Beneficial effects of caffeic acid phenethyl ester (CAPE) on the ischaemia-reperfusion injury in rat skin flaps.

BACKGROUND: Reperfusion injury is a phenomenon that occurs when tissues are subjected to ischaemia for a variable period of time, after which they are reperfused. Many factors have been implicated in the cause of reperfusion injury including free radicals and neutrophils. Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) is an active component of propolis from honeybee; it has anti-inflammatory and immunomodulatory properties, and protective effects against ischaemia-reperfusion (I/R) injury. We investigated the effects of CAPE on the survival of skin flaps in the rat. MATERIALS AND METHODS: Eighteen Wistar rats were used, and randomly divided into three groups (n=6 rats each group): the control group (Group 1), ethanol group (Group 2), and CAPE group (Group 3). A caudally based rectangular flap, 3x10 cm in size, was elevated on the back of the rat, according to the method described by Khouri and colleagues. The flap was sutured back into its original place. In the control group, saline 0.2 ml/day was given intraperitoneally (i.p.). Five percent ethanol 0.2 ml/day was administered i.p. in the ethanol group, and CAPE 50 micromol/kg/day i.p. in the CAPE group. To observe the effects of CAPE, levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured from extracted skin tissue. Flap viability was evaluated seven days after the initial operation, measuring necrotic areas of flaps and total flap areas. RESULTS: MDA and NO levels were significantly decreased in CAPE group; and however, GSH, GSH-Px, and SOD enzyme activities were significantly increased in CAPE group. We believed that the CAPE had beneficial effects to improve the survival of skin flaps since it has antioxidative and anti-inflammatory properties, and protective effects against I/R injury.     

Effects of caffeic acid phenethyl ester on pancreatitis in rats

BACKGROUND: This study investigated the effect of caffeic acid phenethyl ester (CAPE) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. CAPE, an active component of honeybee propolis, has previously been determined to have antioxidant, anti-inflammatory, antiviral, and anticancer activities. MATERIALS AND METHODS: Forty-eight rats were divided into four groups of 12. Group 1 animals received intraductal saline and intravenous saline infusion treatment. Group 2 was given intraductal saline and intraperitoneal CAPE infusion treatment. ANP was induced in the animals in group 3 (ANP with saline infusion), and group 4 had induced ANP plus CAPE infusion treatment (ANP with CAPE infusion). Sampling was performed 48 h after treatment. RESULTS: ANP induction significantly increased mortality rate, pancreatic necrosis, and bacterial infection in pancreatic and extrapancreatic organs. ANP also increased levels of amylase and alanine aminotransferase (ALT) in serum, increased levels of urea and lactate dehydrogenase in bronchoalveolar lavage fluid (BAL LDH), increased the activities of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lung tissue, and decreased the serum calcium levels. The use of CAPE did not significantly reduce the mortality rate but significantly reduced the ALT and BAL LDH levels, the activities of MPO and MDA in the pancreas, the activity of MDA in the lungs, and pancreatic damage. The administration of CAPE did not reduce the bacterial infection. CONCLUSIONS: These results indicate that CAPE had beneficial effects on the course of ANP in rats and suggest that CAPE shows promise as a treatment for ANP.     

咖啡酸苯乙酯对大肠癌细胞增殖和凋亡的影响

目的探讨咖啡酸苯乙酯(caffeic acid phenethyl ester,CAPE)对培养的大肠癌SW480细胞增殖、细胞周期和细胞凋亡的影响。方法不同浓度CAPE处理培养的大肠癌SW480细胞后,采用MTT法检测细胞的增殖活性,流式细胞仪检测细胞周期分布和细胞凋亡率,TUNEL染色观察凋亡细胞。结果CAPE对SW480细胞的生长具有明显的抑制作用,其作用表现为剂量依赖性和时间依赖性。流式细胞仪检测发现2.5、5.0、10mg/L的CAPE对SW480处理24h后,G0/G1期细胞比例上升,S期细胞比例下降,细胞凋亡率上升,呈剂量依赖性。TUNEL染色也发现CAPE作用后凋亡细胞数量增加。结论CAPE对大肠癌SW480细胞株具有明显的增殖抑制作用,其作用机制与阻滞细胞周期G期和诱导细胞凋亡有关。     

Testicular nitric oxide levels after unilateral testicular torsion/detorsion in rats pretreated with caffeic acid phenethyl ester

Nitric oxide (NO) plays an important role in modulating blood flow in normal and in several pathological conditions, and its levels seem to change with ischemia–reperfusion injuries. Caffeic acid phenethyl ester (CAPE), an active component of propolis, exhibits antioxidant properties. This experimental study was designed to determine the changes in NO levels and the effect of CAPE on NO levels after testicular torsion/detorsion in rats. Thirty-five adult male albino rats were divided into four groups: sham operation (n=8), torsion (n=9), saline/detorsion (n=9), and CAPE/detorsion (n=9). Rats in the sham operation group were killed after the testes were handled without torsion. Rats in the torsion group were killed after 720° clockwise testicular torsion for 2 h. CAPE was administered 30 min before detorsion in the CAPE/detorsion group and saline was administered in the saline/detorsion group. After 4 h of testicular detorsion in both of these groups, the rats were killed and bilateral orchiectomy was performed to determine the tissue levels of NO. The level of NO in the torsion group (113.77 ± 33.18 nmol/g protein) was significantly higher than that of the sham operation group (64.53 ± 29.64 nmol/g protein). In the saline/detorsion group, the NO level (31.26 ± 12.58 nmol/g protein) was significantly lower than in the torsion and sham operation groups. CAPE administration in the CAPE/detorsion group seemed to raise the NO level (72.63 ± 23.87 nmol/g protein) above the level of the sham operation group. Contralateral testes were not affected by the torsion/detorsion processes performed on the ipsilateral testes. These results show that NO levels increase with torsion and decrease with detorsion. CAPE administration seems to increase tissue NO levels and this may be important for protecting the testes from torsion/detorsion injuries. Received: 30 December 1999 / Accepted: 8 September 2000     

咖啡酸苯乙酯对结肠癌细胞JNK-paxillin信号通路的影响

目的:探讨咖啡酸苯乙酯(CAPE)对结肠癌细胞增殖抑制作用及对c-jun氨基酸末端激酶(JNK)信号通路的影响。方法:体外培养人结肠癌细胞株(HT-29),采用MTT法观察不同浓度的CAPE在不同时间段对HT-29细胞生长的抑制率;不同浓度的CAPE处理HT-29细胞24 h后,用Western blot法检测细胞中JNK及paxillin两种蛋白表达量的变化。结果:4个浓度(2.5,5.0,7.5,10.0μg/L)的CAPE均能明显抑制结肠癌细胞HT-29的增殖,且呈现明显的浓度和时间依赖性(均P<0.01);4个浓度的CAPE均能降低JNK和paxillin蛋白表达水平,且呈明显的浓度依赖性(均P<0.01)。结论:CAPE可在体外抑制人结肠癌细胞HT-29的增殖,机制可能与其降低JNK-paxillin信号通路的活性有关。     

Effects of caffeic acid phenethyl ester and epidermal growth factor on the development of caustic esophageal stricture in rats

BACKGROUND/PURPOSE:An experimental study was performed to modify the healing response in caustic esophageal burns to prevent stricture development. Two different agents with different modes of actions, caffeic acid phenethyl ester (CAPE) and epidermal growth factor (EGF), were studied. CAPE has antiinflammatory, immunomodulatory, antioxidant, and antimitotic properties. EGF has known properties in supporting wound healing and in protecting esophagus from injuries. METHODS: The model described by Gehanno and its modification by Liu was used to create standard esophageal burns with 50% NaOH. The study was performed with 76 rats in 4 main groups (sham, CAPE, EGF, and control) and 2 subgroups in each for 5 and 28 days of observation. Efficacy of treatment was assessed in 28-day subgroups by measuring weight gain, contrast esophagograms on day 27, histologic evaluation by measuring stenosis index (wall thickness/lumen diameter), and collagen deposition, and biochemically by determining tissue hydroxy proline (OHP) content. RESULTS: In the end of the study, increase rates of mean body weights of the animals in the 28-day subgroups were as follows: sham, 30%; CAPE, 23%; EGF, 22%; and control, 14%. Although all the animals in subgroups significantly gained weight, the mean weight gain was significantly low in controls when compared with sham, CAPE, and EGF groups (P <.05). Contrast esophagograms on day 27 showed no stenosis in the sham, mild stenosis in CAPE and EGF, and severe stenosis with proximal dilatation in controls. Stenosis indices of the subgroups were as follows: sham, 0.29; CAPE, 0.41; EGF, 0.41; control, 0.84. Index was significantly higher in controls (P <.05). Collagen accumulation scores in the esophageal wall were as follows: Sham, 0.0; CAPE, 0.87; EGF, 0.30; control, 2.70. Scores also were significantly higher in controls (P <.05). Tissue (OHP) levels were as follows (mg/g dry tissue): Sham, 1.48; CAPE, 1.53; EGF, 1.90; control, 4.01. Production of OHP was significantly higher in controls. CONCLUSIONS: The results of the parameters in the study indicate that administration of CAPE and EGF has beneficial effects in the prevention of caustic esophageal strictures. Those effects of CAPE may occur through its antiinflammatory, immunomodulatory, and antioxidant properties, and EGF may occur through its induced proliferative properties on the esophagus.     

The effect of caffeic acid phenethyl ester on ischemia-reperfusion injury in comparison with alpha-tocopherol in rat kidneys

Oxygen-derived free radicals have been implicated in the pathogenesis of renal injury after ischemia-reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant and anti-inflammatory properties. To determine whether CAPE offers any advantage over α-tocopherol, we compared their effects on an in vivo model of renal ischemia-reperfusion injury in rats. CAPE at 10 μmol/kg or α-tocopherol at 10 mg/kg was administered intraperitoneally before reperfusion. Acute administration of CAPE suppressed ischemia-reperfusion induced renal lipid peroxidation and tissue injury more than α-tocopherol. CAPE may therefore offer a therapeutic advantage in acute injury settings. Received: 9 October 2000 / Accepted: 23 February 2001     

Effects of exercise and caffeic acid phenethyl ester after chronic exercise rat model

In order to understand whether exercise and caffeic acid phenethyl ester (CAPE) has an effect on obesity and weight control, we investigated the effects of CAPE, and exercise on lipid parameters (triglyceride, total cholesterol, HDL-C, LDL-C), and adipokine substances such as leptin and resistin in rats. 40 male rat were randomly assigned into 4 groups. It was determined that CAPE does not have any significant effect on these parameters but that lipid parameters and leptin values in exercise groups decreased considerably, while no significant change occurred in resistin levels. In order to understand whether diet has an effect on exercise, body weights of all animal groups in pre and post-exercise were compared. A significant weight gain was observed (p = 0.005) in all groups. This study concluded that exercise has a considerable effect on leptin and lipid parameters; however, exercise alone was not sufficient for weight control and could be effective in weight control only when accompanied by a restricted diet.

Key points

• Caffeic acid phenethyl ester is not effective on weight control, lipid parameters, and adipokine substances such as leptin and resistin.
• Exercise can be effective in weight control only when accompanied by a restricted diet.

Key words: Caffeic acid phenethyl ester, exercise, leptin, resistin, weight control     

Caffeic acid phenethyl ester prevents intestinal reperfusion injury in rats.

BACKGROUND/PURPOSE: Ischemia-reperfusion injury is encountered frequently in conditions that diminish intestinal blood flow. Caffeic acid phenethyl ester (CAPE), which is a specific component of the honeybee hive product propolis, exhibits potential antioxidant properties. This experimental study was designed to determine the effect of CAPE on ischemia-reperfusion injury in rat intestine. METHODS: Fifty rats were divided into 5 groups; sham (SH), saline ischemia (SI), saline reperfusion (SR), CAPE ischemia (CI), and CAPE reperfusion (CR). Either CAPE, 10 micromol/kg, or saline was administered intraperitoneally 30 minutes before ischemia. Intestinal ischemia for 30 minutes and reperfusion for 60 minutes were applied. Ileum specimens were obtained to determine the tissue levels of malondialdehyde, superoxide dismutase, catalase, and histological changes. RESULTS: Malondialdehyde levels in the CR group did not increase after reperfusion when compared with the CI group. However, statistically significant differences were observed between the SR and SI groups. Additional mucosal injury in the CR group when compared with the CI group was not observed. Whereas, there was a statistically significant increase in mucosal injury in the SR group. Reperfusion did not cause further injuries through both biochemical and histological parameters in the CR group. CONCLUSIONS: Results of this study showed that prophylactic administration of CAPE in ischemic condition prevents reperfusion injuries by eliminating oxygen radicals and inhibiting polymorphonuclear leukocyte infiltration. CAPE may be useful in combating the diseases of oxidative stress.     

Oxidative stress in testicular tissues of rats exposed to cigarette smoke and protective effects of caffeic acid phenethyl ester

Aim： To show the oxidative stress after cigarette smoke exposure in rat testis and to evaluate the effects of caffeic acid phenethyl ester （CAPE）. Methods： Twenty-one rats were divided into three groups of seven. Animals in Group Ⅰ were used as control. Rats in Group Ⅱ were exposed to cigarette smoke only （4 × 30 min/d） and rats in Group Ⅲ were exposed to cigarette smoke and received daily intraperitoneal injections of CAPE （10 μmol/kg.d）. After 60 days all the rats were killed and the levels of nitric oxide （NO） and anti-oxidant enzymes such as superoxide-dismutase, catalase and glutathione peroxidase （GSH-Px） and the level of malondialdehyde were studied in the testicular tissues of rats with spectrophotometric analysis. Results： There was a significant increase in catalase and superoxide-dismutase activities in Group Ⅱ when compared to the controls, but the levels of both decreased after CAPE administration in Group Ⅲ. GSH-Px activity was decreased in Group Ⅱ but CAPE caused an elevation in GSH-Px activity in Group Ⅲ. The difference between the levels of GSH-Px in Group Ⅰ and Group Ⅱ was significant, but the difference between groups Ⅱ and Ⅲ was not significant. Elevation of malondialdehyde after smoke exposure was significant and CAPE caused a decrease to a level which was not statistically different to the control group. A significantly increased level of NO after exposure to smoke was reversed by CAPE administration and the difference between NO levels in groups Ⅰ and Ⅲ was statistically insignificant. Conclusion： Exposure to cigarette smoke causes changes in the oxidative enzyme levels in rat testis, but CAPE can reverse these harmful effects. （Asian J Andro12006 Mar; 8： 189-193）     

The effects of caffeic acid phenethyl ester (CAPE) on spinal cord ischemia/reperfusion injury in rabbits.

OBJECTIVE: Oxygen-derived free radicals have been implicated in the pathogenesis of spinal cord neuronal injury after both trauma and ischemia-reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. This experimental study was designed to determine the effect of CAPE on ischemia-reperfusion of spinal cord in rabbits. METHODS: Forty-one New Zealand white rabbits were used in the study. The animals undergone aortic occlusion were divided into three groups each consisting of 11 rabbits: methylprednisolone (MP), CAPE, and control. CAPE 10 micromol/kg, methyl prednisolone (MP) 30 mg/kg or similar dose saline were injected intraperitoneally before surgical intervention. Animals were subjected to 21 min of cross-clamp time. At the end of occlusion time, the clamps were removed and restoration of the blood flow was verified visually. Animals in sham group (n = 8) underwent a surgical procedure similar to the other groups but the aorta was not occluded. Neurological status was scored by assessment of hindlimb motor function deficit. RESULTS: The scores in CAPE group was different from control groups at 48 h (3.91+/-0.5 vs. 2.91+/-0.7; P = 0.0013). Spinal cord specimens were obtained to determine the tissue levels of malondialdehyde, superoxide dismutase, catalase, and histological changes. Malondialdehyde levels in control group were increased significantly when compared to sham group (124.22+/-24.36 and 41.92+/-10.08 nmol/g wet tissue, P = 0.0003). MDA levels in the CAPE group were lower than MP group and differences between the two groups were statistically significant (56.77+/-15.265 and 107.74+/-19.31 nmol/g wet tissue, P = 0.0001). We did not observe additional tissue injury in CAPE group when compared to control group. SOD and CAT activities were not concordant in all the groups. CONCLUSIONS: These results suggest that CAPE may be an available agent to protect the spinal cord from ischemia-reperfusion injury.     

Effect of high dose and low dose aspirin on survival of random pattern flaps in rats.

This paper studies which of the physiological effects of aspirin is responsible for increasing the survival of random flaps in rats, found in an earlier experiment. We wished to confirm that the antiaggregating--antithrombotic effect was responsible for the increased survival of flaps without microvascular anastomosis. Three groups of rats with standardised random pattern flaps were used. The first two were given aspirin 200 mg/kg (high dose, n = 27) or 40 mg/kg (low dose, n = 21) and the third (n = 28) acted as controls. The beneficial effects of aspirin were restricted to the high dose group. Since the low dose group also showed antiaggregation of platelets, but without the anti-inflammatory or vasodilatory effects, the results indicate that the antiaggregating effect alone was not responsible for the increased survival of the flaps.     

Comparison of the protective effects of curcumin and caffeic acid phenethyl ester against doxorubicin-induced testicular toxicity

Whether testicular toxicity is mediated by matrix metalloproteinases (MMPs) is an important question that has not been examined. This study investigated the suppressive effect of curcumin and caffeic acid phenethyl ester (CAPE) on oxidative stress, apoptosis, and whether MMPs mediate doxorubicin (DOX)-induced testicular injury. Male rats were randomly divided into eight groups (n = 8 per group). The groups were as follows: sham, dimethyl sulphoxide (100 µL), DOX (3 mg/kg), CAPE (2.68 mg/kg), curcumin (30 mg/kg), DOX+CAPE (3 mg/kg DOX and 2.68 mg/kg CAPE), DOX+curcumin (3 mg/kg DOX and 30 mg/kg curcumin) and DOX+CAPE+curcumin (3 mg/kg DOX, 2.68 mg/kg CAPE and 30 mg/kg curcumin). Injections were administered daily for 21 days. The oxidative stress, MMPs, proinflammatory cytokines and apoptotic markers in the DOX group were higher than the sham group (p < .05); these measures were lower in the groups treated with CAPE and curcumin together with DOX compared with the DOX group (p < .05). The results showed that MMPs mediated DOX-induced testicular injury, but CAPE and especially curcumin suppressed testis injury and cell apoptosis by suppressing DOX-induced increases in MMPs, oxidative stress and proinflammatory cytokines. However, curcumin exhibited more pronounced effects than CAPE in terms of all studied parameters.     

The protective role of caffeic acid phenethyl ester (CAPE) on testicular tissue after testicular torsion and detorsion

Testicular artery occlusion causes an enhanced formation of reactive oxygen species, which contributes to the pathophysiology of tissue damage. Here, we have investigated the effects of caffeic acid phenethyl ester (CAPE), a new antioxidant and antiinflammatory agent, in rats subjected to testicular torsion/detorsion (T/D). Thirty-five male rats were divided into four groups: sham operation group (n=8), torsion group (n=9), T/D+saline group (n=9) and T/D+CAPE group (n=9). Rats, except the sham operation group, were subjected to left unilateral torsion (720° rotation in the clockwise direction) without including the epididymis. After torsion (2 h) and detorsion (4 h) periods, rats were sacrificed and bilateral orchidectomy was performed. Testis tissues were washed with cold saline solution, cut into small pieces with scissors, placed into glass bottles and homogenised in four volumes of ice-cold Tris-HCl buffer. Clear supernatant fluid was used for biochemical analyses. Treating rats with CAPE (applied at 10 µmol/kg, 30 min prior to T/D) attenuated the testicular injury, as well as the increase in the tissue levels of myeloperoxidase and thiobarbituric acid-reactant substances (TBARS) caused by T/D in the testis. Testis tissues showed a significant increase in glutathione peroxidase (GSH-Px) activity compared to the torsion group when CAPE was applied. Taken together, our results clearly demonstrate that CAPE treatment exerts a protective effect on testicular T/D, and part of this effect may be due to inhibiting the neutrophil-mediated cellular injury.     

缺血预处理后热休克蛋白对皮瓣成活的影响及作用机理

目的 探索提高皮瓣成活率有有效方法和途径。方法 采用大鼠背部轴型皮瓣，制成活体原位缺血预处理模型，观察缺血预处理对超长跨区供血皮瓣成活率的影响及热休克蛋白70的表达。结果 缺血预处理后即刻断蒂组（A组）和缺血预处理后24h断蒂组（B组）皮瓣平均存活面积明显高于对照组，A组和B组的皮瓣平均存活面积差异无显著性意义；A组和B组中免疫组化染色可见大量阳性表达，对照组免疫组化染色仅见微量弱阳性表达。结论 缺血预处理能提高超长跨区供血皮瓣的存活率, 其机理可能与缺血预处理后热休克蛋白合成增加所引发的机体自身的保护作用有关。     

Caffeic acid phenethyl ester effects in the kidney during ischemia and reperfusion in rats anesthetized with isoflurane

Background

The purpose of this investigation was to examine the effect of caffeic acid phenethyl ester (CAPE) in renal ischemia/reperfusion injury in rats anesthetized with isoflurane (iso).

Methods

We randomly assigned 26 male Wistar rats anesthetized with isoflurane, intubated and mechanically ventilated to 3 groups: G1 (controls; n = 8), G2 (CAPE; n = 10), and G3 (ethanol; n = 8). Mean arterial pressure was monitored for anesthetic control. Intraperitoneal CAPE (G2) or ethanol (G3) injections were administered 40 minutes before left renal ischemia. All animals underwent right nephrectomy and the left kidney was submitted to ischemia for 25 minutes. Serum creatinine (cr) values were determined at the beginning (M1), end (M2), and 24 hours after the experiment (M3) upon intracardiac blood samples. The left kidney was removed for histologic analysis, using a scale for tubular necrosis (0-5, injury maximum). Statistical analysis was applied to serum creatinine and histological score injury considering statistical differences to be significant when P < .05.

Results

The cr values in the CAPE were significantly higher at M2 (0.8 mg/mL; P = .0012) and M3 (3.7 mg/mL; P = .0014) than the control (0.5 and 0.9 mg/mL) or G3 (0.6 and 1.0 mg/mL), respectively. Histologic examination showed the CAPE group to display more pericapsular tubular necrosis (3.0 [2.0; 3.0]) than the G1 group (2.0 [1.0; 2.0]) or G3 group (1.5 [1.0; 2.0]; P < .001). The CAPE group displayed more medullary tubular necrosis (2.0 [2.0; 3.0] than G1 (2.0 [1.0; 2.0] or G3 (1.0 [0.0; 2.0]; P < .001).

Conclusion

CAPE promoted greater functional and anatomic renal injury when rats were anesthetized with iso than control or ethanol groups, as demonstrated by histologic analysis and serum values.     

咖啡酸苯乙酯对大肠癌SW480细胞生长和周期的影响

目的　探讨咖啡酸苯乙酯 (CAPE)对体外培养的大肠癌细胞SW 4 80增殖和细胞周期的影响。方法　不同浓度CAPE处理体外培养的大肠癌SW 4 80细胞后 ,采用MTT法检测细胞的增殖活性 ;流式细胞仪检测细胞周期分布。结果　CAPE处理SW 4 80细胞后 ,SW 4 80细胞的生长抑制率明显升高 ,抑制作用表现为剂量依赖性和时间依赖性。流式细胞仪细胞周期分析表明CAPE作用 2 4h后 ,细胞G0 /G1期比例上升 ,S期比例下降。同时发现CAPE作用后 ,细胞出现胞浆混浊 ,胞体缩小、变圆、皱缩 ,核固缩粹裂等凋亡形态学特征。结论　CAPE对大肠癌SW 4 80细胞株具有明显的生长抑制作用 ,其作用机制与阻滞细胞周期G1期和诱导细胞凋亡有关。