Caffeic acid phenethyl ester (CAPE) prevents methotrexate-induced hepatorenal oxidative injury in rats

Objectives This study aimed to investigate the antioxidant and anti‐inflammatory effects of caffeic acid phenethyl ester (CAPE) on the methotrexate (MTX)‐induced hepatorenal oxidative damage in rats. Methods Following a single dose of methotrexate (20 mg/kg), either vehicle (MTX group) or CAPE (10 µmol/kg, MTX + CAPE group) was administered for five days. In other rats, vehicle (control group) or CAPE was injected for five days, following a single dose of saline injection. After decapitation of the rats, trunk blood was obtained, and the liver and kidney tissues were removed for histological examination and for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) and sodium potassium‐adenosine triphosphatase (Na⁺/K⁺‐ATPase) activity. TNF‐α and IL‐1β levels were measured in the blood. Key findings Methotrexate administration increased the tissue MDA levels, MPO activity and decreased GSH levels and Na⁺/K⁺‐ATPase activity, while these alterations were reversed in the CAPE‐treated MTX group. Elevated TNF‐α and IL‐1β levels were also reduced with CAPE treatment. Conclusions The results of this study revealed that CAPE, through its anti‐inflammatory and antioxidant actions, alleviates methotrexate‐induced oxidative damage, which suggests that CAPE may be of therapeutic benefit when used with methotrexate.     

Caffeic acid phenethyl ester protects against tamoxifen-induced hepatotoxicity in rats

Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. Adverse effects of TAM include hepatotoxicity. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has been used in folk medicine for diverse ailments. In the current study, the protective effects of CAPE against TAM-induced hepatotoxicity in female rats were evaluated. TAM (45 mg/kg/day, i.p., for 10 consecutive days) resulted in an elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), depletion of liver reduced glutathione (GSH) and accumulation of oxidized glutathione (GSSG) and lipid peroxidation (LPO). Also, TAM treatment resulted in inhibition of hepatic activity of glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). Further, it raised liver tumor necrosis factor-alpha (TNF-α) level and induced histopathological changes. Pretreatment with CAPE (2.84 mg/kg/day; i.p., for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. CAPE significantly inhibited TAM-induced hepatic GSH depletion and GSSG and LPO accumulation. Consistently, CAPE normalized the activity of GR, GPx, SOD and CAT, inhibited the rise in TNF-α and ameliorated the histopathological changes. In conclusion, CAPE protects against TAM-induced hepatotoxicity.     

Pharmacokinetics of caffeic acid phenethyl ester and its catechol‐ring fluorinated derivative following intravenous administration to rats

The pharmacokinetic profiles of caffeic acid phenethyl ester (CAPE) and its catechol‐ring fluorinated derivative (FCAPE) were determined in rats after intravenous administration of 5, 10 or 20 mg/kg for CAPE and 20 mg/kg for FCAPE, respectively. The plasma concentrations of CAPE and FCAPE were measured using a validated liquid chromatography tandem mass spectrometric method. The pharmacokinetic parameters were estimated using non compartmental analysis (NCA) and biexponential fit. The results showed that the area under the plasma concentration‐time curve for CAPE treatment increased in a proportion greater than the increase in dose from 5 to 20 mg/kg of CAPE. Total body clearance values for CAPE ranged from 42.1 to 172 ml/min/kg (NCA) and decreased with the increasing dose of CAPE. Similarly, the volume of distribution values for CAPE ranged from 1555 to 5209 ml/kg, decreasing with increasing dose. The elimination half‐life for CAPE ranged from 21.2 to 26.7 min and was independent of dose. That FCAPE was distributed extensively into rat tissues and eliminated rapidly was indicated by a high value of volume of distribution and similar short elimination half‐life as that of CAPE. Copyright © 2009 John Wiley & Sons, Ltd.     

咖啡酸苯乙酯通过下调LRRK2抑制JNK信号通路减轻大鼠创伤性颅脑损伤

目的 探究咖啡酸苯乙酯（CAPE）对创伤性颅脑损伤（TBI）大鼠的作用及机制。方法 54只SD大鼠随机分为假手术组,模型组,CAPE低、高剂量（5、10 mg·kg^-1）组,CAPE （10 mg·kg^-1）+腺相关病毒阴性对照（oe-NC,1×10⁹ pfu,200 μL）组,CAPE （10 mg·kg^-1）+过表达LRRK2腺相关病毒（oe-LRRK2,1×10⁹ pfu,200 μL）组,每组9只。采用改良的Feeney法制备TBI模型,造模后30 min,CAPE和oe-NC、oe-LRRK2均ip给药,假手术组和模型组大鼠ip等量溶剂。所有大鼠每天给药1次,连续7 d。改良神经功能缺损评分（mNSS）评估大鼠神经功能缺损程度;转棒实验评价大鼠综合运动能力;检测各组大鼠脑组织含水量;ELISA法检测血清神经元特异性烯醇化酶（NSE）、白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α和IL-1β水平;实时荧光定量PCR（qRT-PCR）法检测LRRK2 mRNA表达;Western blotting检测LRRK2、p-JNK和JNK蛋白表达;TUNEL染色检测大脑皮层细胞凋亡;FJB染色检测神经元细胞死亡。结果 与假手术组相比,模型组大鼠mNSS、脑组织含水量、大脑皮层细胞凋亡率、FJB⁺细胞数以及血清中NSE、IL-6、TNF-α和IL-1β含量显著升高（P<0.05）,LRRK2 mRNA和LRRK2、p-JNK/JNK蛋白水平显著升高（P<0.05）,转棒时间显著降低（P<0.05）;与模型组相比,CAPE低、高剂量组大鼠mNSS、脑组织含水量、大脑皮层细胞凋亡率、FJB+细胞数以及血清中NSE、IL-6、TNF-α和IL-1β含量显著降低（P<0.05）,LRRK2 mRNA和LRRK2、p-JNK/JNK蛋白表达显著降低（P<0.05）,转棒时间显著升高（P<0.05）;与CAPE+oe-NC组相比,CAPE+oe-LRRK2组大鼠mNSS、脑组织含水量、细胞凋亡率、FJB+细胞数以及血清中NSE、IL-6、TNF-α和IL-1β含量显著升高（P<0.05）,LRRK2 mRNA和LRRK2、p-JNK/JNK蛋白表达显著升高（P<0.05）,转棒时间显著降低（P<0.05）。结论 CAPE可能通过下调LRRK2表达抑制JNK通路活化,在TBI中发挥保护作用。     

Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats

We have investigated the effect of caffeic acid phenethyl ester (CAPE) on cisplatin-induced nephrotoxicity in rats. Administration of a single dose of cisplatin resulted in the elevation of blood urea nitrogen and creatinine in serum, as well as nitric oxide in kidney tissue of rats. Cisplatin also caused reduction of catalase (P < 0.0001), superoxide dismutase (P = 0.149) and glutathrone peroxidase (P < 0.0001) activities in kidney tissue. Although cisplatin caused elevation in malondialdehyde levels and myeloperoxidase activities in kidney tissue, they were not statistically significant. Caffeic acid phenethyl ester was found to be protective against cisplatin-induced antioxidant enzyme reductions. Treatment with free-radical scavenger CAPE attenuated the increase in plasma blood urea nitrogen and kidney nitric oxide levels, and showed histopathological protection against cisplatin-induced acute renal failure. Extensive epithelial cell vacuolization, swelling, desquamation and necrosis were observed in the kidney of the cisplatin-treated rat. There were also larger tubular lumens in cisplatin-treated rats than those of the control and the CAPE groups. Caffeic acid phenethyl ester caused a marked reduction in the extent of tubular damage. It is concluded that administration of cisplatin imposes an oxidative stress to renal tissue and CAPE confers protection against the oxidative damage associated with cisplatin. This mechanism may be attributed to its free-oxygen-radical scavenging activity.     

Therapeutic efficacy of caffeic acid phenethyl ester in cancer therapy: An updated review

Nowadays, there is a lot of public and scientific interest in using phytochemicals to treat human ailments. Existing cancer medicines still run across obstacles, despite significant advancements in the field. For instance, chemotherapy may result in severe adverse effects, increased drug resistance, and treatment failure. Natural substances that are phytochemically derived provide innovative approaches as potent therapeutic molecules for the treatment of cancer. Bioactive natural compounds may enhance chemotherapy for cancer by increasing the sensitivity of cancer cells to medicines. Propolis has been found to interfere with the viability of cancer cells, among other phytochemicals. Of all the components that make up propolis, caffeic acid phenethyl ester (CAPE) (a flavonoid) has been the subject of the most research. It demonstrates a broad spectrum of therapeutic uses, including antitumor, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and cardioprotective effects. Studies conducted in vitro and in vivo have demonstrated that CAPE specifically targets genes involved in cell death, cell cycle regulation, angiogenesis, and metastasis. By altering specific signaling cascades, such as the NF-κB signaling pathway, CAPE can limit the proliferation of human cancer cells. This review highlights the research findings demonstrating the anticancer potential of CAPE with a focus on multitargeted molecular and biological implications in various cancer models.     

咖啡酸苯乙酯及其苯甲酰基衍生物:合成和单晶X衍射分析(英文)

在Na2CO3的催化下,咖啡酸和β溴乙基苯在非质子性混合溶剂HMPACH3CN中高收率地合成天然蜂胶中主要的生物活性成分咖啡酸苯乙酯(CAPE)。为了更好地探究CAPE的构效关系和活性机理,我们首次成功地合成了单、双苯甲酰基取代的咖啡酸苯乙酯产物,同时单苯甲酰基取代产物结构通过单晶X衍射被确定。     

Protective effects of caffeic acid phenethyl ester on the dose‐dependent acute nephrotoxicity with paraquat in a rat model

Paraquat (PQ), which is used extensively as a potent herbicide throughout the world, is highly toxic in humans. We aimed to determine PQ‐induced biochemical and histologic changes in the kidneys, and to evaluate the ability of the protective effects of caffeic acid phenethyl ester (CAPE) against PQ‐induced injury in rats. Forty‐eight rats were divided into eight groups of six: Group 1: Control; Group 2: 10 μmol/kg CAPE; Group 3: 15 mg/kg PQ; Group 4: 30 mg/kg PQ; Group 5: 45 mg/kg PQ; Group 6: 15 mg/kg PQ+CAPE; Group 7: 30 mg/kg PQ+CAPE; Group 8: 45 mg/kg PQ+CAPE. PQ and CAPE were injected intraperitoneally. The levels of the total oxidant status (TOS) and total antioxidant status (TAS) were determined in the supernatants of the excised left kidney. Right kidney tissue of each rat was removed to obtain a histologic score. When PQ‐administrated (15, 30, 45) groups compared with other groups, TOS values were found to be significantly higher (p < 0.01). PQ (15, 30, 45) groups had significantly diminished values of TAS than the other groups (p < 0.001). Of histologic score evaluation, only the PQ45 group had a significantly higher value than the sham, and CAPE groups (p < 0.05). Moreover, in CAPE+PQ45 group, the level of histologic score was decreased compared to PQ45 group (p < 0.001). In conclusion, the evaluation of the data suggests that CAPE can be used to prevent the acute effects of PQ nephrotoxicity. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 375–381, 2015.     

Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor

BACKGROUND AND PURPOSE

Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration.

EXPERIMENTAL APPROACH

Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine.

KEY RESULTS

CAPE protected dopaminergic neurons in slice cultures from IFN-γ/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice.

CONCLUSION AND IMPLICATIONS

CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.     

Caffeic acid phenethyl ester (CAPE) revisited: Covalent modulation of XPO1/CRM1 activities and implication for its mechanism of action

Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti‐inflammatory, anticarcinogenic, antioxidant, and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE. In particular, we showed that CAPE could specifically target the non‐catalytic and conserved Cys⁵²⁸ of XPO1 through the means of mass spectrometric analysis. In addition, we demonstrated that the mutation of Cys⁵²⁸ residue in XPO1 could rescue the nuclear export defects caused by CAPE. Furthermore, we performed position‐restraint molecular dynamics simulation to show that the Michael acceptor moiety of CAPE is the warhead to enable covalent binding with Cys⁵²⁸ residue of XPO1. The covalent modulation of nuclear export by CAPE may explain its diverse biological effects. Our findings may have general implications for further investigation of CAPE and its structural analogs.     

Ebselen attenuates cadmium-induced testicular damage in mice

This study was designed to examine if ebselen, an organoselenium compound with antioxidant and glutathione peroxidase-mimetic properties, attenuates testicular injury caused by intraperitoneal administration of CdCl(2). A number of toxicological parameters were evaluated in the testes of mice, such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, ascorbic acid levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Ebselen attenuated lipid peroxidation levels altered by CdCl(2). delta-ALA-D activity inhibited by the highest dose of CdCl(2) was attenuated by ebselen. A significant negative correlation between lipid peroxidation levels and delta-ALA-D activity was observed. Ebselen restored ascorbic acid levels reduced by CdCl(2). A significant negative correlation between ascorbic acid levels and delta-ALA-D activity reinforces the idea that ebselen attenuated the damage induced by CdCl(2) via its antioxidant property. The significant correlation between ALT and delta-ALA-D activity supports the assumption that ebselen prevented damage caused by CdCl(2). The results show that ebselen attenuated oxidative stress, a process important for CdCl(2) toxicity.     

Effects of caffeic acid phenethyl ester on glycerol-induced acute renal failure in rats

1. Free radicals and nitric oxide (NO) play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). The aim of the present study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an anti-oxidant, on the myoglobinuric ARF induced by intramuscular hypertonic glycerol injection. 2. Thirty rats were divided equally into three groups. Rats in group 1 were given saline and those in groups 2 and 3 were injected with glycerol (10 mL/kg, i.m.). Concomitant and 24 h after glycerol injection, CAPE (10 micromol/kg, i.p.) was administered to group 3 rats. Forty-eight hours after glycerol injection, blood samples and kidney tissues of rats were taken under anaesthesia. 3. Plasma concentrations of urea, creatinine, malondialdehyde (MDA) and NO were determined, as were superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities and MDA levels in kidney tissues. Kidney morphology was also investigated. 4. In the group receiving CAPE, although SOD enzyme activity was found to be increased, we failed to find any protective effect of CAPE on other parameters investigated. Moreover, although CAPE significantly decreased NO levels, it increased plasma concentrations of urea and MDA. 5. We suggest that the effect of CAPE in decreasing NO concentrations may further increase the renal ischaemia in this model. Thus, CAPE may have a worsening rather than beneficial effect under these conditions in this model of ARF.     

Absorption properties and effects of caffeic acid phenethyl ester and its p-nitro-derivative on P-glycoprotein in Caco-2 cells and rats

Context: Caffeic acid phenethyl ester (CAPE), isolated from honeybee propolis, has pharmacological applications. A synthesized CAPE derivative, p-nitro-caffeic acid phenethyl ester (CAPE-NO₂), showed similar activities with CAPE. The pharmacological activities of CAPE and CAPE-NO₂ are related to their absorption properties.

Objective: To understand the pharmacokinetic profiles of CAPE and CAPE-NO₂ in rats and investigate the absorption mechanisms and effects on P-glycoprotein in Caco-2 cells.

Materials and methods: The pharmacokinetic profiles of CAPE and CAPE-NO₂ were obtained after oral administration (10?mg/kg) to rats. Transport studies of CAPE and CAPE-NO₂ (5, 10, 20?μM) were performed in Caco-2 cell model. P-gp activities were assayed by rhodamine 123 cellular retention. Expression of P-gp was determined after the cells were administrated with CAPE and CAPE-NO₂ (5, 20?μM) for 48 and 72?h.

Results: The AUC_(0?t) of CAPE-NO₂ (3239.9?±?352?ng?×?h/mL) was two-time greater than CAPE (1659.6?±?152?ng?×?h/mL) in rats. The P_app values of CAPE and CAPE-NO₂ were (4.86?±?0.90)?×?10^?6?cm/s and (12.34?±?1.6)?×?10^?6?cm/s, respectively. The accumulation of rhodamine 123 was increased by 1.3- to 1.9-fold and 1.4- to 2.3-fold in CAPE and CAPE-NO₂ groups after 1?h administration, respectively. However, CAPE and CAPE-NO₂ increased the P-gp levels by 2.1- and 1.7-fold, respectively.

Conclusion: The absorption of CAPE-NO₂ can be enhanced in rats and Caco-2 cells compared with CAPE. The two compounds are potential inhibitors of P-gp. The increased P-gp levels generated by CAPE and CAPE-NO₂ played a role as a defense mechanism by limiting intracellular xenobiotic levels.     

咖啡酸苯乙酯通过Nrf-2途径抑制地塞米松诱导的成骨细胞凋亡

目的 探讨Nrf-2途径在咖啡酸苯乙酯(CAPE)抑制地塞米松(DEX)诱导成骨细胞凋亡中的作用.方法 用细胞贴壁法培养小鼠颅顶前骨细胞(MC3T3-E1),采用10μmol/L DEX建立细胞损伤模型,以不同浓度CAPE(0.05、0.25、1μmol/L)预处理细胞2h后加入地塞米松共孵育24h;细胞增殖-毒性检测试剂盒(CCK-8)检测细胞增殖活性;依据CCK-8检测结果确定药物浓度后将实验分为对照组、咖啡酸苯乙酯组(CAPE组)、地塞米松组(DEX组),咖啡酸苯乙酯+地塞米松组(CAPE+DEX组);DCFH-DA荧光探针检测细胞内活性氧(reactive oxygen species,ROS)水平;Caspase-3活性检测试剂盒检测Caspase-3酶活性,Western blot法检测Nrf-2 途径相关蛋白Nrf-2和血红素氧合酶1(heme oxygenase,HO-1)蛋白表达水平;流式细胞仪检测细胞凋亡率.结果 10μmol/L DEX作用下细胞形态发生明显变化,损伤作用明显.与对照组相比,DEX组内细胞存活率显著下降(P＜0.01),而细胞内 ROS水平、细胞凋亡率及Caspase-3酶活性显著增加(P＜0.01);同时,Nrf-2途径相关蛋白 Nrf-2及HO-1表达量减少,差异有统计学意义(P＜0.01).与DEX组相比,CAPE+DEX组细胞存活率显著上升(P＜0.01),Nrf-2途径相关蛋白 Nrf-2及HO-1表达明显增加(P＜0.01);此外,CAPE+DEX组细胞内 ROS 水平、细胞凋亡率及Caspase-3酶活显著降低,差异有统计学意义(P＜0.01).结论 咖啡酸苯乙酯可以通过Nrf-2途径降低细胞内ROS水平进而减轻地塞米松诱导的氧化应激所致细胞损伤及凋亡.     

Reversal of cadmium-induced vascular dysfunction and oxidative stress by meso-2,3-dimercaptosuccinic acid in mice

Cadmium (Cd) is a heavy metal which causes concern as an environmental toxicant. Therapy with chelating agents is considered to be the rational treatment against metal poisoning. This study was designed to evaluate whether meso-2,3-dimercaptosuccinic acid (DMSA) could alleviate oxidative stress and vascular dysfunction in mice with subchronic exposure to Cd. Male ICR mice received CdCl₂ (100 mg/L) via drinking water for 8 weeks. After Cd exposure, DMSA at a dose of 25 mg/kg or 50 mg/kg was intragastrically administered once daily for 5 consecutive days at the end of Cd treatment. It was found that Cd-induced hypertension and markedly blunted vascular responses to vasoactive agents, including acetylcholine, phenylephrine and sodium nitroprusside. Treatment with DMSA significantly restored blood pressure and improved vascular responsiveness when compared with Cd-treated controls. Moreover, DMSA protected against Cd-induced severe oxidative stress by normalization of the redox ratios of glutathione to glutathione disulfide and suppression of plasma malondialdehyde, plasma protein carbonyl, urinary nitrate/nitrite, and superoxide production from thoracic aorta. DMSA partially reduced Cd contents in the blood, heart, liver and kidneys. In conclusion, our present study provides the first evidence of the therapeutic efficacy of DMSA against oxidative stress and vascular dysfunction in Cd-intoxicated mice.     

Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl₄)-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl₄ significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl₄-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl₄-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl₄-induced Fas/FasL protein expression levels and, in turn, attenuated CCl₄-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl₄ bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl₄-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl₄-induced acute liver injury may involve its ability to block CYP2El-mediated CCl₄ bioactivation and to protect against Fas/FasL-mediated apoptosis.     

Cytotoxic constituents of propolis inducing anticancer effects: a review

Objectives Propolis is a honeybee product used extensively in traditional medicine for its antioxidant, anti‐inflammatory, immunomodulatory and anticancer effects. Propolis exhibits a broad spectrum of biological activities because it is a complex mixture of natural substances. In this review, the antitumour effects of propolis extracts and its constituents (e.g. flavonoids, terpenes and caffeic acid phenethyl ester) are discussed. Key findings The effect of propolis on experimental carcinogenesis is discussed, as well as its possible mechanisms of action against tumours, involving apoptosis, cell cycle arrest and interference on metabolic pathways. Propolis seems to be efficient against different tumour cells both in vitro and in vivo, which suggests its potential in the development of new anticancer drugs. Summary Propolis extracts may be important economically and would allow a relatively inexpensive cancer treatment. Preclinical investigations are needed to further elucidate the benefits of propolis and its antitumour properties.     

Evaluation of anti-allergic properties of caffeic acid phenethyl ester in a murine model of systemic anaphylaxis

Caffeic acid phenethyl ester (CAPE) is an active component of honeybee propolis extracts. It has several positive effects, including anti-inflammatory, anti-oxidation, anti-cancer, anti-bacterial, anti-viral, anti-fungal, and immunomodulatory effects. In particular, the suppressive effect of NF-kappaB may disrupt a component of allergic induction. The principal objective of this experimental study was to evaluate the effects of CAPE on the active systemic anaphylaxis induced by ovalbumin (OVA) challenge in mice. Mice were intraperitoneally sensitized and intravenously challenged with OVA. Histopathological analysis, nuclear factor (NF)-kappaB activation, and the plasma levels of histamine and total IgE after allergen challenge were evaluated. After challenges, all of the sham-treated mice developed anaphylactic symptoms, increased plasma levels of histamine and OVA-specific IgE, marked vascular leakage, NF-kappaB activation, platelet-activating factor (PAF) production, and histological changes including pulmonary edema and hemorrhage in the renal medullae within 20 min. By way of contrast, a reduction in the plasma levels of histamine and OVA-specific IgE and an inhibition of NF-kappaB activation and PAF release were observed in the CAPE-treated mice. In addition, a significant prevention of hemoconcentration and OVA-induced pathological changes were noted. These results indicate that CAPE demonstrates an anti-allergic effect, which may be the result of its protective effects against IgE-mediated allergy.     

Protective effect of caffeic acid phenethyl ester on tert-butyl hydroperoxide-induced oxidative hepatotoxicity and DNA damage

Increased oxidative stress and associated high levels of free radical generation have been described to occur during the pathogeneses of various diseases in animal models. In the present work, we investigated the protective effects of the phenethyl ester of caffeic acid (CAPE), an active component of honeybee propolis, on tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in a cultured HepG2 cell line and in rat liver. CAPE was found to significantly reduce t-BHP-induced oxidative injury in HepG2 cells, as determined by cell cytotoxicity, and lipid peroxidation and reactive oxygen species (ROS) levels in a dose-dependent manner. Furthermore, CAPE protected HepG2 cells against t-BHP-induced oxidative DNA damage, as determined by the Comet assay. Consistently, CAPE reduced hydroxyl radical-induced 2-deoxy-d-ribose degradation by ferric ion-nitrilotriacetic acid and H2O2, and also removed the superoxide anion generated by a xanthine/xanthine oxidase system. Our in vivo study showed that pretreatment with CAPE prior to the administration of t-BHP significantly and dose-dependently prevented increases in the serum levels of hepatic enzyme markers (alanine aminotransferase and aspartate aminotransferase) and reduced lipid peroxidation in rat liver. Moreover, histopathological evaluation of livers consistently revealed that CAPE reduced liver lesion induction by t-BHP. Taken together, these results suggest that the protective effects of CAPE against t-BHP-induced hepatotoxicity may, at least in part, be due to its ability to scavenge ROS and protect DNA from oxidative stress-induced damage.