CN104095835A - Application of p-hydroxy benzalacetone in preparation of medicines for preventing and/or treating liver ischemia/reperfusion injury - Google Patents
Application of p-hydroxy benzalacetone in preparation of medicines for preventing and/or treating liver ischemia/reperfusion injury Download PDFInfo
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- CN104095835A CN104095835A CN201410280926.0A CN201410280926A CN104095835A CN 104095835 A CN104095835 A CN 104095835A CN 201410280926 A CN201410280926 A CN 201410280926A CN 104095835 A CN104095835 A CN 104095835A
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Abstract
The invention discloses application of p-hydroxy benzalacetone in the preparation of medicines for preventing and/or treating liver ischemia/ischemia-reperfusion injury. According to the pharmacological research, when the p-hydroxy benzalacetone is used for preparing the medicines for treating liver ischemia and reperfusion injury, the treatment effect is excellent. According to the invention, the research results show that the p-hydroxy benzalacetone is a compound with excellent treatment effect and low toxic and side effect from the aspects of liver physiological function, cell biochemistry and the like, and the curative effect is better than that the conventional related hepatopathy treatment medicines, so that the p-hydroxy benzalacetone possibly becomes a novel medicine for treating liver ischemia, reperfusion injury and liver injury.
Description
Technical field
The present invention relates to, to the new purposes of the one of hydroxyl benzylideneacetone, be specifically related to hydroxyl benzylideneacetone to prevent and/or treat the application in During Hepatic Ischemiareperfusion Injury medicine in preparation.
Background technology
In liver surgery, effectively controlling intraoperative hemorrhage becomes the important prerequisite that completes smoothly operation.Implement pringle maneuver and be widely used as reducing an important technology of liver section blood loss, improved to a great extent the safety of operation on liver, promoted carrying out of complicated operation on liver.At present the clinical hepatic vascular exclusion mode of having applied mainly contains: Pringle method, full hepatic vascular exclusion method, half hepatic vascular exclusion method and retain half liver blood confession enter hepatic vascular exclusion method, hepatic segments bloodstream blocking method etc.But these blocking-up methods have experienced ischemia/reperfusion process mostly, inevitably can make remaining liver in metabolism, function and structure, produce a series of damages in various degree, even there is liver failure.Hepatic ischemia-reperfusion injury (HIRI) is the common pathological process of clinical surgery of liver, it can make, and hepatic metabolism detoxification ability reduces, microcirculation resistance raises, severe patient can cause liver failure, directly has influence on prognosis, success rate of operation and patient's survival rate of disease.Therefore, thus taking suitable intervening measure to reduce HIRI is the successful key point of operation on liver.Cause the reason of HIRI a lot, definite mechanism is still not fully aware of so far.In order to alleviate HIRI, Chinese scholars has been done a large amount of research, the at present measure of prevention HIRI have medicine pretreatment, ischemia pretreatment, localized heat stress pretreatment, heat-shock pretreatment, sub-low temperature pretreatment, ozone oxidation pretreatment, anoxia pretreatment, ischemia post processing etc., the most wide with the pretreated application prospect of medicine again in numerous treatment measures.
HIRI medicine pretreatment clinical and that laboratory research is more at present mainly comprises: xanthine oxidase inhibitor alleviates liver injury by the generation that prevents quick ischemic stage active oxygen (ROS); Protein kinase C (PKC) inhibitor Herba Chelidonii Soviet Union alkali can weaken the ischemia effect of pig model liver; Ulinastatin (UTG) can effectively suppress the release of the various inflammatory mediators that hepatic portal occlusion causes and remove oxygen-derived free radicals and endotoxic function, thereby alleviates HIRI; Aprotinin, as soybean trypsin inhibitor etc. has inhibitory action to trypsin, reduces the generation of oxygen-derived free radicals; Anti-TNF monoclonal antibody or tnf inhibitor, can reduce the TNF level in liver and blood plasma after liver IR, armour, alleviates the damage that HIRI causes; The hepatic injury that calcitonin-gene-related peptide (CGRP) can antagonism be caused by Endothelin, alleviates gastric mucosa and myocardial damage that IR brings out, the hepar damnification that can prevent IR to cause in entirety, and make hepatic lipid peroxidation have the trend of alleviating; Fructose-1,6-bisphosphate (FBP), as glycolysis high energy mesostate, can improve cellular energy metabolism, reduces the generation that extracellular calcium suppresses oxygen-derived free radicals, thereby alleviates the damage that liver IR causes; Isopropyl liver upper parathyrine, adenosine can be protected sinusoid endotheliocyte, reduce graft damage, improve graft function,, improve survival rate; PGE1, cell adhesion molecule antibody and Antineutrophil antibody all have protective effect to liver IR; Sodium Aescinate can significantly reduce the decline of ischemia-reperfusion rat hepatocytes ATP content and energy charge, and then minimizing hypoxanthine bulk deposition, while making to pour into, the generation of OFR reduces again, and Sodium Aescinate increases hepatocellular energy, has suppressed the startup link of IR generation OFR; Platelet activating factor (PAF) antagonist BN52021 increases hepatocyte energy, suppresses consuming excessively of ATP, antiinflammatory, protection vascular permeability.
During liver transplantation, ischemia pretreatment is implemented more limitedly, therefore uses medicine pretreatment induce the Delayed Protection of IP and Simulation with I PC or directly protect the liver after IR, has wide potential applicability in clinical practice, is worth further research.Although at present a lot of medicines have shown stronger law during ischemia/reperfusion protective effect, there is no medicine, the especially chemical medicine of clear and definite curative effect.
To hydroxyl benzylideneacetone, its chemical formula is: C
10h
9o
2, molecular weight is 162, its chemical structural formula (1) is as follows:
Not yet have at present pair hydroxyl benzylideneacetone be applied to liver protection, for preventing and/or treating the report of Ischemia-reperfusion Injury in Rat, by inferring to the known character of hydroxyl benzylideneacetone whether it has the effect of the hepatopathy of preventing and/or treating.
Summary of the invention
The object of the present invention is to provide hydroxyl benzylideneacetone is prevented and/or treated to the application in liver disease drug in preparation.
The technical scheme that the present invention addresses the above problem is:
Hydroxyl benzylideneacetone is prevented and/or treated to the application in liver disease drug in preparation, and described hepatopathy is During Hepatic Ischemiareperfusion Injury.
To hydroxyl benzylideneacetone and pharmaceutically acceptable carrier and/or mixing diluents, form a kind of pharmaceutical composition.
Of the present invention when hydroxyl benzylideneacetone is used, can make water preparation, powder pin, tablet or capsule etc., adopt respectively intravenous injection, intramuscular injection or oral method.According to different animals and experimental model, consumption is 0.1～80mg/kg.
Of the present invention to hydroxyl benzylideneacetone for the preparation of preventing and/or treating mammal During Hepatic Ischemiareperfusion Injury medicine.Described mammal comprises people.
The present invention is by showing that in body zoopery the hepatopathy that hydroxyl benzylideneacetone is caused During Hepatic Ischemiareperfusion Injury has remarkable therapeutical effect.
The present invention shows by experiment hydroxyl benzylideneacetone energy anti peroxidation of lipid, anti-apoptosis, protects impaired hepatocyte, thus the hepatopathy effect that performance treatment During Hepatic Ischemiareperfusion Injury causes.
The invention provides hydroxyl benzylideneacetone in the application aspect During Hepatic Ischemiareperfusion Injury protection.
The invention has the beneficial effects as follows:
The present invention finds, when the liver disease drug that hydroxyl benzylideneacetone is caused as preparation treatment During Hepatic Ischemiareperfusion Injury is applied, have good therapeutical effect for During Hepatic Ischemiareperfusion Injury by pharmacological research.Research of the present invention shows that from aspects such as liver physiological function, cellular biochemicals to hydroxyl benzylideneacetone be a compound that therapeutic effect is good, toxicity is low, curative effect is better than existing relevant liver blood vessel medicine, likely develops into the new drug for the treatment of liver blood vessel disease, antagonism hepatic ischemia and reperfusion injury and hepatic injury.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further illustrated, but be not limited to this.
Embodiment is used is that laboratory is synthetic voluntarily to hydroxyl benzylideneacetone, purity 99%.
Embodiment
The present invention relates to the anti-Ischemia-reperfusion Injury in Rat drug action of hydroxyl benzylideneacetone experimentation.
1 materials and methods
60 of the healthy male SD rats of 1.1 laboratory animals, clean level, body weight 220～260g, Guangzhou General Hospital Guangzhou Military Command's Experimental Animal Center provides.Nitric oxide (NO) test kit is purchased from Nanjing and builds up the ET-1 of Bioengineering Research Institute, IL-10, TNF-α and measure test kit and all put and exempt from institute purchased from Science and Technology Development Center of Chinese People's Liberation Army General Hospital.Bax/Bcl-2 is purchased from Beijing Bo Aosen Bioisystech Co., Ltd.Apoptosis test kit (POD) is purchased from Roche Holding Ag.
1.2 animal groupings and method SD rat are divided 4 groups, every group of 15 rats at random.
I group: sham operated rats, anaesthetize merely (10% chloral hydrate intraperitoneal injection of anesthesia, 300mg/kg) and open abdomen, isolate hepatoduodenal ligament, not vascular inflow occlusion.
II group: ischemia-reperfusion group, after anesthesia, close left liver leaf, middle lobe of the liver hepatic pedicle with not damaged bulldog clamp folder, after 40min, remove bulldog clamp and recover perfusion.Before opening abdomen, 10min is to the slow injecting normal saline of vena dorsalis penis (10ml/kg body weight).
III group: to hydroxyl benzylideneacetone pretreated group (2mg/kg body weight), open the front 10min of abdomen and inject hydroxyl benzylideneacetone liquid to vena dorsalis penis is slow.
IV group: to hydroxyl benzylideneacetone pretreated group (60mg/kg body weight), open the front 10min of abdomen and inject hydroxyl benzylideneacetone liquid to vena dorsalis penis is slow.
1.3 draw materials and measure each group leaves standstill 30min respectively at pouring into after 6h to abdominal aortic blood 4ml room temperature again, and the centrifugal 30min of 3000r/min, extracts serum specimen-20 DEG C and preserve NO to be measured, ET-1, TNF-α and IL-10.Get 1.0 × 1.0 × 0.5cm
3the tissue of the left liver fixed position of size, is placed in 10% neutral formalin solution fixing, and om observation liver histopathology changes.The mensuration of Serum ALT, AST adopts automatic clinical chemistry analyzer; NO and ET-1 adopt respectively nitrate reductase method and radioimmunology; TNF-α and IL-10 adopt the method for exempting from of putting.
It is fixing that pathology of hepar observation hepatic tissue is placed in 10% neutral formalin solution, paraffin embedding, section, and HE dyeing, under light microscopic, tissues observed changes; Use immunohistochemistrySP SP detects Bax and Bcl-2 protein expression, and positive criteria is that Bax, the dyeing of Bcl-2 Cytoplasm are all brown color.Micro-Microscopic observation, every slice, thin piece is chosen 5 visuals field at random, utilizes MIAS-2000 graphical analysis positive region mean light absorbency value (A), with the size of A value represent positive products express number; TUNEL method detects apoptotic index (AI), and Microscopic observation apoptotic cell, has the positive cell of atropurpureus in nucleus.Every slice, thin piece is chosen at random 5 visuals field under 200 times of high power fields, calculates the apoptosis cell in average every 100 cells, and is expressed as a percentage as AI.Adopt SPSS13.0 statistical software to carry out statistical analysis, data represent with x ± s, relatively adopt variance analysis and q inspection between group.
2 results
The change of 2.1 serum biochemistry zymetologys, NO and ET-1 level is in table 1.
Hepatic ischemia/reperfusion injury 40min pours into II after 6h, III, IV group Serum ALT, AST level again apparently higher than I group (p < 0.01); III, IV group are starkly lower than II group (p < 0.01).The horizontal II of serum NO level and III, IV group are starkly lower than I group (p < 0.01), III, IV group be apparently higher than II group (p < 0.01), and the II of ET-1 and III, IV group are apparently higher than I group (p < 0.01); III, IV group are starkly lower than II group (p < 0.01).
Serum biochemistry zymetology, NO and ET-1 level comparison (x ± s, n=15) after table 1 Liver Ischemia-reperfusion Injury of Rat
Note:
*p<O.01, with sham operated rats comparison;
▲ ▲p<O.01, with ischemia-reperfusion group comparison.
2.2 TNF-αs and IL-10 level are in table 2.
Hepatic ischemia/reperfusion injury 40min pours into TNF-α after 6h, the horizontal II of IL-10, III, IV group again apparently higher than I group (p < 0.01); The horizontal III of IL-10, IV group are apparently higher than II group (p < 0.01), and TNF-α is starkly lower than II group (p < 0.01).
TNF-α and IL-10 level comparison (x ± s, n=15) after table 2 Liver Ischemia-reperfusion Injury of Rat
Note:
*p<O.01, with sham operated rats comparison;
▲ ▲p<O.01, with ischemia-reperfusion group comparison.
2.3 pathology of hepar.
I group liver rope and sinus hepaticus queueing discipline under light microscopic.II group hepatic tissue structure disturbance, a large amount of inflammatory cells are assembled, are infiltrated, and central veins of hepatic lobules and hepatic sinusoid congestion are obvious, and sinus hepaticus is narrow, liver rope hole irregular arrangement, hepatocyte swelling and the degeneration of cavity sample in various degree, occasionally has spotty necrosis; The lobules of liver of III, IV group and hepatic sinusoid congestion degree are lighter, lobules of liver structure normal, and cytopathy is not obvious, and inflammatory cell infiltration is few, has no obvious hepatic necrosis.
The expression of 2.4 hepatic tissue Bax and Bcl-2 and respectively organize hepatocellular apoptosis situation in table 3.
In I group, Bax and Bcl-2 express morely, and the expression of II group Bax and Bcl-2 is compared with I group, and difference has statistical significance (p < 0.01); III, IV group are low compared with the expression of II group Bax, and difference has statistical significance (p < 0.01).The rarely seen a small amount of apoptotic cell of I group hepatic tissue, and II and III, IV group apoptotic cell are expressed showed increased (p < 0.01), III, IV group AI value are low compared with II group, and difference has statistical significance (p < 0.01).
After table 3 Liver Ischemia-reperfusion Injury of Rat, hepatic tissue Bax, Bcl-2 express and hepatocellular apoptosis level comparison (x ± s, n=10)
Note:
*p<O.01, with sham operated rats comparison;
▲ ▲p<O.01, with ischemia-reperfusion group comparison.
In sum, can protect the hepatic tissue after liver IRI to hydroxyl benzylideneacetone, this may to have antioxidation relevant with anti-apoptotic effect with it.
Claims (4)
1. pair hydroxyl benzylideneacetone prevents and/or treats the application in liver disease drug in preparation.
2. application according to claim 1, is characterized in that: described hepatopathy is During Hepatic Ischemiareperfusion Injury.
3. application according to claim 1 and 2, is characterized in that: to hydroxyl benzylideneacetone and pharmaceutically acceptable carrier and/or mixing diluents, form a kind of pharmaceutical composition.
4. application according to claim 3, is characterized in that: described pharmaceutical composition and other drug share in preparation and prevent and/or treat the application in During Hepatic Ischemiareperfusion Injury medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102697757A (en) * | 2012-05-18 | 2012-10-03 | 广州军区广州总医院 | Application of p-hydroxy benzylidene acetone in preparation of drugs for preventing and/or treating encephalopathy |
| CN102802622A (en) * | 2009-05-14 | 2012-11-28 | 艾雪米克斯公司 | Compositions and methods for treating ischemia and ischemia-reperfusion injury |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102802622A (en) * | 2009-05-14 | 2012-11-28 | 艾雪米克斯公司 | Compositions and methods for treating ischemia and ischemia-reperfusion injury |
| CN102697757A (en) * | 2012-05-18 | 2012-10-03 | 广州军区广州总医院 | Application of p-hydroxy benzylidene acetone in preparation of drugs for preventing and/or treating encephalopathy |
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Application publication date: 20141015 |