particle, tablet, or injection for preventing and treating fatty liver, alcoholic liver, hepatitides, rheumatism, osteoporosis, gout, diabetes, cardiovascular and cerebrovascular diseases, etc, preventing cancer, delaying sanility, improving immunity, etc is disclosed.
Description
Technical field
The present invention relates to suppress the field of liver stem cells apoptosis and liver function protecting than safe grace protection liver stem cells
Background technology
China is the viral hepatitis district occurred frequently, has 1.2 hundred million people to carry hepatitis B virus approximately, is one of disease of serious harm China people ' s health.The final final result of hepatitis trilogy---chronic hepatitis is drawn together rehabilitation, hepatic fibrosis and liver cirrhosis, hepatocarcinoma.The liver function mistake that hepatopathy causes is compensatory to have become the serious threat hepatopath and the lethal main cause that disables.Along with improving constantly of people's living standard, diet is unhealthy in addition, alcoholic hepatitis, hepatic fibrosis, liver cirrhosis (alcoholic hepatic scleroses, AHS) and non-alcoholic liver cirrhosis (nonalcoholicsteatohepatitis, NASH) also cumulative year after year of sickness rate can cause also that finally liver function loses compensatory.In addition, also have the hepatic injury of some unknown causes, bad as long-term nutrition, monophagia, nutritional imbalance, vitamin deficiency, overtired, long-term oral to the prejudicial medicine of liver, long-term contact harmful gas or liquid, the harmful well water of long-term drink or river, the food of edible pollution by pesticides for a long time, all might cause hepatic injury or hepatic fibrosis, even liver cirrhosis and hepatocarcinoma.
Than safe grace is a kind of chemosmosis agent, chemistry Glycocoll betaine by name, and molecular formula is (CH
3)
3NCH
2COOH.Cl/NO
3, molecular weight is 118+35.5/62, its content in plant, vegetable, Chinese herbal medicine is abundant, but also chemosynthesis.It generally is used for cosmetics as a kind of surfactant, toothpaste or high-grade abluent.The people is also arranged as Italy's (the country one belongs to's pharmacopeia) abroad, the U.S. is used for the treatment of the nonspecific hepatitis that alcoholic hepatitis and a variety of causes cause, liver cirrhosis (Barak, et al.United States Patent, 5,428,063), and belong to the patent of the nineties in 20th century, and do not come into one's own as yet at present at home (Chinese patent retrieval and literature search).
A large amount of studies show that; can be than safe grace by strengthening the expression of heme oxidase; promote that endogenic CO produces in the hepatocyte; the CO of low concentration has the protection cell and suppresses apoptotic effect; promote the activity of the sweet cyclase of acid of bird, c-GMP concentration is increased, activate mitogen activated protein kinase (MAPK); suppress apoptotic pathways and promote the synthetic of the interior sweet methionine of S-gland of liver, the activity of Profilin kinase c (PKC) is protected hepatocyte.Nearest studies show that; in the inductive liver injury animals model of bile acid, can suppress cytochrome C and from mitochondrion, be released into cytoplasm by stablizing mitochondrial membrane than Tai En; thereby suppress the activation of Caspase-9, finally suppress apoptosis and protection hepatocyte.
Liver stem cells has the ability of stem cells hyperplasia and differentiation, and hepatocellular basic function is arranged again.The normal adult liver is an immobilized relatively organ, and hepatocyte is different because of the size of degree of injury for the reaction of growth signals.Lose continuously or/and growth response when being suppressed when ripe hepatocyte, liver stem cells is activated, increases; If but the liver major part is damaged or liver cell proliferation is suppressed, liver stem cells then is activated, hypertrophy, produces elliptocyte, and further is divided into hepatocyte and bile duct cell.The research prompting is arranged, merge in the rat model of carbon tetrachloride poisoning liver damage at acrylic ethanol, not downright bad hepatocyte begins hypertrophy in the liver acinus after rat poisoned 24 hours; After poisoning lasted till 48 hours, the cell of portal vein edges of regions began hypertrophy, then entered liver acinus and was divided into hepatocyte, and this process promptly may be the hypertrophy (werlich etc., 1999) of liver stem cells.Existing studies show that; acute severe hepatitis, chronic hepatitis are shown effect repeatedly; chronic alcoholic hepatitis, hepatic fibrosis and liver cirrhosis; hepatocyte loss due to its inflammation relies on the liver stem cells amplification greatly and replenishes; therefore, protection hepatocyte and liver stem cells have crucial meaning to safeguarding the normal hepatocytes function.
Virulence factor acts on a large amount of damages or the death that causes hepatic parenchymal cells, liver endothelial cell repeatedly, the hepatocyte of damage secretes the excretory increase of activation, propagation, migration and cellular matrix that a large amount of inflammatory factors is induced hepatic stellate cell (being the Ito cell) again, and above-mentioned factor combined effect is the direct inducement that causes hepatic fibrosis.Therefore protect hepatocyte and hepatic sinusoid endotheliocyte that the generation development that prevents hepatopathy is had crucial meaning.
Summary of the invention
The invention provides the new purposes than safe grace, it can protect liver stem cells, hepatocyte and liver stem cells apoptosis that inhibition is caused by chemicals (comprising drinks), thus protect impaired liver and liver function.Can be used for treating various hepatitis, hepatic fibrosis and liver cirrhosis, acute and chronic alcoholism, fatty liver etc. clinically with in the practice; Also can be used as health food or food additive and be used for normal person's liver protecting.
Foreign literature and patent are all only paid attention to the therapeutical effect to alcoholic hepatitis and fatty liver than safe grace, and be then not mentioned to its normal health-care effect, and the dosage of its therapeutical effect is up to 500-2000mg/kg body weight (mice).It is because wherein contain abundant than safe grace that many plants and Chinese herbal medicine (as Fructus Lycii, Radix Angelicae Sinensis, beet tops etc.) have obvious health care effect, vitamin etc., and can keep the growth of hepatocyte and liver stem cells when the low concentration and suppress apoptosis than safe grace, therefore, another object of the present invention be than safe grace can be used for normal person, old people, work life nervous, take harmful medicine and valetudinarian's normal physiological health care for a long time.
In animal body, than safe grace is synthetic by Choline dehydrogenase (human body lacks this enzyme) catalysis in liver by choline, it has participated in amino acid whose synthetic and metabolism, it is the substrate than safe grace homocysteine methyltransgerase, participate in homocysteine and change into methionine (alternative route) through methyl, it also is the main source of S-ademetionine in the body, the S-ademetionine is the main donor of one carbon unit (methyl) in the body, participate in comprising in the body that nucleic acid is synthetic, amino acid metabolism, the synthetic and metabolism of haemachrome, CO's is synthetic, synthetic and reduction, metabolism of cell membrane phospholipid or the like of glutathione.The S-ademetionine at present clinical success be used for the treatment of hepatitis, liver cirrhosis, alzheimer disease, epilepsy, migraine and osteoarthritis etc.Result of the present invention shows, can protect the rat hepatocytes of the In vitro culture that is brought out by carbon tetrachloride to damage under 10-100 μ Mol condition than safe grace, obviously reduces GOT in the culture medium supernatant, the vigor of enzymes such as AST.Under 10-100 μ Mol condition, can keep the survival of liver stem cells in the cultivation and promote growth than safe grace, suppress rats'liver stem cell apoptosis by the In vitro culture of tetrachloro-methane induction.
Result of the present invention also shows, can protect the rat acute hepatic injury that is brought out by carbon tetrachloride than safe grace under 500-2000mg/kg body weight condition, obviously reduces serum alt, and the vigor of liver sero-enzymes such as AST improves the morphological change of necrosis of liver tissue.Under 500-3000mg/kg body weight condition, prolonged application can be protected the chronic hepatic injury of large and small Mus that is brought out by carbon tetrachloride, obviously reduces r-GT in the serum than safe grace, and the vigor of enzymes such as hyaluronidase alleviates the morphological change of hepatic fibrosis regulating liver-QI fatization.
According to its pharmacological action, can be used for the treatment of people's (ethanol, virus and non-specific) hepatitis, liver cirrhosis and fatty liver than safe grace, treatment is the 100-500mg/kg body weight with dosage.
Can not synthesize in human body than safe grace, so belong to a kind of material of vitamins, because of its function with the anti-apoptosis of the anti-infringement of multiple physiology, biochemistry and wide spectrum, therefore, it also can be used for health care, and dosage is the 10-100mg/kg body weight.
According to the such use than safe grace, it can use with other preparation or compatibility of drugs, also can be used as mix preparation and uses.Can be single or be mixed and made into capsule, oral liquid, granule with other medicines, tablet or injection can oral or intravenous injections.
The present invention also provides two groups based on the new prescription than safe grace:
Prescription 1: utilize to be major ingredient, be equipped with liver extract (liver extract), multivitamin, plant extract and egg albumen powder and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (health food) than safe grace.
Optimization formula 1: than 500 parts of safe grace: 20 parts of liver extracts: VB
110 parts: VB
1220 parts: 5 parts of 100 parts of VE: VA: VC50 part: 50 parts in nicotinic acid: 100 parts of wolfberry fruit extracts: 200 parts of lactalbumin powders;
Selecting prescription can be that major ingredient combines for optional above-mentioned two-eight kinds than safe grace, and the amount of combination can be with requiring and become, and as can be 10-500 part than safe grace, liver extract can be 10-100 part, and VB1 can be 1-50 part, and VE can be 10-200 part or the like.
Utilize optimization formula 1 and Bi Tai grace to act on the chronic hepatic injury of mice that is damaged by carbon tetrachloride, optimization formula 1 and Bi Tai grace all can be protected by CCl
4Mice chronic hepatic injury that causes and opposing hepatic fibrosis, and optimization formula obviously is better than singly using than safe grace (P＜0.05).
Prescription 2: utilize to be major ingredient, be equipped with multivitamin and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (health food) than Tai En and arginine.
Optimization formula 2: than 500 parts of safe grace: 100 parts of arginine: VB
110 parts: VB
220 parts: VB
650 parts: VB
122 parts: 100 parts of VE: VA5 part: VC50 part: 50 parts in nicotinic acid: 0.3 part of biotin: 1 part in pantothenic acid: 2 parts in folic acid; Trace element.
Select prescription 2, being that major ingredient combines for optional above-mentioned two-14 kinds than Tai En and arginine, the amount of combination can be with requiring and become, as can be 10-500 part than safe grace, arginine 1-100 part, liver extract can be 0-100 part, VB1 can be 0-50 part, and VE can be 0-200 part or the like.
Utilize optimization formula 2 to act on the fatty liver rat model of feeding by ethanol and high lipid food, optimization formula can promote that intrahepatic fat shifts outside liver, can treat alcoholic fatty liver effectively, improve pathological change and hemospermia zymetology index that liver fat becomes, and be the dosage action effect.
Utilize optimization formula 2 to make the multidimensional HUAGAN JIAONANG, be used for 28 routine alcoholic fatty liver patients clinically, can treat alcoholic fatty liver effectively, effective percentage reaches 100%.Effect obviously is better than the general fatty liver medicine based on methionine or S-ademetionine.
According to than safe grace, arginine and the multivitamin mechanism of action, optimization formula 1 and 2 also can be used for treating a series of and oxidative stress, homocysteine and hepatic disease complications associated with arterial system such as multiple diseases such as hepatogenous diabetes, endocrine disturbance, insomnia forgetfulness, depression, rheumatism, osteoporosis, atherosclerosis, hypertension, senile dementia, gout, hepatorenal syndrome and hepatopulmonary syndrome.Optimization formula 1 and 2 also can be used for anti-aging and anti-canceration.
The specific embodiment
The present invention is described further below in conjunction with embodiment, but do not limit innovation of the present invention and performance.
Embodiment one, than safe grace to rats'liver stem cell and hepatocellular influence in cultivating
One, the superfine hyclone of material inlet (fetal bovine serum, FBS, Gibco), import FBS and homemade newborn calf serum (newborncalf serum, NCS; Provide by Sijiqing Bioengineering Material Inst., Hangzhou City).DMEM/F12 (high sugar, no Sodium Pyruvate, sigma), non essential amino acid (* 100, Gibco), than safe grace (sigma, purity 99.9%).Conalbumin (Conalbumin, Sigma).Fast blue BB salt (Fast blue BB salt, Sigma) and naphthols-AS-MX (Naphthol ASMX phosphate, Sigma).
Liver stem cells culture medium: 5%FBS (homemade or import), 10% homemade NCS, β-ME of 0.14mM, 40ng.ml
-1Conalbumin, bovine serum albumin, the leukaemia inhibitory factor (LIF) of 1-5 μ g/ml, the high sugared DMEM/F12 culture medium of 1% non essential amino acid.0.2% gelatin: (Sigma), with 0.01M PBS preparation, autoclaving is standby for A type, G2500 for gelatin.
Two, Mus embryo (14-18 age in days) is got in the hepatocellular preparation of method rat embryonic, gets liver and shreds, and 0.1% collagenase digests step by step.The prior gelatin with 0.2% of 96 well culture plates or bottle is coated with culture plate or, 37 ℃ are spent the night at bottle the end, and PBS gives a baby a bath on the third day after its birth inferior, and airing is standby.By 1 * 10
5～2 * 10
5.ml
-1Divide plate or divide flask culture, 12hr changes liquid.After covering with, cell should in time go down to posterity with pancreatin.
Liver stem cells detection of alkaline phosphatase (alkaline phosphatase, AKP) dyeing, list of references method
[1]Carry out.
Determination of activity: 0,2,10,20,50,100,200 μ Mol/L join (96 orifice plate) in above-mentioned three groups respectively than safe grace, carry out mtt assay determination of activity (document behind the 72hr
[2]).
Three, result
1, than of the influence of safe grace to the liver stem cells growth behavior.
Each organizes rat embryo liver stem cells adherent growth.At matched group (0 dosage), cell proliferation slowly and very fast differentiation, liver stem cells (little garden shape or ovum garden shape cell) is few, cell is polygon or fusiformis more.At low dose group (2-10 μ Mol/L), the cell well-grown goes down to posterity when cultivating 2-3 days, and the growth of little garden shape or ovum garden shape cell (the AKP positive) is arranged.At dosage group (20-100 μ Mol/L), the cell well-grown goes down to posterity when cultivating 2-3 days, and the growth of more little garden shape or ovum garden shape cell is arranged.
2, the influence (table 1) that liver stem cells growth colony is formed than safe grace
We select the homemade FBS+0.14mM beta-mercaptoethanol of 10% homemade NBS+5%, and (β-ME)+ordinary culture medium adds 10ng.ml as the liver stem cells culture medium in this culture medium
-1BFGF and 1000u.m
-1MLIF is as complete liver stem cells conditioned medium, have or the condition of incomparable safe grace (20 μ Mol/L) under observe the ability that liver stem cells forms cell colony.
Table 1 than safe grace to the liver of going down to posterity in the influence of cell growth colony
| Than safe grace | FGF +mLIF | Passage number | |||||||
| 1 | 2 | 3 | 4 | 6 | 8 | 9 | |||
| The complete ES cell conditioned medium of liver stem cells culture medium | - + - + | - - + + | 21* 23 15 20 | 10 17 14 18 | 1 8 7 14 | 0 5 4 11 | 0 0 2 16 | 0 0 0 21 | 0 0 0 28 |
*, numeral is every bottle of (25cm in the table
2) ES cell colony number
Table 1 shows, adds the complete ES conditioned medium of bFGF and mLIF, under the condition that exists than safe grace, is passaged to after 4 generations, and class ES cell (AKP stained positive cell) is the trend that increases gradually, and successfully reaches for 9 generations.And under the condition of incomparable safe grace or bFGF and mLIF, the class ES cell in the cultivation is on a declining curve, and main cause may be due to liver stem cells differentiation or the undergrowth.
3, than of the influence (table 2) of safe grace to the hepatocyte succinic dehydrogenase activity.
Table 2. than safe grace to the influence of hepatic cell growth (the OD value, X ± s, n=4)
| Concentration (μ Mol/L) | The OD value |
| 0 2 10 20 50 100 200 | 0.279±0.03 0.288±0.04 0.296±0.03 0.316±0.03 0.341±0.02 0.366±0.03 0.298±0.01 |
Four results show: rat embryo liver stem cells energy adherent growth, but matched group little garden shape and ovum garden shape cell are few; And using experimental group, and Mus tire liver stem cells well-grown, little garden shape or ovum garden shape cell number are many.Can promote the growth regulating liver-QI stem cell colonies of MICE FETAL LIVER cell to form than safe grace, and present the dosage correlation effect.
Embodiment two, than safe grace to CCl in the In vitro culture
4The influence of the rat hepatocytes of damage
Purpose: former primary cultures of rat hepatocyte, observe than safe grace CCl
4The protective effect of the rat hepatocytes of damage
1, material and method 1.1 SD male rats (Zhongshan University's medical college Experimental Animal Center provides), body weight 180-220g, free diet.
1.2 main agents: than safe grace, collagenase (II type), insulin be Sigma company product (St.Louis, MO, USA); 1640 culture medium be the Gibco product (GrandIsland, NY); Bovine serum albumin (BSA) is a Hangzhou Ilex purpurea Hassk.[I.chinensis Sims company product; CCl
4(analytical pure).
1.3 hepatocellular separation and former be commissioned to train foster: with 3% the eleventh of the twelve Earthly Branches barbital sodium anesthetized rat, portal catheterization, cut off postcava, pour into fast with the residual blood of flush away with D-Hanks liquid, flow velocity 30-40ml/min, about 10min changes the Hanks perfusion that contains 0.05% collagenase, flow velocity 5ml/min is about perfusion 10min.Take off liver, tear peplos gently off, hepatocyte is scattered in the Hanks liquid of pre-cooling, 200 mesh filter screens filter, and centrifugal give a baby a bath on the third day after its birth time is suspended in 5% calf serum, 1640 culture medium with hepatocyte, includes penicillin 100U/ml, streptomycin 100 μ g/ml, insulin 10
-8Mol/L, dexamethasone 10
-8Mol/L.Survey cell survival rate with the 0.4% trypan blue row method of dying.Transferring density is 2 * 10
5Cell/ml is inoculated in the 96 porocyte culture plates (Costar), places saturated humidity, 37 ℃ and 5%CO
2Incubator in cultivate.
1.4 CCl
4Damage method: after cell inoculation was cultivated 18-20h, the serum-free RPMI-1640 culture fluid that changes with insulin-containing continued to cultivate 24h, adds 20%CCl
4Alcoholic solution, CCl
4Final concentration 15mmol/L.Measure alanine aminotransferase (ALT), K in the culture fluid behind the 40min
+The gentle mtt assay of fugitive water is surveyed the vigor of succinate dehydrogenase in the cell.
1.5 the mensuration that ALT, K+ spill is got contamination back culture fluid 50 μ l, and is centrifugal, stays supernatant.Survey K in the supernatant
+Concentration is represented the vigor with ALT with mmol/L, represents with U/L.
2, the result than safe grace to CCl
4Poisoning hepatocyte enzyme vigor, the influence of ALT and K concentration sees Table 3 in the supernatant.
To cultivate hepatocyte and be divided into four groups: matched group and Bi Tai grace group, damage group (CCl
415mmol/L), protection group is (than safe grace 50 μ mol/ml+CCl
415mmol/L).The result shows, CCl
4Group cellular enzymes vigor significantly reduces than matched group, causes cell death and can obviously reduce CCl4 than Tai En, and its enzyme activity is raise; Can significantly reduce CCl
4Poison and cause spill (table 3) of interior alanine aminotransferase of cell and K.
Table 3. than safe grace to CCl
4Poisoning rat hepatocytes vigor, and the influence of ALT and K concentration in the supernatant (n=8, x ± s)
| OD value (mtt assay) | ALT(U/L) | K +(mmol/L) | |
| Matched group is than safe grace group CCl 4Group CCl 4+ compare Tai Enniu | 1.93±0.03 2.43±0.03 0.84±0.01 * 1.62±0.02 ** | 22.3±1.2 21.6±1.0 89.4±5.2 * 47.8±3.6 ** | 5.11±0.13 5.14±0.22 6.21±0.33 * 5.46±0.18 ** |
+, with matched group relatively, p＜0.05; *, with matched group relatively, p＜0.01; With * * CCl
4Group compares, P＜0.01.
3, the result shows: can protect the toxic hepatocyte injury that is caused by chemicals than Tai En.
Embodiment three, than safe grace to CCl
4The influence of the rat acute hepatic injury of damage
CCl
4After entering in the body, activate, generate trichloromethyl free radical (CCl through liver cytochrome P 450
3), attack phospholipid molecule on the endoplasmic reticulum by the absorption of hydrogen, cause the lipid peroxidation of film, CCl
3Then carry out covalent bond with membrane lipid and protein macromolecule, cause the destruction of membrane structure and functional completeness, CCl
3The activity of calcium ion pump makes Ca on film also capable of inhibiting cell and the microsomal membrane
2+Stream increases in the ion, thereby causes cytotoxic death.Present embodiment utilizes CCl
4Make the hepatic injury mouse model, observe than of the protective effect of safe grace to the Mouse Liver infringement.
1, materials and methods: 32 of 1.1 healthy male HIH mices, provide by my Zhongshan University's medical college Experimental Animal Center, body weight 18～20g, sub-cage rearing, standard diet is freely drunk water, and is used for experiment after one week at this laboratory rearing.
1.2 divide 4 groups at random, blank group, carbon tetrachloride (2.0ml/kg) model group and high and low dose be than safe grace group, 8 every group.High and low two neat amounts distinguish 600mg/kg and 300mg/kg, gastric infusion, continuous 10 days, CCl than safe grace group dosage
4Behind the contamination 24h, win eyeball, get blood, separation of serum.With the mice sacrificed by decapitation, get liver immediately, wash residual blood with normal saline, be fixed in 10% formalin that pH7.4 PBS is made into paraffin embedding, section, hematoxylin-eosin staining then.Observe down in light microscopic.
1.3 alanine aminotransferase in the serum (alaninetransaminase, ALT) and aspartic transaminase (aspartatetransaminase AST), measures with reitman-frankel method, and unit is a U/L serum.
2, result and discussion
2.1 morphological observation is the result show, CCl
4Group, mouse liver cell bar rope arrangement disorder, karyopyknosis appears in the extensive hydropic degeneration of hepatocyte, necrocytosis, and inflammatory cell infiltration and central vein hyperemia are arranged.And give than safe grace group, hepatic injury then obviously alleviates, and the lobules of liver structure is clear, and visible hepatic cords still radially distributes around central vein.The small amount of water sample degeneration is only arranged, a small amount of hepatic necrosis, but do not have obvious inflammatory cell infiltration and central vein hyperemia.Light microscopy checking shows, obviously alleviates CCl than safe grace
4Damage to hepatic tissue.
2.2 serum zymetology result shows, can reduce CCl than safe grace
4The ALT of the acute liver damage mice of causing, the AST activity also is dosage relevant (table 4).
Table 4 than safe grace to CCl
4Hepatic injury mice serum transaminase's influence (x ± s, n=8)
| ALT(U/L) | AST(U/L) | |
| Normal control group CCl 4Group than safe grace 600mg/kg than safe grace 300mg/kg | 41.03±5.40 402.95±5.69 260.01±17.05** 324.48±29.76* | 48.32±6.43 316.68±5.60 230.46±14.06* 275.91±18.90 |
*P＜0.05，**P＜0.01 compared with CCl4group
2.3 the result shows: than safe grace acute chemical hepatic injury is had protective effect.
Embodiment four, than safe grace to CCl
4The influence of chronic hepatic injury Mouse Liver animal model
1, purpose: observe than the therapeutical effect of safe grace to mice CCl4 chronic injury hepatitis.
2, material and method:
2.1 the female BALB/C mice of materials A, animal: 18-22g, is provided by Zhongshan Medical Univ.'s Experimental Animal Center by 30.B, reagent: 1) CCl4 Guangzhou chemical reagents corporation product.2) than safe grace, and Sigma company product (St.Louis, MO, USA).3) defend barbital sodium, Guangzhou chemical reagents corporation product.
2.2 the female BALB/C mice of method mice chronic hepatitis model, random packet.Behind the fasting 12h, press 0.5ml/kg body weight lumbar injection CCl
4(10% paraffin oil solution), secondary weekly, totally eight times.
Experiment is divided into three groups, irritates stomach every day than safe grace group by the 600mg/kg body weight, and normal control group and damage matched group give corresponding normal saline.Last administration was killed Mus on the 3rd day, get hematometry ALT and serum albumin (A, g/L).Get a fritter hepatic tissue of hepatomegaly leaf same area simultaneously, after 10% formalin fixed, do check pathological section.Total survival rate that animal is also added up in experiment.
3, inflammatory cell infiltration is obvious around the result's 3.1 CCl4 poisoning groups, lobules of liver, visible proliferation of fibrous tissue, and big the hepatic necrosis in lobule center is obvious, and part of hepatocytes fat becomes the apparition of cavity sample; Changing than the liver histological of safe grace treatment group has obviously differently with CCl4 poisoning group, and liver proliferation of fibrous tissue and obvious hepatic necrosis are not seen in most visuals field, and inflammatory cell infiltration and fat-like degeneration are lighter.
3.2 serum zymetology and serum albumin check result see Table 5.
Table 5 than safe grace to CCl4 chronic hepatic injury mice serum transaminase and sero-abluminous influence (x ± s, n=10)
| ALT(U/L) | A(g/L) | |
| Matched group CCl 4Group is than safe grace 600mg/kg | 29.03±2.03 102.95±8.76 58.64±7.26** | 48.23±8.33 33.42±4.31 39.24±6.18** |
**P＜0.01 compared with CCl
4 group
4, the result shows, can improve the degeneration of chronic hepatic injury hepatic tissue cavity sample, liver fatization and Fibrotic morphological change than safe grace, obviously reduces albuminous content during liver transaminase disappears with lifting blood in the serum, liver function protecting.
Embodiment five, utilization are major ingredient than safe grace, can make injection, injectable powder and tablet (hepatinica).
Embodiment six, utilization are major ingredient than safe grace, are equipped with liver extract (liver extract), multivitamin, plant extract and egg albumen powder and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (health food).
Optimization formula 1: than 500 parts of safe grace: 20 parts of liver extracts: VB
110 parts: VB
1220 parts: 5 parts of 100 parts of VE: VA: VC50 part: 50 parts in nicotinic acid: 100 parts of wolfberry fruit extracts: 200 parts of lactalbumin powders;
Selecting prescription can be that major ingredient combines for optional above-mentioned two-eight kinds than safe grace, and the amount of combination can be with requiring and become, and as can be 10-500 part than safe grace, liver extract can be 10-100 part, and VB1 can be 1-50 part, and VE can be 10-200 part or the like.
Embodiment seven, optimization formula 1 (multidimensional liver-protecting tablet) are to mice CCl
4The influence of chronic hepatic injury model
1, experimental technique utilizes than safe grace 500g: liver extract 20g:VB with reference to embodiment four
110g:VB
1220g:VE 100g:VA 5g:VC50g: nicotinic acid 50g: wolfberry fruit extract 100g: lactalbumin powder 200g; Mouse feed is made into multidimensional hepatoprotective (optimization formula 1) mouse feed for 9 kilograms in addition.Being made into than safe grace mouse feed to add mouse feed 9.5kg than safe grace 500g, is contrast with common mouse feed, observes optimization formula and Bi Tai grace to mice CCl
4The protective effect of chronic hepatic injury.Above-mentioned animal is got serum and measures ALT according to a conventional method in the 9th all sacrificed by decapitation.Get right lobe of liver, conventional VG dyeing.Measure the gross area and the area percent of VG dyeing collagen fiber with MPIAS-500 multi-media color pathology picture and text analytical system.
2, result
2.1 pathology detect: CCl
4Matched group: normal lobules of liver is destructurized, by extensive outgrowth fibrous tissue lobules of liver is cut apart, hold the hepatocyte group that becomes to differ in size, form pseudolobuli, the inner swelling of liver cell of pseudolobuli becomes circle, endochylema is netted (water degeneration), part of hepatocytes steatosis, visible hepatocellular spotty necrosis in its endochylema.And the hepatocellular steatosis and the water degeneration of 1 group of optimization formula obviously alleviate, and fibrous connective tissue obviously reduces, and do not see that tangible pseudolobuli forms.Than safe grace group and CCl
4Matched group is compared, and the collagen fiber hypertrophy obviously alleviates, and surrounds around the pseudolobuli.Part of hepatocytes has steatosis, but does not see tangible water degeneration.
2.2 than Tai En and multidimensional hepatoprotective (optimization formula 1) feedstuff to experiment people's Mus ALT activity influence (table 6)
Table 6 than Tai En and multidimensional hepatoprotective feedstuff to CCl
4Chronic hepatic injury mice serum transaminase (x ± s, influence n=10)
| ALT(U/L) | |
| CCl 4Matched group multidimensional hepatoprotective thin,tough silk is than safe grace 600mg/kg | 147.05±12.03 49.62±5.33** 63.04±9.34** |
**P＜O.01 compared with CCl
4 group
2.3 than the influence (table 7) of Tai En and multidimensional hepatoprotective (optimization formula 1) feedstuff to collagen in the hepatic tissue
CCl
4Matched group area of collagen and total area ratio percent obviously increase, and than Tai En and multidimensional hepatoprotective group and CCl
4Matched group is compared obvious decline, has significant difference (P＜O.01) to see Table 7.
Table 7 than Tai En and multidimensional hepatoprotective feedstuff to the gross area and area of collagen percent (x ± s, influence n=10)
| The gross area | Area of collagen percent | |
| CCl 4Matched group multidimensional hepatoprotective group is than safe grace 600mg/kg | 15384.6±3358.7 6049.5±1657.8 9266.1±1695.4 | 11.09±1.87 5.77±1.11** 7.18±1.21** |
**P＜O.01 compared with CCl
4 group
3, the result shows: optimization formula 1 and Bi Tai grace all can be protected by CCl
4Mice chronic hepatic injury that causes and opposing hepatic fibrosis, and optimization formula 1 obviously is better than singly using than safe grace group (P＜O.05).
Embodiment eight, utilization are major ingredient than Tai En and arginine, are equipped with multivitamin and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (health food).
Optimization formula 2: than 500 parts of safe grace: 100 parts of arginine: VB
110 parts: VB
220 parts: VB
650 parts: VB
122 parts: 100 parts of VE: VA5 part: VC50 part: 50 parts in nicotinic acid: 0.3 part of biotin: 1 part in pantothenic acid: 2 parts in folic acid; Trace element.
Select prescription 2, can be being that major ingredient combines for optional above-mentioned two-14 kinds than Tai En and arginine, the amount of combination can be with requiring and become, as can be 10-500 part than safe grace, arginine 1-100 part, liver extract can be 0-100 part, VB1 can be 0-50 part, and VE can be 0-200 part or the like.
Embodiment nine, alcoholic liver disease comprise alcoholic fatty liver, alcoholic hepatitis, alcoholic fibrosis and alcoholic cirrhosis; The 4th, gradual process also can dissimilarly exist simultaneously.This research is set up chronic alcoholic fatty liver animal model by giving rat every day with Chinese liquor and high lipid food, observes the influence of multidimensional hepatoprotective element (optimization formula 2) to the rat chronic alcoholic fatty liver.
One, material and method
1, laboratory animal
Adopt health, sexual maturity, 36 of the Wistar rats of first quality standard, male, body weight 180-200g divides cage to feed.
2, experimental technique
2.1 chronic alcoholic fatty liver modeling:
Each all gives 56 Chinese liquor (strong, colourless liquor distilled from sorghum, Beijing Red Star brewery) of spending every day during organizing rat experiment, on average is added in the drinking water with 10ml/100ml and the high lipid food nursing, the prescription reference literature is also improved, adopt 88% normal feedstuff, 10% Adeps Sus domestica, 2% cholesterol.
2.2 experimental program and grouping.
Healthy Wistar rat 36 machines are divided into 2 groups, and 12 of A groups are as the alcoholic fatty liver group; 24 of B groups as experimental group, are male.A group is killed one of Mus respectively at experiment back 2,4 or 8W and is got liver and blood, does pathological section and Serological testing, observes the formation situation of model, when 4W after the modeling success, and remaining 10 inactive ethanol.Each group continues to raise with high lipid food, and matched group is freely drunk water with common; Experiment component is: 1, multidimensional hepatoprotective element (optimization formula 2) group: high dose group, and 12, by 2%; 2, low dose group, 12, by 1%; All add in the drinking-water and freely drink.
2.3 sample preparations
Each organize rat respectively at administration after 4wk, get 1 rat behind 8wk or the 12wk at random and put to death with the femoral artery depletion method.Get blood and do every Serological testing, get liver after the execution immediately, the back of weighing is fixed with formalin solution, does the routine paraffin wax stripping and slicing, HE dyeing, microscopic examination.The result treats successfully when 8W, puts to death whole rats, gets blood and does every Serological testing, gets liver after the execution immediately, and the back of weighing is fixed with formalin solution, does the routine paraffin wax stripping and slicing, HE dyeing, microscopic examination.
2.4 detection content
(1) ordinary circumstance: the mental status in the animal feeding process, active situation, hair luster, appetite, defecation situation etc.
(2) liver specimens is seen substantially: weigh and observe size, color and luster, quality, tangent plane situation of liver etc.Calculate the liver index: liver is heavy/body weight * 100%.
(3) serology detects index: ALT, AST, TG, TC.
(4) get leftlobe of liver 0.2g, make 10% liver homogenate under 4 ℃, use chloroform: methanol (2: 1v/v) liquid extracting lipid, promptly the supernatant soluble fraction is measured by the test kit operating procedure with enzyme process, and TG represents intrahepatic fat content, and unit represents with mmol/L.
(5) the liver tissues of rats paraffin section is done HE dyeing, and light microscopic detects.
3, statistical procedures: measurement data is with (x ± s) expression uses SPSS10.0 software, and measurement data relatively adopts variance analysis between each group, and ranked data are checked with Ridit, and P＜0.05 is that there were significant differences.
Two, result
1, modeling result: adopt Chinese liquor and 4 weeks of high lipid food feed rat, successfully make rat alcoholic fatty liver model.
2, respectively organize the rat ordinary circumstance: at the 8th weekend after the treatment, high dose group rat hair color is bright and new, and it is good to ingest, quick active; Low dose group rat hair color is near normal, and appetite is normal, and reaction is quick.Control rats hair color dimness, inappetence, slow lazyness is moving.
3, treatment the 8th week of back is not killed Mus, and the liver of experimental group and matched group is seen substantially: the matched group liver is a khaki, the peplos anxiety, and the edge circle is blunt, and tangent plane is greasy; And experimental group is similar with the normal liver outward appearance, is magenta color, and tunicle is more smooth, and the edge is sharper keen, and tangent plane is brighter and cleaner; Illustrate that multidimensional hepatoprotective element (optimization formula 2) can treat fatty liver, reduce fat content in the liver.
4, respectively organizing the rat liver pathologic condition is: big fat drop is full of hepatocyte in matched group great majority (80-90%) hepatocyte, and nucleus is shifted to periphery, and part of hepatocytes is under the adipose cell sample mirror to be seen.And fat drop obviously reduces in the high dose group hepatocyte, rare big fat drop, but still visible little fat cavity.Low dose group contains the hepatocyte quantity of big fat drop with the apparent in view minimizing of matched group, and about 50-60% hepatocyte morphosis is normal substantially.
5, multidimensional hepatoprotective element (optimization formula 2) sees Table 8 to the influence of fatty liver rat model intrahepatic fat content and various serological index.
Table 8 multidimensional hepatoprotective element (optimization formula 2) to the influence of rat intrahepatic fat content and serological index (x ± s, n=10)
| Liver index (%) | Intrahepatic fat content (mmol/L) | ALT (U/L) | AST (U/L) | TG (mmol/L) | TC (mmol/L) | |
| Fatty liver matched group high dose group (2%) low dose group (1%) | 4.471±0.231 3.016±0.274** 3.636±0.226* | 8.631±1.263 3.133±0.527** 5.562±0.883* | 141.03±35.40 58.24±14.23** 96.33±28.54* | 189.33±15.33 43.66±13.40** 62.82±15.46** | 0.921±0.088 1.112±0.054* 1.082±0.071 | 1.804±0.048 1.611±0.049* 1.723±0.066* |
*P＜0.05，**P＜0.01 compared with control group
Table 8 shows: matched group liver index is apparently higher than experimental group, wherein high dose group to the exponential reduction effect of liver greater than low dose group (P＜0.05); Fat content reduction effect in the liver has also been shown similar result.Multidimensional hepatoprotective element can obviously reduce the level of ALT and AST in the blood, and is the dosage action effect.A little more than matched group, may promote that intrahepatic fat shift relevant outside liver to the content high dose group of total triglyceride in the blood with multidimensional hepatoprotective element (optimization formula 2).Multidimensional hepatoprotective element (optimization formula 2) can obviously reduce the content of T-CHOL in the blood, and its effect may be relevant with the promotion bile excretion.
Three, conclusion
Multidimensional hepatoprotective element (optimization formula 2) can promote that intrahepatic fat shifts outside liver, can treat alcoholic fatty liver effectively, improve pathological change and serum zymetology index that liver fat becomes, but triglyceride rises slightly in the blood.
Embodiment ten, according to the biological characteristics and the pharmacological action of multiple-biological liver-care preparations, the animal of multiple-biological liver-care preparations presses down the cancer test and anti-ly causes prominent, carcinogenic test just in contrived experiment.
Embodiment 11, according to the biological characteristics and the pharmacological action of multidimensional hepatoprotective element (optimization formula 2), and can protect liver plasma membrane than safe grace, promote hepatic cell growth, suppress hepatocellular apoptosis; Arginine is protected the hepatic sinusoid endotheliocyte, improves the microcirculation of liver blood sinus.Zoopery proves: the multiple-biological liver-care preparations can be protected by the drug-induced hepatic injury of chemical, can reduce the activity of liver transaminase in the blood.
In China, along with the raising of people's living standard, drink with rice harm also increasing.Long-term heavy drinking can cause fatty liver, alcoholic hepatitis, liver cirrhosis.Wherein see still do not have special effect medicine therapeutic at present so that alcoholic fatty liver more.We adopt multidimensional HUAGAN JIAONANG (optimization formula 2) treatment alcoholic fatty liver 28 examples, and warp compares with matched group, satisfactory effect, and the result is as follows.
One, materials and methods
1, case is selected: with reference to " alcoholic liver disease diagnostic criteria "
[3], alcoholic fatty liver case inclusion criteria is as follows: 1. duration of alcohol consumption is more than 5 years, and every day, drinking amount was on average greater than 40g ethanol amount.2. liver dysfunction (AST/ALT＞2).3. B ultrasonic changes: the high echo of liver parenchyma point-like (the echo level is higher than spleen, kidney); The decay of the intensive enhancing of near field echo and far field; Vascular shows unclear in the liver.4. get rid of the hepatic injury that viral infection, Developmental and Metabolic Disorder and medicine etc. cause.Select case 49 examples altogether, be the male.Observation group's 28 examples, men age 27～58 years old, average 38.8 years old; Matched group 21 examples, 25～60 years old age, average 36.5 years old.Clinical setting no significant difference between two groups (p＞0.05).
2, Therapeutic Method: it is oral that observation group gives multidimensional hepatoprotective element (optimization formula 2) capsule (0.2g/ grain), every day 3 times, each 3,3 months courses of treatment.Matched group is given and DONGBAO GANTAI PIAN (Dongbao of Tonghua Pharmaceutical), every day 3 times, each 4,3 months courses of treatment.Advise patient's teetotalism during the treatment, suitably reduce heat and take in, observe symptom and sign weekly, liver function of check in every month is simultaneously by special messenger's action row liver ultrasonography.
3, curative effect determinate standard is: 1. Sx disappears; 2. liver function recovery is normal; 3. B ultrasonic is detected the disappearance of fatty liver image.Reach above-mentioned 3 index persons for curing, reach 2 persons and be produce effects, reach 1 person for effective.
Two, ALT, AST situation of change see Table 9 before and after therapeutic outcome 1, the two groups of patient treatments.
Table 9, and changes of liver function comparison before and after two groups of patient treatments (X ± SD)
| n | AST(u/L) | ALT(u/L) | |||
| Before the treatment | After the treatment | Before the treatment | After the treatment | ||
| The experimental group matched group | 28 21 | 195.8±61.2 188.3±51.6 | 41.6±15.2*，+ 54.3±16.8+ | 88.4±43.2 92.3±46.5 | 36.5±8.6*，+ 57.2±10.3+ |
Annotate: compare * P＜0.01 with matched group; Relatively preceding with the treatment of this group ,+P＜0.01
2, two groups of patient treatment front and back comprehensive therapeutic effects relatively see Table 10.
Curative effect relatively before and after the table 10 liang group patient treatment
| Cure | Produce effects | Effectively | Invalid | Total effective rate (%) | |
| The experimental group matched group | 15 6 | 9 3 | 4 7 | 0 5 | 100 76 |
Annotate: analyze P＜0.05 between two groups through Ridit
Three, conclusion
Alcoholic fatty liver (AFL) is that alcoholic liver disease shows in early days, also is the modal hepatic lesions of alcoholism.Vitamin B group lacks generally among the AFL, especially vitamin B1, B2, B6 and folic acid.Multidimensional HUAGAN JIAONANG and DONGBAO GANTAI PIAN
[4]All contain vitamin B1, B2, B6 and folic acid, contain methionine in the DONGBAO GANTAI, and the multidimensional HUAGAN JIAONANG contains than safe grace, can promote that than Tai En homocysteine changes into methionine in the body, reduce the homocysteine mass formed by blood stasis that causes because of ethanol.And directly replenish the content that methionine might increase homocysteine in the body, thereby increase the weight of oxidative stress and er stress.
Because the activity of chronic hepatitis patients liver S-adenosylmethionine synzyme and phosphatidyl hydramine-N-transmethylase descends, the clearance rate of blood plasma methionine descends, a large amount of replenish methionine and S-ademetionine (SAM) also can cause in the blood or body in sulfur-containing amino acid increase, sulfur-containing amino acid generates methanthiol, ethyl mercaptan and diformazan sulfide at intestinal through antibacterial deaminizating and decarboxylation, normally at liver metabolism, its blood content increases during serious hepatopathy, influences the integrity of blood brain barrier, with NH
3Collaborative toxic action is arranged.Therefore, prolonged application methionine and S-ademetionine (SAM) treatment might increasing the weight of hepatitis chronicity and the generation of inducing hepatic coma.So this class medicine is seldom used in recent years.
Originally discover that the multidimensional HUAGAN JIAONANG can be treated alcoholic hepatitis, effective percentage reaches 100%, can obviously reduce the level of transaminase, particularly AST in patient's blood.The multidimensional HUAGAN JIAONANG has pharmacological effect widely, is a more satisfactory medicine for the treatment of AFL at present.It is mainly vitamin, has no adverse reaction, and the patient tolerates, but must be noted that in conjunction with alleviating alcohol addiction, dietetic therapy etc.
The clinical practice of multidimensional hepatoprotective element is safe and effective; can protect hepatocyte; promote hepatic cell growth; the medicine or the health food that suppress hepatocellular apoptosis and protection hepatic sinusoid endotheliocyte; to reach the protection hepatocyte; prevent the hepatic injury that causes by hepatitis (viral) and ethanol (chemical), stop the continuation development of hepatic injury and the generation of hepatic fibrosis, liver cirrhosis and hepatocarcinoma, safeguard that people's is healthy.
Liver is the maincenter of three big metabolism (sugar, fat, protein), is again important endocrine organ, is the unique internal organs of biochemical antidotal in the body.Therefore, hepatic dysfunction can cause a series of diseases, and abnormal carbohydrate metabolism can cause the hepatogenous diabetes of non-insulin-dependent; Lipid metabolism can cause hyperlipemia unusually, and the LDL in the blood, cholesterol and triglyceride increase, easily atherogenicity; Protein and disorder of nucleic acid metabolism can cause that uric acid increases the initiation gout and false neurotransmitter increases initiation nervousness, hepatic coma; Endocrine function can cause that unusually the body inner estrogen increases generation vasodilation and spider angioma; Function of detoxification has unusually more increased the weight of the infringement of liver.According to the mechanism of action and drug effect, can treat multiple diseases such as a series of and hepatic disease complications associated with arterial system such as hepatogenous diabetes, endocrine disturbance, insomnia forgetfulness, depression, rheumatism, osteoporosis, atherosclerosis, gout, hepatorenal syndrome regulating liver-QI lung syndrome than Tai En and multidimensional hepatoprotective element than safe grace.
List of references
1, Zou Qingyan, Zhang Yijun, etc.The separation and Culture of rats'liver stem cell.Practical hepatopathy magazine, 2000,5 (4): 195-198
2, Zou Qingyan, Kong Xiangping, etc.Piglets brain extract and cerebrolysin are to the neuronic influence of tire Mus cerebral cortex in cultivating.Tianjin medicine, 1994,11 (4): 661-664
3, alcoholic liver disease diagnostic criteria, Chinese Medical Association's hepatology branch fatty liver and alcoholic liver disease group, Chinese hepatopathy magazine, 2003,11 (2): 72
4, Zhu Jun, Fan Jiangao, etc., DONGBAO GANTAI is to the preventive effect of rat high fat diet fat hepatitis.The modern medicine health, 2003,19 (8): 951-952
Claims (10)
1, has the protection liver stem cells; suppress the liver stem cells apoptosis than safe grace; by promoting the metabolism of cell S-methylmethionine; stabilizing cell membrane and mitochondrial membrane; inhibition apoptosis signal pathway is protected liver stem cells and the hepatocyte in live body or the In vitro culture; suppress apoptosis, thereby promote liver regeneration regulating liver-QI injury repairing.
2, by the safe grace of right 1 described ratio, can from plant, extract, but also chemosynthesis can be used for the treatment and the health care of hepatic disease, but chemosynthesis than safe grace requirement purity more than 98%.
3, by the safe grace of right 2 described ratios, can be used for the treatment of people's (ethanol, viral and non-specific) hepatitis, liver cirrhosis and fatty liver, treatment is the 100-500mg/kg body weight with dosage.Also can be used for health care, dosage is the 10-50mg/kg body weight.
4, by the purposes of the safe grace of right 3 described ratios, also applicable to treating hepatitis in the various hepatitis animals, the dosage that wherein is used for mice is the 1000-3000mg/kg body weight, and the dosage of rat is the 500-2000mg/kg body weight.
5, by the purposes of the safe grace of right 3 described ratios, also can use, also can be used as mix preparation and use with other preparation or compatibility of drugs.
6, by the safe grace of right 3 described ratios, can be single or be mixed and made into capsule, oral liquid, granule with other medicines, tablet or injection can oral or intravenous injections.
7, by the safe grace of right 2 described ratios, utilize to be major ingredient than safe grace, be equipped with liver extract (liver extract), multivitamin, plant extract and egg albumen powder and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (medicine or health food).
8, by the safe grace of right 2 described ratios, utilize to be major ingredient than Tai En and arginine, be equipped with multivitamin and adjuvant and can make oral liquid, capsule, or oral or chewable tablet (medicine or health food).
9, by right 7 and right 8 described two kinds to be the prescription of major ingredient than safe grace, be mainly used in the treatment of hepatopathys such as fatty liver, alcoholic liver, acute, chronic hepatitis.
10, by right 7 and right 8 described two kinds being the prescription of major ingredient than safe grace, have effects such as anti-cancer, anti-aging, hypermnesis, raising immunity, conditioning endocrine, also can be used for rheumatism, autoimmune disease, the prevention of osteoporosis, gout, diabetes, atherosclerosis and cardiovascular and cerebrovascular disease and treatment.
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