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1、World J. Acu-Moxi. Vol. 16, No. 1， March， 2006 45 Review ACUPUNCTURE-MOXIBUSTION, HEAT SHOCK PROTEIN 70 AND CYTOPROTECTION * PENG Yan(彭艳） Supervisor: YI Shou_xiang(易受乡） CHANG Xiaorong(常小荣） Department of Acupuncture & Moxibustion， Hunan College of TCM， Changsha， 410007， China ABSTRACT Heat shock prot

2、ein 70 (HSP70) is a kind of non-specific cytoprotective protein, and its genera- tion can be indjced by acupuncture and moxibustion. In the present paper, the authors review the protective actions of HSP70 on the heart, gastric mucosa, liver, brain tissues, kidney, etc., and the relationship among a

3、cupuncture/moxibustion, heat shock protein and the cytoprotective actions. It is worth studying the cytoprotective effect of acupuncture and moxibustion by way of the resultant generation of HSP70 in the organism. KEY WORDS Heart shock protein70 (HSP70) Acupuncture and moxibustion Cytoprotective act

4、ion Heat shock proteins (HSPs) are a group of stress-associated proteins with high conservatism generated by living body or in vitro cultured cells under abnormal environment, and they can protect cells from injury or from severe injury*-1-. HSP70 family are the most abundant group of intracellular

5、molecules and are present in all cells of all organisms; they are most sensitive to extracullular abnormal changes, are the most substances generated by stress stimulation, and have a wide variety of biological functions-2-. At present, studies indicate that HSP70 has a protective action on cells in

6、 the gastrointestinal tract, heart, brain, liver and other tissues. 1 PROTECTIVE ACTIONS OF HSP70 ON ORGANS AND TISSUES 1.1 Protective actions of HSP70 on the heart When the heart is stimulated by heat or other stress, heat shock protein (HSPs) will be produced to protect the cellular homeostasis*-3

7、-*. HSP70 plays a very important role in anti-myocardial ischemia. Zhang, et al. find in isolated ischemia-reperfusion heart of the rat with heat pretreatment that the heat shock response has a protective action on cardiac functions of the reperfusion heart. Donnelly, et al. indicate in a study that

8、 over-expression of HSP70 is one of the important ways for increasing tolerance of myocardium to ischemia-reperfusion (I/R). It is found in transgenic rats that over-expressions of HSPs (HSP70 being predominant) obviously increase functions of the heart of reperfusion injury, promote recovery of myo

9、cardial metabolism, and significantly reduce the myocardial infarction area6-. Also a study proves that heat stimulation of the whole body can increase contents of HSPs in myocardium, and make the isolated blood or buffer perfusion heart tolerate to subsequent ischemia- reperfusion injury7-. Ischemi

10、c pretreatment also can induce rapid expression of HSP70 mRNA in myocardial cells at early stage, and show the tendency to raising expression within a certain period of ischemia-reperfu- sion8. Additionally， gene conversion can induce high expression of HSF70 to protect myocardial cells9. * This stu

11、dy is financially supported by Chinese National Foundation of Natural Sciences (NO. 30572310) and Hunan Provincial Fbundation of Natural Sciences (No. 05JJ4008) 46 World J. Acu-Moxi. Vol. 16 y No. 1, March t 2006 In pathological process of ischemic-reperfusion, a large number of oxygen free radicals

12、 are produced, which cause reversible or irreversible injury of myocardial cells， and they are important factors for IR injury of myocardial cells10. In the period of ischemia， changes of cellular internal envirorment， generation of free radicals， W cellular calcium load, and depletion of ATP, cause

13、 changes of the tertiary protein structure, which induce functional changes, leading to inactivation of important enzymes in cells, particularly, loss of the functions of SOD and other anti-oxidases. Under the circumstances, HSP70 increases greatly, which combines with the hydrophilic surface of den

14、atured or abnormal protein molecules to protect the proper configuration of new synthetic protein molecules, so as to maintain normal functions. 1.2 Protective actions of HSP70 on the gastric mucosa The gastric mucosa is often stimulated by foods, alcohol, pathogens and other factors, and cellular s

15、tress may induce apoptosis* However, according to the principle of cell adaptation, epithelial cells of the gastric mucosa can actively regulate the protective mechanism, for example, promoting synthesis of HSPs, reducing stress injury. Among them， HSP70 is one kind of main HSPs for protecting the g

16、astric mucosa. Warm-heat re-treatment in the restraint and water-immersion stress gastric ulcer model can significantly enhance the expression of HSP70 family in the fundus of stomach, the pyloric mucxsa and the peripheral lymph nodes, and significantly decrease the ratio of the stress ulcerative in

17、dex to the ulcerative area, and the death rate of the stress model rat12-. Kawai， et al. 13 find that in the restraint and water-immersion stress rat，syntheses of HSP70 and HSP70 mR- NA in the gastric mucosa are induced within 30 min, and the synthesis-induced degrees are correlated negatively with

18、lesion degrees of the gastric mucosa, indicating that HSP70 plays an important role in protecting gastric mucosa from stress injury. Tsukimi, et al. in the study on chronic gastric ulcer induced by acetic acid find that with healing of the ulcer, expression of HSP70 in the ulcerative margin increase

19、d gradually, suggesting that HSP70 can quicken healing of the ulcer. DU， et al. 15 find that the positive cells of HSP70 distributed on the surface of the gastric mucosa, the neck of the gastric gland and the fundus of stomach in the rat who drunk 6 % alcohol in water for 314 days, and the positive

20、cells of HSP70 in the neck of the gastric gland are confirmed as the stem cell of the gastric gland. In this period, the cells of the neck of the gastric gland as an accessory factor of DNA polymerase are involved in the positive immune response of PCNA and HSP70 synthesized by DNA. It is suggested

21、that chronic stimulation of lower content of alcohol can induce expression of HSP70 in the stem cells of the gastric mucxjsa, and is involved in the process of proliferation and differentiation of the stem cells. 1.3 Protective actions of HSP70 on the liver Some studies-16-19indicate that ischemic p

22、re-treatment could induce generation HSP70 of hepatic cells so as to alleviate ischemia-reperfusion injury of the liver and protect liver cells. However, expression amount of HSPs is different at different stages after the treatment. LIU, et al. *-20 investigate the expression of HSP70 mRNA of the l

23、iver in the rat after I/R， and Hnd no expression of HSP70 mRNA in the liver after I/R for 15 min and 30 min, and the expression of HSP70 mRNA after ischemia for 60 min followed by reperfusion for 2 h, and that the high expression of HSP70 mRNA lasts for 12 h and peaks at reperfusion for 4 h. Inducti

24、on of HSIO needs ischemia of longer time, indicating that only injury of molecules in cells reaches to a certain degree, can HSP70 gene be activated. Strengthening of HSP70 gene expression induces accumulation of HSP7021 ZHENG, et al. 16-* report that sjmthesis of HSP70 can effectively inhibit synth

25、esis of TNF-a in Kupffer*s cells of the liver, so as to exert cytoprotective action. The protective action on hepatic cells is closely related with its effects on the mechanism of I/R injury, which are carried out possibly mainly via increasing or maintaining the activity of endogenous SOD, keeping

26、the balance of calcium in the cells, stabilizing some enzymes in cells, reducing cellular World. Acu-Moxi. Vol. 16, No. 1, March, 2006 47 biological membrane injury .18 1.4 Protective actions of HSP70 on brain tissues Cerebral ischemia can induce generation of HSPs, with 70 kd being predominant. HSP

27、s are followed with interest increasingly as protective substances of neurons induced after cerebral ischemia. FAN, et al. 22 find that high expression of HSP70 occurs in the brain tissue of the rat with cerebral ischemia， and the longer the cerebral ischemia, the higher the expression of HSP70. Als

28、o, ZHAO, et al. in the rat of ischemic pretreament of the whole brain find no expression of HSP70 in the pre-ischemia 1 min group, a little expression in the 2 min group, a great number of expression in the 5 min group, and decrease of the expression in the 10 min group, suggesting that HSP70 is a s

29、ensitive stress marker for cerebral ischemia, and it is related with the mechanism of cerebral ischemia tolerance, and there is dose-effect relationship within a certain ischemic time window. Medicine can also intervene expression of HSP70. Animal experiment has indicated that Topamax can promote ex

30、pression of HSF70, attenuate infarct size, with protection from the cerebral I/R injury-24-. Buyang Huanwu Decoction (补阳还五汤 ）， a Chinese medicine recipe, not only can influence expression of HSP70, but also has a certain some action on repair of neurons after cerebral ischemia-25-. Plumier, et al. r

31、eport that transgenic mice expressing the human inducible HSP70 has hippocampal neurons resistant to ischemic injury. A study considers that HSPs can reduce production of oxygen free radicals to protect cerebral cells and clear away abnormal proteins in cells， and accelerate repair of the injured ce

32、rebral cells， alleviate the denaturation of the cell membrane protein induced by injury stimulation or stress response, and protect proteins of the cerebral cells via the back donation, and at the same time， HSPs are closely related with apoptosis of neurons27. 1.5 Protective actions of HSP70 on the

33、 kidney When the renal parenchyma cells are stimulated by viral infection, ischemia, anoxia and medicine, syntheses of HSPs will increase, which can alleviate and avoid more severe destruction and injury of the renal parenchyma cells in the rabbit28. XIAO， et al. 29 in the renal I/R injury rat model

34、 find that after ischemic pretreatment, the expression of HSP70 in the renal tissue strengthens significantly, mainly on the epithelial cells of the renal tubular, showing ischemic pretreatment can increase HSP70 synthesis in the renal tissue. It is indicated that the cytoprotective action of HSP70

35、is possibly one of the protective mechanisms of ischemic pretreatment. LIU et al. also indicate that the mechanism of the protective action of ischemic pretreatment on renal I/R injury in the rat is related with the increase of HSP70 synthesis. In the study of ischemic acute renal failure， it is fou

36、nd that heat shock pretreatment can significantly increase expressions of HSP70, HSP90a and HSP25 in the renal tissue of mice, and significantly alleviate the increases of blood urea nitrogen and serum creatinine levels induced by renal I/R, indicating that inducible HSPs play an important role in p

37、reventing ischemia-induced acute renal failure in the mice31 . HSPs also have actions of protecting the activity of antioxidase in the kidney, and alleviate renal injury after bum-32-. 1,6 Protective actions of HSP70 on the lung Expressions of HSPs in the tissues and cells of the lung induced or inc

38、reased by previous heat stress, medicines or gene transfer and other methods have protective actions on acute lung injury caused by phasphatidase A2， endotoxin, I/R and other factors-33. In the lung transplantation animal model, the increase of HSP70 expression in the lung tissue by the heat pretrea

39、tment of the donor can significantly enhance the arterial pressure of oxygen, and decrease the activity of myoloperoxidase in the lung tissue and the ratio of wet weight and dry weight of the 48 World J. Acu-Moxt. VoL 16， No 1， March， 2006 lung after the transplantation, and heat shock pretreatment

40、protects pulmonary isografits from subsequent I/R injury-34. Induction of HSPs also prevents pulmonary injury induced by improper mechanical ventilation-35-. 2 CYTOPROTECTIVE ACTIONS OF ACUPUNCTURE AND MOXIBUSTION It is indicated by a study that acupuncture and moxibustion have protective action on

41、ischemic injury of the heart and brain. In the rat of acute myocardiac ischemia, WANG, et al. find that electroacupuncture at Neighuan (内关 PC 6) and Jianshi (间使 PC 5) can significantly increase plasma ET content and decrease NO content. ZHANG, et al.37-* report that electracupuncture can decrease th

42、e serum creatinine kinase (CK) activity and MDA content, and raise the serum SOD activity and the ratio of CGRP/ET in the rat of acute myocardial ischemia. Electroacupncture has prevention and treatment actions on acute myocardial ischemia in rats, and can protect myocardium, improve myocardial isch

43、emic injury*-37. After acupuncture anesthesia in the patient undergoing cardiac operation, it is found that acupuncture has a regulative action on the circulative function, and strengthens the capability of the organism in removing oxygen free radicals, and up-regulates gene expression of HSPs, and

44、alleviates myocardial I/R injury38-. HE, et al. 39- confirm that acupuncture has a protective effect on cerebral I/R injury in the rat with cerebral I/R. Also, acupuncture can significantly increase the volume of local cerebral blood flow after acute cerebral bleeding, and attenuate a series of the

45、pathological phenomena induced by the decrease of the volume of local cerebral blood flow-40. HU,et al. adopt Xingnao Kaiqiao (Hfi restoring consciousness and inducing resuscitation) needling methcxl in cerebral I/R rabbit model and find that acupuncture not only raises SOD activity and also directl

46、y inhibits generation of oxygen free radicals so as to inhibit peroxidation of lipids, and protect the cerebral tissues and cells. In recent years, there are more studies on the protective action of acupuncture and moxibution on gastric mu- cosa. CHANG, et al. 42-* have found in the rabbit of gastri

47、c mucosa injury induced by gastric perfusion of absolute ethyl alcohol that electroacupuncture at Zusanli (JHM ST 36) can decrease the index of gastric mucosa injury, i.e. protecting the gastric mucosa from injury. YAN, et ah 43 also confirm that electroacupuncture at acupoints of different segments

48、 of the Foot-Yangming Channel in the rabbit has protective actions on the injured gastric macosa cells， and Zusanli (ST 36) has the most satisfactory result, which are carried out via promoting synthesis, secretion and release of EGF and PGE2, etc. , and possibly inhibiting secretion and release of

49、SS, and lowering SSR mRNA expression on local gastric mucosa。 44 _ Moxibustion also has a protective action on gastric mucosa. Gastric ulcer can cause metabolic derangement of microelements in the organism, and moxibustion can improve the metabolism of the organism45-. Protective action of moxibustion on the gastric mucosa axe possibly related with NO46， and mucus47 SUN, et al. 48- hold that acupuncture and moxibustion exert the protective actions on the gastric mucosa mainl