Caffeic Acid Phenethyl Ester Administration Research Articles

Caffeic Acid Phenethyl Ester (CAPE) Synergistically Enhances Paclitaxel Activity in Ovarian Cancer Cells.

Caffeic acid phenethyl ester (CAPE) belongs to the phenols found in propolis. It has already shown strong antiproliferative, cytotoxic and pro-apoptotic activities against head and neck cancers and against breast, colorectal, lung and leukemia cancer cells. Ovarian cancer is one of the most dangerous gynecological cancers. Its treatment involves intensive chemotherapy with platinum salts and paclitaxel (PTX). The purpose of this study was to evaluate whether the combined use of CAPE and paclitaxel increases the effectiveness of chemotherapeutic agents. The experiment was performed on three ovarian cancer lines: OV7, HTB78, and CRL1572. The effect of the tested compounds was assessed using H-E staining, a wound-healing test, MTT and the cell death detection ELISAPLUS test. The experiment proved that very low doses of PTX (10 nM) showed a cytotoxic effect against all the cell lines tested. Also, the selected doses of CAPE had a cytotoxic effect on the tested ovarian cancer cells. An increase in the cytotoxic effect was observed in the OV7 line after the simultaneous administration of 10 nM PTX and 100 µM CAPE. The increase in the cytotoxicity was dependent on the CAPE dosage (50 vs. 100 µM) and on the duration of the experiment. In the other cell lines tested, the cytotoxic effect of PTX did not increase after the CAPE administration. The administration of PTX together with CAPE increased the percentage of apoptotic cells in the tested ovarian cancer cell lines. Moreover, the simultaneous administration of PTX and CAPE enhanced the anti-migration activity of the chemotherapeutic used in this study.

Anti-inflammatory effect of caffeic acid phenethyl ester supplementation on TNF-α and NF-κB expressions throughout experimental tooth movement in vivo

Context: Orthodontic tooth movement (OTM) changes the periodontal tissue and increases the incidence of root resorption (OIRR). Caffeic acid phenethyl ester (CAPE), an antioxidant and anti-inflammatory chemical generated from honey propolis, might be useful in controlling inflammation during OTM and so reducing the risk of OIRR. Aims: To evaluate if CAPE supplementation has an anti-inflammatory impact on tumor necrosis factor-α (TNF-α) and nuclear transcription factor κB (NF-κB) during experimental OTM in male Wistar rats (Rattus novergicus). Methods: Forty-eight healthy male Wistar rats were divided into positive control group (OTM 10 g/mm2 force application) and experimental group (OTM application and CAPE administration). Each groups were observed for 3, 7, 14 days. A nickel-titanium closed coil spring that was 8.0 mm long, thick was inserted between the upper left first molar and upper central incisor in order to move the molar mesially. A 20 mg/kg body weight dose of CAPE was taken orally. Using immunohistochemistry, the expression of TNF-α and NF-κB was examined on the compression side of the OTM. Both the Tukey's honest significant difference test and the one-way analysis of variance test were applied (p<0.05). Results: TNF-α and NF-κB expression in the compression side differed considerably across groups (p<0.05). Daily administration of CAPE significantly downregulates TNF-α and NF-κB expression on the compression side. Conclusions: Administration of CAPE throughout OTM can successfully reduce the number of TNF-α and NF-κB expressions in the compression side in vivo.

Caffeic Acid Phenethyl Ester With Mesenchymal Stem Cells Improves Behavioral and Histopathological Changes in the Rat Model of Parkinson Disease.

Parkinson disease (PD) results from the destruction of dopaminergic neurons in the brain. This study aimed to investigate the protective effects of natural antioxidants such as caffeic acid phenethyl ester (CAPE) to maintain these neurons. CAPE is one of the main ingredients of propolis. Intranasal administration of 1-methyl-4-phenyl-2;3;4;6-tetrahydropyridine (MPTP) was used to generate a PD model in rats. A total of 2×bone marrow stem cells (BMSCs) were injected from the tail vein. Behavioral tests, immunohistochemistry, DiI, cresyl fast violet, and TUNEL staining were used to evaluate the rats 2 weeks after treatment. In all treatment groups with stem cells, the DiI staining method revealed that the cells migrated to the substantia nigra pars compacta after injection. Treatment with CAPE significantly protects dopaminergic neurons from MPTP. The highest number of tyrosine hydroxylase (TH) positive neurons was seen in the pre-CAPE+PD+stem cell (administration of CAPE, then the creation of PD, finally injection of stem cells) group. The number of TH+cells in all groups that received CAPE was significant compared to groups that received the stem cells only (P<0.001). Intranasal administration of MPTP significantly increases the number of apoptotic cells. The lowest number of apoptotic cells was in the CAPE+PD+stem cell group. The results showed that the use of CAPE and stem cells in Parkinson rats caused a significant reduction in the apoptotic cells.

Sıçan beyninin deneysel periodontitis modelinde DDD ve KAFE uygulamasının toplam antioksidan ve toplam oksidan düzeyleri üzerine etkileri

Aim: Observing the effects of caffeic acid phenethyl ester (CAPE) and/or low dose doxycycline (LDD) on total antioxidant and oxidant status of brain in experimental periodontitis is the purpose of the study.Methods: 48 male Wistar albino rats were designed as the following: control group (C, n=8), periodontitis + CAPE group (PC, n=10), periodontitis + LDD (PD, n=10), periodontitis + LDD + CAPE group (PCD, n=10), and periodontitis group (P, n=10). The time period for the experiment was 14 days. 10µmol/kg/day of CAPE was administered using an intraperitoneal injection (IP). 10 mg/kg/day of LDD was administered using an oral gavage method. Histopathological changes were evaluated.Results: Beneficial results were seen in all of the groups after LDD and/or CAPE administration on decreasing the alveolar bone loss level and oxidative stress. All of the experimental groups showed signs of periodontitis with alveolar bone loss. The P group leads with the most alveolar bone loss compared to the other periodontitis groups and the lowest group was the PC group in the periodontitis groups. The evolution of alveolar bone loss from high to low was that group P, group PD, group PCD, group PC, and group C (P &amp;lt; 0.05). However, there is no statistical difference between brain total antioxidant status and brain total oxidant status average values according to brain groups (p &amp;gt; 0.05).Conclusion: The combination of LDD and CAPE are not significantly different when applied alone or together on oxidative status. But both of the agents have beneficial effects on reducing the oxidative stress and tissue damages.

CAPE and its synthetic derivative VP961 restore BACH1/NRF2 axis in Down Syndrome

The cells possess several mechanisms to counteract the over-production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Moreover, an important sensor involved in the anti-oxidant response is KEAP1-NRF2-ARE signaling complex. Under oxidative stress (OS), the transcription factor NRF2 can dissociate from the KEAP1-complex in the cytosol and translocate into the nucleus to promote the transcriptional activation of anti-oxidant genes, such as heme oxygenase 1 and NADPH quinone oxidoreductase. Within this context, the activation of NRF2 response is further regulated by BACH1, a transcription repressor, that compete with the KEAP1-NRF2-ARE complex. In this work, we focused on the role of BACH1/NRF2 ratio in the regulation of the anti-oxidant response, proposing their antithetical relation as a valuable target for a therapeutic strategy to test drugs able to exert neuroprotective effects, notably in aging and neurodegenerative diseases. Among these, Down syndrome (DS) is a complex genetic disorder characterized by BACH1 gene triplication that likely results in the impairment of NRF2 causing increased OS. Our results revealed that BACH1 overexpression alters the BACH1/NRF2 ratio in the nucleus and disturbs the induction of antioxidant response genes ultimately resulting in the accumulation of oxidative damage both in Ts2Cje mice (a mouse model of DS) and human DS lymphoblastoid cell lines (LCLs).Based on this evidence, we tested Caffeic Acid Phenethyl Ester (CAPE) and the synthetic analogue VP961, which have been proven to modulate NRF2 activity. We showed that CAPE and VP961 administration to DS LCLs was able to promote NRF2 nuclear translocation, which resulted in the amelioration of antioxidant response. Overall, our study supports the hypothesis that BACH1 triplication in DS subjects is implicated in the alteration of redox homeostasis and therapeutic strategies to overcome this effect are under investigation in our laboratory.

Caffeic Acid Phenethyl Ester Attenuates Dextran Sulfate Sodium-Induced Ulcerative Colitis Through Modulation of NF-κB and Cell Adhesion Molecules.

Ulcerative colitis (UC) is a serious health condition and defined as inflammation in the colon. Untreated, UC can develop into colitis-associated cancer (CAC), for which effective medicines are not available. Natural products are a better choice to treat UC by alleviating the inflammation. Caffeic acid phenethyl ester (CAPE) is a phenolic compound and known for its beneficial effects, including antibacterial, anti-inflammatory, anti-diabetic, and anticancer. We aimed to study the effect of CAPE on dextran sulfate sodium (DSS)-induced UC in mouse model. Administration of CAPE to DSS-induced mice protected against colon damage by improving body weight of mice, reducing the weight of spleen, and increased colon length. In addition, administration of CAPE resulted reduced the activity of myeloperoxidase (MPO) and CD68+ positive cells. Furthermore, a significant decrease in the production of key cytokines and the expression of nuclear factor (p65-NF)-κB. Moreover, p65-NF-κB activation was reduced in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells from mouse origin. CAPE treatment leads to the reduced expressions of intercellular adhesion molecules (ICAM)-1 and vascular cell adhesion molecules (VCAM), both are key cell adhesion molecules. The results of this study clearly indicate that CAPE can potentially control inflammation in the colon and can be used as a therapy for UC.

Caffeic Acid Phenethyl Ester reduces Pro Inflammatory Cytokines in Moderate Swimming Test in Growing Rats Model.

BackgroundCaffeic acid phenethyl ester (CAPE) is a naturally occurring polyphenolic concentrated in propolis of honeybee hives. CAPE has been shown various physiological and pharmacologic properties. The aim of the present study was to investigate the effects of CAPE on proinflammatory markers in growing rats by performing the moderate swimming test.MethodsA total number of 21 male Wistar albino rats were separated into three groups (n = 7): sedentary: negative control group; exercise: positive control group received vehicle orally and exercise + CAPE: CAPE treated group: treated with CAPE (20 mg/kg) orally 30 min before exercise, for 5 days. The animals were left free to swim in the tank, 20 minutes/day for 5 days. At 24 hours after finishing the experiment, rats were euthanised and blood was collected to analyze the level of serum interleukin IL-6 and tumor necrosis factor–α (TNF-α).ResultsGrowing rats subjected to the moderate swimming test and in those treated with CAPE showed a lower level of TNF-α compared to the negative control. More interestingly, the one-way ANOVA data demonstrated a decreased level of proinflammatory IL-6 in the CAPE-treated group compared to the negative control.ConclusionResults of this study indicate that short-term administration of CAPE may modulate proinflammatory cytokine profiles during moderate exercise and may serve to boost the anti-inflammatory effects of exercise. Further studies are needed to evaluate the efficacy and safety of long-term administration of CAPE as an adjective anti-inflammatory agent.

Neuroprotective Effect of Intrastriatal Caffeic Acid Phenethyl Ester Treatment in 6-OH Dopamine Model of Parkinson's Disease in Rats.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the main cause of PD is still not known. Until now, no cure for Parkinson's disease is yet in sight. Caffeic acid phenethyl ester (CAPE) is a polyphenolic component of the propolis, which can be derived from honeybee hive propolis. We aimed to determine the effect of intrastriatal CAPE administration as a neuroprotective agent on 6-hydroxydopamine (6-OHDA)-induced PD model. Adult male Wistar rats weighing 280–320 g were used. The PD model was induced with unilateral intrastriatal 6-OHDA injection. Treatment groups received 20 μmol/5 μL/4 day and 80 μmol/5 μL/4 day CAPE 24 h after 6-OHDA injection. Eight days after 6-OHDA application, behavioral studies (adhesive tape removal test, open-field test, cylinder test, and apomorphine-induced asymmetric rotational behavior) were performed once more to compare the effects of CAPE on behavior tests. Striatal histological verifications, immunohistochemistry, and stereological quantitation were performed. Our results for the first time showed that, besides improving the motor performance, CAPE treatment also prevents 6-OHDA-induced loss of TH-positive neurons. From our results, CAPE may be a promising clinical agent in the treatment of PD.

Zinc Deficiency‐Induced NFκB Activation Promotes Hypertension by Driving Renal Na + Reabsorption

Background : Zinc deficiency (ZnD) is a common comorbidity with chronic disorders including diabetes and kidney disease. Patients with these diseases also have a higher incidence of hypertension. Recently, we reported that a zinc deficient diet is sufficient to induce hypertension in mice. Changes in blood pressure were accompanied by increased Na+ reabsorption via the renal sodium chloride cotransporter (NCC). Although our novel results indicate that zinc plays a critical role in NCC regulation and its downstream effects on blood pressure, the specific mechanisms involved are unknown. Hypothesis : Since nuclear factor-κB (NFκB) is a key transcription factor implicated in ZnD-mediated effects, we tested the hypothesis that ZnD stimulates renal NFκB activation which drives NCC upregulation and thereby promotes hypertension. Experimental Design : Adult, male C57BL/6 mice were fed a zinc adequate (ZnA; 50ppm) or a ZnD (1ppm) diet for 6 weeks. To examine the role of NFκB in ZnD-induced hypertension, mice were switched from a ZnA-diet to a ZnD-diet for 5 weeks. After, ZnD mice were administered caffeic acid phenethyl ester (CAPE), an NFκB inhibitor, for 1 week. In mice, NCC expression (qRT-PCR) and blood pressure (tail-cuff) were measured. To further investigate the role of NFκB in NCC expression (qRT-PCR and Western blot), mouse distal convoluted tubule (mDCT) cells were treated with TPEN (a zinc chelator) or vehicle (DMSO) ± CAPE. Results : Compared to ZnA mice, NCC mRNA abundance was increased in ZnD mice (7.625 ± 1.747 vs 1.0 ± 0.127) and was accompanied by enhanced renal NFκB nuclear localization. In mDCT cells, TPEN-induced ZnD stimulated NCC mRNA expression (3.152 ± 0.966 vs 1.0 ± 0.174) and NFκB upregulation (1.573 ± 0.117 vs 1.0 ± 0). However, NFκB inhibition by CAPE prevented TPEN-induced NCC mRNA (0.636 ± 0.178 vs 3.152 ± 0.966) and protein (1.039 ± 0.018 vs 2.335 ± 0.062) expression in mDCT cells. Finally, CAPE administration lowered blood pressure (154.5 ± 5.42 vs 138.1 ± 1.97 mm Hg) in ZnD mice. Summary : These results demonstrate that 1) renal NFκB is a Zn2+-regulated transcription factor, 2) NFκB is involved in NCC regulation and 3) NFκB mediates ZnD-induced blood pressure increases. Significance : Taken together, these data indicate that ZnD stimulates NFκB activation thereby driving NCC upregulation and hypertension.

Resveratrol (3,4ʹ,5-trihydroxy-trans-stilbene) or caffeic acid phenethyl ester supplementation prevents premature ovarian insufficiency due to chemotherapy

IntroductionThis study was planned to investigate the protective effect of resveratrol (RSV), caffeic acid phenethyl ester (CAPE), and coenzyme Q10 (CoQ10) on chemotherapy-induced premature ovarian insufficiency (POI).Material and methodsTwenty-eight female rats were divided into four groups with 7 rats in each group. The groups consisted of a vehicle-treated control group (group 1), rats treated with chemotherapy followed by intraperitoneal RSV injection (group 2) or rats treated with chemotherapy followed by CoQ10 (group 3), or rats treated with chemotherapy followed by intraperitoneal CAPE injection (group 4). Cisplatin was administered intraperitoneally once daily at doses of 2.0 mg/kg for 10 days. Rats in groups 2, 3, and 4 were given RSV (100 mg/kg, i.p.), CoQ10 (20 mg/kg, oral), and CAPE (10 mg/kg, i.p.) respectively. Five animals in the sham group underwent laparotomy for ovarian weight measurements on the first day of cisplatin injection. Animals in the treatment and control groups were sacrificed two weeks later, and their ovaries were excised for histopathological analysis. Serum levels of anti-Mullerian hormone (AMH) were also analyzed.ResultsRats in groups 2 and 4 showed vaginal smears under estrogenic effect. At the end of the second week, the total body weight and ovarian weight of the animals in group 1 increased. Significantly higher mean follicle count was detected in groups 2 and group 4 compared to group 3. The ovaries of the rats in the control group showed follicles in all stages of development. While the ovaries of the rats in the RSV or CAPE showed significantly decreased numbers of primordial follicles they showed increased numbers of early growing follicles.ConclusionsBoth RSV and CAPE administration might improve follicle survival and AMH production in rats with chemotherapy-induced POI but further research is necessary.

Caffeic acid phenethyl ester mitigates cadmium-induced hepatotoxicity in mice: Role of miR-182-5p/TLR4 axis

Cadmium (Cd), an environmental pollutant, is evidenced to cause hepatotoxicity. In this study, the potential protective effect of caffeic acid phenethyl ester (CAPE) on cadmium-induced liver damage was investigated. Forty male mice were treated daily with either CdCl2 (1.5 mg/kg body weight (b.w.), gavage) or CAPE (10 μmol/kg b.w., gavage) or both for 4 weeks. CAPE administration significantly reduced Cd level and liver and body weight, and increased AST, ALT and ALP level. Moreover, CAPE prevented CdCl2-induced oxidative stress via PI3K/Akt/mTOR pathway and inhibited apoptosis by regulating apoptosis markers. CAPE also suppressed the CdCl2-induced inflammation by reducing the inflammatory mediators, including TNF-α, IL-6 and IL-1β. Furthermore, CAPE alleviated CdCl2-induced reduction of TLR4. It should be noted that this effect was achieved by targeting miR-182-5p, and CAPE improved miR-182-5p level. The improvement of the liver tissue histopathology by CAPE confirmed the biochemical data. These results show for the first time that miR-182-5p/TLR4 axis involved in CAPE's protection against CdCl2-induced hepatotoxicity, and may provide novel insights into the treatment of cadmium-related diseases.

Zinc Deficiency‐Induced NFkB Activation Promotes Hypertension by Driving Renal Na+ Reabsorption

BackgroundZinc deficiency (ZnD) is a common comorbidity with chronic disorders including diabetes and kidney disease. Patients with these diseases also have a higher incidence of hypertension. Recently, we reported that a zinc deficient diet is sufficient to induce hypertension in mice. Changes in blood pressure were accompanied by increased Na+ reabsorption via the renal sodium chloride cotransporter (NCC). Although our novel results indicate that zinc plays a critical role in NCC regulation and its downstream effects on blood pressure, the specific mechanisms involved are unknown.HypothesisSince nuclear factor‐kB (NFkB) is a key transcription factor implicated in ZnD‐mediated effects, we tested the hypothesis that ZnD stimulates renal NFκB activation which drives NCC upregulation and thereby promotes hypertension.Experimental DesignAdult, male C57BL/6 mice were fed a zinc adequate (ZnA; 50ppm) or a ZnD (1ppm) diet for 6 weeks. To examine the role of NFkB in ZnD‐induced hypertension, mice were switched from a ZnA‐diet to a ZnD‐diet for 5 weeks. After, ZnD mice were administered caffeic acid phenethyl ester (CAPE), an NFkB inhibitor, for 1 week. In mice, NCC expression (qRT‐PCR) and blood pressure (tail‐cuff) were measured. To further investigate the role of NFkB in NCC expression (qRT‐PCR and Western blot), mouse distal convoluted tubule (mDCT) cells were treated with TPEN (a zinc chelator) or vehicle (DMSO) ± CAPE.ResultsCompared to ZnA mice, NCC mRNA abundance was increased in ZnD mice (7.625 ± 1.747 vs 1.0 ± 0.127) and was accompanied by enhanced renal NFkB nuclear localization. In mDCT cells, TPEN‐induced ZnD stimulated NCC mRNA expression (3.152 ± 0.966 vs 1.0 ± 0.174) and NFkB upregulation (1.573 ± 0.117 vs 1.0 ± 0). However, NFkB inhibition by CAPE prevented TPEN‐induced NCC mRNA (0.636 ± 0.178 vs 3.152 ± 0.966) and protein (1.039 ± 0.018 vs 2.335 ± 0.062) expression in mDCT cells. Finally, CAPE administration lowered blood pressure (154.5 ± 5.42 vs 138.1 ± 1.97 mm Hg) in ZnD mice.SummaryThese results demonstrate that 1) renal NFkB is a Zn2+‐regulated transcription factor, 2) NFkB is involved in NCC regulation and 3) NFkB mediates ZnD‐induced blood pressure increases.SignificanceTaken together, these data indicate that ZnD stimulates NFkB activation thereby driving NCC upregulation and hypertension.Support or Funding InformationAHA‐16SDG27080009 and NIH‐R21DK119879

Caffeic acid phenethyl ester, a propolis polyphenolic, attenuates potentially cadmium-induced testicular dysfunction in mice

Cadmium (Cd) as environmental pollutant can induce severe damage, particularly to the testis. This study investigated the effects of Caffeic acid phenethyl ester (CAPE) on testicular dysfunction induced by Cd. Adult mice were intraperitoneally injected with cadmium chloride (CdCl2) with different doses of CAPE pretreatment. After CdCl2 injection, body/testis weight ratio decreased, Cd levels accumulated and zinc levels decreased in testis. Furthermore, Cd intoxication caused a significant increase of oxidative stress levels, antioxidant enzymes activities, and glutathione levels. Interestingly, significant improvements were observed after the administration of CAPE. Our results demonstrated the protective effect of CAPE, linking Cd testicular dysfunction to oxidative stress.

Cardioprotective effect of caffeic acid phenethyl ester on cardiac contusion following blunt chest trauma in rats

ABSTRACTWe investigated the effects of caffeic acid phenethyl ester (CAPE) on cardiac damage after blunt chest injury. Forty male adult Wistar albino rats were divided into four groups; control, cardiac contusion, cardiac contusion + CAPE, and CAPE. CAPE, 10 mmol/kg, was administered intraperitoneally for 7 days following cardiac contusion. Heart tissue and blood were obtained at the end of the experimental period. Cardiac histopathology was determined using hematoxylin & eosin (H & E) staining. Expression of tumor necrosis factor-alpha (TNF-α) in cardiomyocytes was determined using immunohistochemistry. Cardiac apoptosis was determined using the TUNEL method. Serum creatine kinase (CK), creatine kinase-muscle/brain (CK-MB) and lactate dehydrogenase (LDH) levels were determined using spectrophotometric methods. The serum cardiac troponin I (C-TI) level was measured using the ELISA method. Myofibril loss was detected in the cardiomyocytes of the cardiac contusion group. Increased apoptosis and TNF-α expression were observed in the cardiac contusion group compared to the control group. Increased CK, CK-MB, LDH and C-TI levels were found in the cardiac contusion group. We found that CAPE administration improved myocardial function. Compared to the cardiac contusion group, CK, CK-MB, LDH and C-TI levels decreased significantly in the cardiac contusion + CAPE group. Administration of CAPE significantly inhibited apoptosis and cardiac TNF-α expression. Our findings demonstrate the therapeutic effects of CAPE for cardiac contusion damage after blunt chest trauma.

Caffeic Acid Phenethyl Ester Rescues Pulmonary Arterial Hypertension through the Inhibition of AKT/ERK-Dependent PDGF/HIF-1α In Vitro and In Vivo.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.

Evaluation of Caffeic Acid Phenethyl Ester Administration in Chronically Stressed Rats with Experimental Periodontitis.

Objectives: The aim of the present study was to investigate the therapeutic effects of systemic caffeic acid phenethyl ester treatment on oxidative stress and alveolar bone destruction in lipopolysaccharide (LPS)-induced periodontitis in chronically stressed rats.Materials and Methods: Fourty male Sprague Dawley rats were divided into four groups: 1) control group, 2) experimental periodontitis (EP), 3) EP and chronic stress (CS) group (EP-CS), and 4) EP-CS treated with CAPE (EP-CS-CAPE). To induce periodontitis, LPS was administered into the buccal gingiva of the test groups, and pure saline was administered for the control group. Two test groups were exposed to restraint stress and one group of these groups was treated with only a single dose of CAPE (10 mmol/kg). Likewise, saline was administered in the control, EP, and EP-CS groups. After 14 days, serum samples were collected from the heart, and all rats were sacrificed for analyses. Oxidative stress and interleukin (IL)-1β were investigated. The receptor activator of the nuclear factor kappa B ligand (RANKL) and alveolar bone loss were determined by immunohistochemical analysisResults: The oxidative stress, alveolar bone loss, IL-1β and RANKL levels were found significantly higher in the EP-CS group compared with control and EP groups (p&amp;lt;0.05). However, the administration of CAPE significantly reduced oxidative stress and IL-1β in the EP-CS-CAPE group compared with the EP-CS group (p&amp;lt;0.05). Also, CAPE treatment significantly reduced RANKL and alveolar bone loss in the EP-CS-CAPE group compared with the EP-CS group (p&amp;lt;0.05)Conclusions: The present results indicated that CAPE may inhibit alveolar bone loss by modulating the immune response and inflammatory process.

Caffeic acid phenethyl ester (CAPE) reverses fibrosis caused by chronic colon inflammation in murine model of colitis

Fibrosis is known to be the hallmarks of chronic inflammation of the bowel. Epithelial damage due to inflammation compromises the barrier function of the gastrointestinal tract. This barrier dysfunction leads to further spread of inflammation resulting in a chronic state of inflammation. This chronic inflammation leads to development of fibrosis, which has very limited therapeutic options and usually requires surgical removal of the affected tissue. Our previous work has shown that Caffeic acid phenethyl ester (CAPE) is a naturally occurring anti-inflammatory agent, found in propolis, has been found to be protective in experimental colitis via enhancement of epithelial barrier function. However, the impact of CAPE on resolution of fibrosis in the long-term is unknown. The aim of this follow up study was to investigate the effect of CAPE on colon fibrosis in a chronic model of Dextran sulphate sodium induced colitis in mice. Dextran sulphate sodium (DSS) 2.5% w/v was administered in drinking water to induce colitis in C57/BL6 mice for 5 days on the 6th day DSS was stopped and test group mice were treated with intraperitoneal administration of CAPE (30 mg kg−1 day−1) for a further 7 days. Disease activity index (DAI) score, colon length and tissue histology and level of tissue fibrosis was observed. CAPE-treated mice had significantly lower levels of DAI, tissue inflammation scores and fibrosis as compared with control group. Our results show that CAPE is effective in resolving colon fibrosis in chronic inflammation. Thus, we can conclude CAPE could be a potential therapeutic agent for further clinical investigations for treatment of fibrosis in inflammatory bowel diseases in humans.

Caffeic acid phenethyl ester promotes wound healing of mice pressure ulcers affecting NF-κB, NOS2 and NRF2 expression

AimsIn pressure ulcers, the synthesis of reactive oxygen species induced by ischemia and reperfusion leads to chronic inflammation and tissue damage, which impair the closure of these lesions. Caffeic acid phenethyl ester (CAPE), found in propolis, promotes cutaneous wound healing of acute lesions and severe burns. However, the effects of CAPE on wound healing of pressure ulcers have not been investigated. This study investigated the effects of CAPE administration in a murine model of pressure ulcers. Main methodsTo induce pressure ulcers, two cycles of ischemia and reperfusion by external application of two magnetic plates were performed in the skin dorsum of mice. After the last cycle, animals were treated daily with CAPE or vehicle until they were euthanized. Key findingsThe nitric oxide synthesis, lipid peroxidation, macrophage migration, protein nuclear factor kappa B and nitric-oxide synthase-2 expression were increased 3 days after ulceration but decreased 7 days later, in pressure ulcers of the CAPE group compared to that of the control group. CAPE reduced the protein expression of nuclear factor-erythroid2-related factor 2 in pressure ulcers 3 days after ulceration, but increased 7 days later. Myofibroblast density was increased in the CAPE group 7 days after ulceration, but reduced 12 days later when compared to control group. In addition, CAPE promoted collagen deposition, re-epithelialization and wound closure of mice pressure ulcers 12 days after ulceration. SignificanceCAPE brings forward inflammatory response and oxidative damage involved in injury by ischemia and reperfusion, promoting dermal reconstruction and closure of pressure ulcers.

Caffeic acid phenethyl ester rescued streptozotocin-induced memory loss through PI3-kinase dependent pathway

The present study was undertaken to elucidate the role of PI3-kinase signaling in memory enhancing potential of caffeic acid phenethyl ester (CAPE) against cognitive defects in rats after centrally administered streptozotocin as a model of Alzheimer’s disease. The Morris water maze and elevated plus maze paradigms showed profound loss of memory in adult Wistar rats (180–200 g) injected with streptozotocin (3 mg/kg) bilaterally (STZ-ICV) on day 1 and 3. Intraperitoneal administration of CAPE (6 mg/kg, i.p., 28 days) attenuated STZ-ICV triggered memory loss in rats. Treatment with PI3-kinase inhibitor (wortmannin, 5 μg/rat, ICV) or NOS blocker (L-NAME, 20 mg/kg, i.p., 28 days) interfered with memory restorative function of CAPE in STZ treated rats. In biochemical analysis markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-α, eNOS and NFκB were measured in brain of rats on day 28. Interestingly, L-Arginine (100 mg/kg, i.p., 28 days) group exhibited moderate (p > 0.05) decline in memory functions. The brain oxidative stress, TNF-α, AChE activity and NFκB levels were elevated, and eNOS level was lowered by STZ-ICV treatment. Administration of CAPE lowered oxidative stress, AChE, nitrite and TNF-α levels in brain of rats. The eNOS level was enhanced and NFκB level was decreased by CAPE in STZ treated rats. Wortmannin injection elevated the brain oxidative stress, AChE activity and TNF-α levels, and decreased the nitrite, eNOS and NFκB level. Rise of brain oxidative stress parameters, AChE activity, TNF-α, eNOS and NFκB levels, and decline in brain nitrite content was observed in L-NAME treated group. L-Arginine administration showed modest effects (p > 0.05) on oxidative stress parameters. Brain nitrite content was enhanced although eNOS, NFκB levels, and AChE activity was decimated by L-Arginine treatment. It can be concluded that PI3-kinase mediated nitric oxide facilitation is an essential feature of CAPE action in STZ-ICV treated rats.

Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer's Disease Involves Nrf2/HO-1 Pathway.

Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.