Neuroprotective effects of Caffeic acid phenethyl ester on experimental traumatic brain injury in rats

The aim of this study was to evaluate the therapeutic efficacy of caffeic acid phenethyl ester (CAPE) with an experimental traumatic brain injury (TBI) model in rats. Twenty-four adult male Sprague–Dawley rats were randomly divided into three groups of 8 rats each: control, TBI, and TBI + CAPE treatment. In TBI and TBI + CAPE treatment groups, a cranial impact was delivered to the skull from a height of 7 cm at a point just in front of the coronal suture and over the right hemisphere. Rats were sacrificed at 4 h after the onset of injury. Brain tissues were removed for biochemical and histopathological investigation. To date, no biochemical and histopathological changes of neurodegeneration in the frontal cortex after TBI in rats by CAPE treatment have been reported. The TBI significantly increased tissue malondialdehyde (MDA) levels, and significantly decreased tissue superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, but not tissue catalase (CAT) activity, when compared with controls. The administration of a single dose of CAPE (10 μmol/kg) 15 min after the trauma has shown protective effect via decreasing significantly the elevated MDA levels and also significantly increasing the reduced antioxidant enzyme (SOD and GPx) activities, except CAT activity. In the TBI group, severe degenerative changes, shrunken cytoplasma and extensively dark picnotic nuclei in neurons, as well as vacuolization indicating tissue edema formation. The morphology of neurons in the CAPE treatment group was well protected. The number of neurons in the trauma alone group was significantly less than that of both the control and TBI +CAPE treatment groups. The caspase 3 immunopositivity was increased in degenerating neurons of the traumatic brain tissue. Treatment of CAPE markedly reduced the immunoreactivity of degenerating neurons. TBI caused severe degenerative changes, shrunken cytoplasma, severely dilated cisternae of endoplasmic reticulum, markedly swollen mitochondria with degenerated cristae and nuclear membrane breakdown with chromatin disorganization in neurons of the frontal cortex. In conclusion, the CAPE treatment might be beneficial in preventing trauma-induced oxidative brain tissue damage, thus showing potential for clinical implications. We believe that further preclinical research into the utility of CAPE may indicate its usefulness as a potential treatment on neurodegeneration after TBI in rats.     

Protective effects of caffeic acid phenethyl ester on skeletal muscle ischemia-reperfusion injury in rats

There is a great evidence that reactive oxygen species (ROS) play an important role in the pathophysiology of ischemia −reperfusion(I/R)injury in skeletal muscle.Caffeic acid phenethyl ester(CAPE)is a component of honeybeep ropolis.It has antioxidant, anti−inflammatory and free radical scavenger properties.The aim of this study is to determine the protective effects of CAPE against I/R injury in respect of protein oxidation, neutrophil in filtration, and the activities of xanthine oxidase(XO)and adenosine deaminase(AD)onan<invivomodel of skeletal muscle I/R injury.Rats were divided into three equal groups each consisting of sixrats:Sham operation, I/R, and I/R plus CAPE(I/R+CAPE)groups.CAPE was administered intraperitoneally 60 min before the beginning of the reperfusion.At the end of experimental procedure, blood and gastrocnemius muscle tissues were used for biochemical analyses.Tissue protein carbonyl(PC)levels and the activities of XO, myeloperoxidase(MPO) and AD in I/R group were significantly higher than that of control(p0.01, p0.05, p0.01, p0.005, respectively).Administration of CAPE significantly decreased tissue PC levels, MPO and XO activities in skeletal muscle compared to I/R group(p0.01, p0.05, p0.05, respectively).In addition, plasma creatine phosphokinase(CPK), XO and ADactivities were decreased in I/R+CAPE group compared to I/R group(p0.05, p0.05, p0.001). The results of this study revealed that free radical attacks may play an important role in the pathogenesis of skeletal muscle I/R injury. Also, the potent free radical scavenger compound, CAPE, may have protective potential in this process. Therefore, it can be speculated that CAPE or other antioxidant agents may be useful in the treatment of I/R injury as well as diffused traumatic injury of skeletal muscle.     

Caffeic acid phenethyl ester improves oxidative organ damage in rat model of thermal trauma

Severe burn injuries cause functional impairment in distant internal organs. Although this mechanism is not clear, it is possible that free radical toxicity plays an important role. Research in animals and clinical studies have shown that there is a close relationship between a lipid peroxidative reaction and secondary pathological changes following thermal injury. It has been demonstrated that antioxidant treatment prevents oxidative tissue damage associated with thermal trauma. This study was designed to determine the possible protective effect of caffeic acid phenethyl ester (CAPE) treatment against oxidative damage in the kidney and lung induced by thermal injury. Rats were decapitated either 1, 3 or 7 days after burn injury. CAPE was administered intraperitoneally immediately after thermal injury. Kidney and lung tissues were taken for the determination of malondialdehyde (MDA) level, myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD) and xanthine oxidase (XO) activities. Severe skin thermal injury caused a significant decrease in SOD and CAT activities, as well as significant increases in MDA level, XO and MPO activities in tissues during the postburn period. Treatment of rats with CAPE (10 micromol/kg) significantly elevated the decreased SOD and CAT activities, while it decreased MDA levels and MPO as well as XO activity.     

Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication

Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee. We investigated a potential molecular mechanism underlying a CAPE-mediated protective effect against ischemia/reperfusion (I/R) injury and analyzed the structure contributing to the CAPE effect. CAPE induced hypoxia-inducible factor-1 (HIF-1) α protein, concomitantly transactivating the HIF-1 target genes vascular endothelial growth factor and heme oxygenase-1, which play a protective role in I/R injury. CAPE delayed the degradation of HIF-1α protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel–Lindau-dependent HIF-1α degradation. CAPE inhibition of HPH and induction of HIF-1α protein were neutralized by an elevated dose of iron. The catechol moiety, a chelating group, is essential for HPH inhibition, while hydrogenation of the double bond (–CC–) in the Michael reaction acceptor markedly reduced potency. Removal of the phenethyl moiety of CAPE (substitution with the methyl moiety) severely deteriorated its inhibitory activity for HPH. Our data suggest that a beneficial effect of CAPE on I/R injury may be ascribed to the activation of HIF-1 pathway via inhibition of HPH and reveal that the chelating moiety of CAPE acted as a pharmacophore while the double bond and phenethyl moiety assisted in inhibiting HPH.     

Caffeic acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes

Background

5-lipoxygenase (5-LO) catalyses the transformation of arachidonic acid (AA) into leukotrienes (LTs), which are important lipid mediators of inflammation. LTs have been directly implicated in inflammatory diseases like asthma, atherosclerosis and rheumatoid arthritis; therefore inhibition of LT biosynthesis is a strategy for the treatment of these chronic diseases.

Methodology/Principal Findings

Analogues of caffeic acid, including the naturally-occurring caffeic acid phenethyl ester (CAPE), were synthesized and evaluated for their capacity to inhibit 5-LO and LTs biosynthesis in human polymorphonuclear leukocytes (PMNL) and whole blood. Anti-free radical and anti-oxidant activities of the compounds were also measured. Caffeic acid did not inhibit 5-LO activity or LT biosynthesis at concentrations up to 10 µM. CAPE inhibited 5-LO activity (IC₅₀ 0.13 µM, 95% CI 0.08–0.23 µM) more effectively than the clinically-approved 5-LO inhibitor zileuton (IC₅₀ 3.5 µM, 95% CI 2.3–5.4 µM). CAPE was also more effective than zileuton for the inhibition of LT biosynthesis in PMNL but the compounds were equipotent in whole blood. The activity of the amide analogue of CAPE was similar to that of zileuton. Inhibition of LT biosynthesis by CAPE was the result of the inhibition of 5-LO and of AA release. Caffeic acid, CAPE and its amide analog were free radical scavengers and antioxidants with IC₅₀ values in the low µM range; however, the phenethyl moiety of CAPE was required for effective inhibition of 5-LO and LT biosynthesis.

Conclusions

CAPE is a potent LT biosynthesis inhibitor that blocks 5-LO activity and AA release. The CAPE structure can be used as a framework for the rational design of stable and potent inhibitors of LT biosynthesis.     

C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow (P < 0.05), left ventricular developed pressure (LVDP) (P < 0.01), and the maximal rate of development of LVDP (+dP/dt(max)) compared with I/R hearts obtained from rats given 0.9% NaCl (P < 0.01). N(G)-nitro-L-arginine methyl ester (L-NAME) (50 micromol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 +/- 24 PMNs/mm(2) in untreated hearts to 44 +/- 10 and 58 +/- 25 PMNs/mm(2) in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl (P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.     

Caffeic acid phenethyl ester attenuates allergic airway inflammation and hyperresponsiveness in murine model of ovalbumin-induced asthma

Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis, which has several interesting biological properties, including antioxidant and anti-inflammatory; however, its anti-allergic effects are poorly understood. The objective of this study was to determine whether treatment with CAPE results in significant inhibition of asthmatic reactions in a mouse model. Mice sensitized and challenged with ovalbumin (OVA) had the following typical asthmatic reactions: an increase in the number of eosinophils in bronchoalveolar lavage (BAL) fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and airway luminal narrowing; the development of airway hyperresponsiveness (AHR); the presence of tumor necrosis factor-alpha (TNF-alpha) and Th2 cytokines, including IL-4 and IL-5, in the BAL fluid; and the presence of allergen-specific IgE in the serum. Five successive intraperitoneal administrations of CAPE before the last airway OVA challenge resulted in significant inhibition of characteristic asthmatic reactions. We determined that increased generation of reactive oxygen species (ROS) by inhalation of OVA was diminished via the administration of CAPE in BAL fluid, as well as nuclear factor-kappaB (NF-kappaB) DNA binding activity. These findings indicate that oxidative stress may have a crucial function in the pathogenesis of bronchial asthma, and that CAPE may be useful as an adjuvant therapy for the treatment of bronchial asthma.     

Caffeic acid phenethyl ester suppresses oxidative stress in Escherichia coli-induced pyelonephritis in rats

Although oxidative damage is known to be involved in inflammatory-mediated tissue destruction, modulation of oxygen free radical production represents a new approach to the treatment of inflammatory diseases. Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, has antioxidant, anti-inflammatory and antibacterial properties. For that reason, we aimed to investigate the efficiency of CAPE administration in preventing oxidative damage in pyelonephritis (PYN) caused by Escherichia coli. In this study, 35 Wistar rats were grouped as follows: control, PYN 24 h, PYN 48 h, PYN 72 h, CAPE 24 h, CAPE 48 h and CAPE 72 h. E. coli (1 × 10⁹ c.f.u.) were inoculated into the rats in both PYN and CAPE groups via urethral catheterization. Ten μM/kg-body weight CAPE was injected to the rats in all CAPE groups 24 h before E. coli infection, and injections were repeated at 24-h intervals. Rats were sacrificed 24 h, 48 h and 72 h after infection in both PYN and CAPE groups. Malondialdehyde (MDA) and nitric oxide (NO) levels were significantly increased in kidneys of PYN groups. The activities of the antioxidant enzymes, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XO) were also elevated by E. coli. However, CAPE administration reduced MDA and NO levels, as well as XO activity, although it increased SOD and GSH-Px activities. Histopathological examination showed that CAPE reduced the inflammation grade induced by E. coli. In conclusion, CAPE administrations decrease the oxidative damage occurring in PYN and therefore could be used for medical management of bacterial nephropathy.     

Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells

Caffeic acid phenyl ester (CAPE), a biologically active ingredient of propolis, has several interesting biological properties including antioxidant, anti-inflammatory, antiviral, immunostimulatory, anti-angiogenic, anti-invasive, anti-metastatic and carcinostatic activities. Recently, several groups have reported that CAPE is cytotoxic to tumor cells but not to normal cells. In this study, we investigated the mechanism of CAPE-induced apoptosis in human myeloid leukemia U937 cells. Treatment of U937 cells with CAPE decreased cell viability in a dose-dependent and time-dependent manner. DNA fragmentation assay revealed the typical ladder profile of oligonucleosomal fragments in CAPE-treated U937 cells. In addition, as evidenced by the nuclear DAPI staining experiment, we observed that the nuclear condensation, a typical phenotype of apoptosis, was found in U937 cells treated with 5 μg/ml of CAPE. Therefore, it was suggested that CAPE is a potent agent inducing apoptosis in U937 cells. Apoptotic action of the CAPE was accompanied by release of cytochrome C, reduction of Bcl-2 expression, increase of Bax expression, activation/cleavage of caspase-3 and activation/cleavage of PARP in U937 cells, but not by Fas protein, an initial mediator in the death signaling, or by phospho-eIF2α and CHOP, crucial mediators in ER-mediated apoptosis. From the results, it was concluded that CAPE induces the mitochondria-mediated apoptosis but not death receptors- or ER-mediated apoptosis in U937 cells. Jin and Song contributed equally to this article.     

Caffeic acid phenethyl ester ameliorates cerebral infarction in rats subjected to focal cerebral ischemia

The effects of caffeic acid phenethyl ester (CAPE), an antioxidant derived from propolis, on the infarct volume elicited by focal cerebral ischemia were studied on Long-Evans rats. Cerebral infarction was induced by microsurgical procedures with ligation of the right middle cerebral artery (MCA) and clipping of bilateral common carotid arteries (CCA) for 60 min. The rats were sacrificed 24 h later and serial brain slices of 2 mm thickness were taken and stained for the measurement of infarct area. CAPE was administered intravenously 15 min before MCA occlusion. Pretreatment of CAPE (0.1, 1 and 10 microg/kg) significantly reduced the total infarct volume from 169.6 +/- 14.5 mm3 (control) to 61.0 +/- 24.1 mm3 (0.1 microg/kg CAPE), 47.4 +/- 9.1 mm3 (1 microg/kg CAPE), and 42.4 +/- 8.7 mm3 (10 microg/kg CAPE), respectively. Plasma nitric oxide (NO) content was significantly increased in rats subjected to focal cerebral ischemia. It is concluded that CAPE possesses neuroprotective properties in focal cerebral ischemia injury in rats possibly through its antioxidant effect and/or via the upregulation of NO production.     

Caffeic acid phenethyl ester modulates aflatoxin B1‐induced hepatotoxicity in rats

Aflatoxin B1 (AFB1) is the most potent of the mycotoxins and is widely observed in nutrition abnormalities. There are some studies suggesting oxidative stress‐induced toxic changes on liver related to AFB1 toxicity. The aim of the present study was to evaluate whether antioxidant caffeic acid phenethyl ester (CAPE) relieves oxidative stress in AFB1‐induced liver injury in rat. Twenty‐four male rats were equally divided into three groups. The first group was used as a control. The second group received three doses of AFB1. The three doses of CAPE were given to constitute the third group with doses of AFB1. After 10 days of experiment, liver and serum samples were taken from all animals. Serum gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), glutathione s‐transferase (GST), nitric oxide (NO) and sulfhydryl values were higher in the AFB1 group than in control, whereas serum GGT, ALP, GST and NO values were decreased by in the AFB1 + CAPE group than in AFB1 group. Liver GST, total oxidant capacity, sulfhydryl, apoptosis index and ischemia‐modified albumin values were higher in the AFB1 group than in control, whereas the GST activity and apoptosis index were lower in the AFB1 + CAPE group than in the AFB1 group. There were histopathological degeneration and apoptosis in hepatocytes of AFB1 group. The findings were totally recovered by CAPE administration. In conclusion, we observed that AFB1 caused oxidative and nitrosative hepatoxicity to hepatocytes in the rat. However, CAPE induced protective effects on the AFB1‐induced hepatoxicity by modulating free radical production, biochemical values and histopathological alterations. Copyright © 2013 John Wiley & Sons, Ltd.     

Caffeic acid phenethyl ester changes the indices of oxidative stress in serum of rats with renal ischaemia–reperfusion injury

Oxygen‐derived free radicals have been implicated in the pathogenesis of renal injury after ischaemia–reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. To investigate whether treatment with either CAPE or alpha‐tocopherol modifies the levels of the endogenous indices of oxidant stress, we examined their effects on an in vivo model of renal ischaemia–reperfusion injury in rats. CAPE at 10 μmol kg^?1 or alpha‐tocopherol at 10 mg kg^?1 was administered intraperitoneally before reperfusion. Acute administration of both CAPE and alpha‐tocopherol altered the indices of oxidative stress differently in renal ischaemia–reperfusion injury. Copyright © 2001 John Wiley & Sons, Ltd.     

Caffeic acid phenethyl ester ameliorates changes in IGFs secretion and gene expression in streptozotocin-induced diabetic rats

The protective effect of caffeic acid phenethyl ester (CAPE) against diabetes-induced alteration of IGFs protein and gene expression was investigated in serum, liver, heart, and kidney. In the present study, diabetic rats exhibited the decrease of IGF-I content in serum, liver and heart but the increase of that in kidney and CAPE blocked them. Diabetic rats also manifested the increase of IGF-II content in serum, liver, heart, and kidney and CAPE prevented them. CAPE prevented the diabetes-induced decrease of liver IGF-I mRNA and IGF-II mRNA, which is similar to pattern of IGFs mRNA in kidney. Moreover, diabetic rats exhibited the decrease of heart IGF-I mRNA but the increase of IGF-II mRNA and CAPE blocked them. In conclusion, CAPE, in part, prevented diabetes-induced alteration of IGF-I and IGF-II protein and gene expression in liver, heart, and kidney in rats.     

Protein kinase C-zeta inhibition exerts cardioprotective effects in ischemia-reperfusion injury

Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC-zeta peptide inhibitor was used to test the hypothesis that PKC-zeta inhibition could attenuate PMN-induced cardiac contractile dysfunction by suppression of superoxide production from PMNs and increase nitric oxide (NO) release from vascular endothelium. The effects of the PKC-zeta peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC-zeta inhibitor (2.5 or 5 microM, n = 6) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts (n = 6) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (+dP/dt(max)) cardiac function indexes (P < 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (50 microM). Furthermore, the PKC-zeta inhibitor significantly increased endothelial NO release 47 +/- 2% (2.5 microM, P < 0.05) and 54 +/- 5% (5 microM, P < 0.01) over basal values from the rat aorta and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate-stimulated rat PMNs by 33 +/- 12% (2.5 microM) and 40 +/- 8% (5 microM) (P < 0.01). The PKC-zeta inhibitor significantly attenuated PMN infiltration into the myocardium by 46-48 +/- 4% (P < 0.01) at 2.5 and 5 microM, respectively. In conclusion, these results suggest that the PKC-zeta peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs thereby attenuating PMN infiltration into I/R myocardium.     

Effect of caffeic acid phenethyl ester on treatment of experimentally induced methicillin-resistant Staphylococcus epidermidis endophthalmitis in a rabbit model

This study investigated the anti-inflammatory effects of caffeic acid phenethyl ester (CAPE), a natural bee-produced compound, and compared it with corticosteroids in the treatment of experimentally induced methicillin-resistant Staphylococcus epidermidis (MRSE) endophthalmitis in addition to intravitreal antibiotics. An experimental endophthalmitis model was produced in 24 New Zealand albino rabbits by unilateral intravitreal injection of 0.1 ml of 4.7 x 10(4) colony-forming units (CFU) methicillin-resistant S. epidermidis. The animals were then divided randomly into three treatment groups and a control group, group 1 (six rabbits), received only intravitreal vancomycin (1.0 mg/0.1 ml); group 2 (six rabbits), received both intravitreal vancomycin (1.0 mg/0.1 ml) and intravitreal dexamethasone (400 microg/0.1 ml) and group 3 (six rabbits), received both intravitreal vancomycin (1.0 mg/0.1 ml) and subtenon CAPE (10 mg/0.3 ml) after 24 h post-infection. No treatment was given to the control group. Treatment efficacy was assessed by clinical examination, vitreous culture and histopathology. There were no statististically significant differences between clinical scores of all groups in examinations at 24 and 48 h post-infection (p = 0.915 and p = 0.067 respectively), but in examinations at 72 h post-infection and after 7 days post-infection, although the clinical scores of treatment groups were not significantly different from each other, they were significantly lower than the control group (p < 0.05). The culture results of all groups were sterile. As a result, CAPE was found to be as effective as dexamethasone in reducing inflammation in the treatment of experimental MRSE endophthalmitis when used with antibiotics. More studies are needed to determine the optimal administration route and effective dosage of this compound.     

Caveolin-1 peptide exerts cardioprotective effects in myocardial ischemia-reperfusion via nitric oxide mechanism

Caveolin-1 is a protein constituent of cell membranes. The caveolin-1 scaffolding region (residues 82-101) is a known inhibitor of protein kinase C. Inhibition of protein kinase C results in maintained nitric oxide (NO) release from the endothelium, which attenuates cardiac dysfunction after ischemia-reperfusion (I/R). Therefore, we hypothesized that the caveolin-1 scaffolding region of the molecule, termed caveolin-1 peptide, might attenuate postischemia polymorphonuclear neutrophil (PMN)-induced cardiac dysfunction. We examined the effects of caveolin-1 peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. Caveolin-1 peptide (165 or 330 microg) given intravenously 1 h before I/R significantly attenuated postischemic PMN-induced cardiac dysfunction, as exemplified by left ventricular developed pressure (LVDP) (P < 0.01) and the maximal rate of developed pressure (+dP/dt(max)) (P < 0.01), compared with I/R hearts obtained from rats given 0.9% NaCl. In addition, caveolin-1 peptide significantly reduced cardiac PMN infiltration from 195 +/- 5 PMNs/mm2 in untreated hearts to 103 +/- 5 and 60 +/- 5 PMNs/mm2 in hearts from 165 and 330 microg caveolin-1 peptide-treated rats, respectively (P < 0.01). PMN adherence to the rat coronary vasculature was also significantly reduced in rats given either 165 or 330 microg caveolin-1 peptide compared with rats given 0.9% NaCl (P < 0.01). Moreover, caveolin-1 peptide-treated rat aortas exhibited a 2.2-fold greater basal release of NO than vehicle-treated aortas (P < 0.01), and this was inhibited by NG-nitro-L-arginine methyl ester. These results provide evidence that caveolin-1 peptide significantly attenuated PMN-induced post-I/R cardiac contractile dysfunction in the isolated perfused rat heart, probably via enhanced release of endothelium-derived NO.     

PR-39, a potent neutrophil inhibitor, attenuates myocardial ischemia-reperfusion injury in mice

We investigated the effects of PR-39, a recently discovered neutrophil inhibitor, in a murine model of myocardial ischemia-reperfusion injury. Mice were given an intravenous injection of vehicle (n = 12) or PR-39 (n = 9) and subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. In addition, the effects of PR-39 on leukocyte rolling and adhesion were studied utilizing intravital microscopy of the rat mesentery. The area-at-risk per left ventricle was similar in vehicle- and PR-39-treated mice. However, myocardial infarct per risk area was significantly (P < 0.01) reduced in PR-39 treated hearts (21.0 +/- 3.8%) compared with vehicle (47.1 +/- 4.8%). Histological analysis of ischemic reperfused myocardium demonstrated a significant (P < 0.01) reduction in polymorphonuclear neutrophil (PMN) accumulation in PR-39-treated hearts (n = 6, 34.3 +/- 1.7 PMN/mm(2)) compared with vehicle-treated myocardium (n = 6, 59.7 +/- 3.1 PMN/mm(2)). In addition, PR-39 significantly (P < 0.05) attenuated leukocyte rolling and adherence in rat inflamed mesentery. These results indicate that PR-39 inhibits leukocyte recruitment into inflamed tissue and attenuated myocardial reperfusion injury in a murine model of myocardial ischemia-reperfusion.     

Caffeic acid phenethyl ester (CAPE) protects brain against oxidative stress and inflammation induced by diabetes in rats

Diabetic patients reveal significant disorders, such as nephropathy, cardiomyopathy, and neuropathy. As oxidative stress and inflammation seem to be implicated in the pathogenesis of diabetic brain, we aimed to investigate the effects of caffeic acid phenethyl ester (CAPE) on oxidative stress and inflammation in diabetic rat brain. Diabetes was induced by a single dose of streptozotocin (45 mg kg⁻¹, i.p.) injection into rats. Two days after streptozotocin treatment 10 μM kg⁻¹ day⁻¹ CAPE was administrated and continued for 60 days. Here, we demonstrate that CAPE significantly decreased the levels of nitric oxide and malondialdehyde induced by diabetes, and the activities of catalase, glutathione peroxidase, and xanthine oxidase in the brain. However, glutathione levels were increased by CAPE. The mRNA expressions of tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and inducible nitric oxide synthase (iNOS) were remarkably enhanced in brain by diabetes. CAPE treatments significantly suppressed these inflammatory cytokines (about 70% for TNF-α, 26% for IFN-γ) and NOS (completely). Anti-inflammatory cytokine IL-10 mRNA expression was not affected by either diabetes or CAPE treatments. In conclusion, diabetes induces oxidative stress and inflammation in the brain, and these may be contributory mechanisms involved in this disorder. CAPE treatment may reverse the diabetic-induced oxidative stress in rat brains. Moreover, CAPE reduces the mRNA expressions of TNF-α and IFN-γ in diabetic brain; suggesting CAPE suppresses inflammation as well as oxidative stress occurred in the brain of diabetic patients.     

Caffeic acid phenethyl ester enhances TRAIL-mediated apoptosis via CHOP-induced death receptor 5 upregulation in hepatocarcinoma Hep3B cells

Molecular and Cellular Biochemistry - Caffeic acid phenethyl ester (CAPE) exhibits various pharmaceutical properties, including anti-bacterial, anti-inflammatory, anti-viral, anti-cancer, and...