Progress in Colloid Delivery Systems for Protection and Delivery of Phenolic Bioactive Compounds: Two Study Cases-Hydroxytyrosol and Curcumin.

Insufficient intake of beneficial food components into the human body is a major issue for many people. Among the strategies proposed to overcome this complication, colloid systems have been proven to offer successful solutions in many cases. The scientific community agrees that the production of colloid delivery systems is a good way to adequately protect and deliver nutritional components. In this review, we present the recent advances on bioactive phenolic compounds delivery mediated by colloid systems. As we are aware that this field is constantly evolving, we have focused our attention on the progress made in recent years in this specific field. To achieve this goal, structural and dynamic aspects of different colloid delivery systems, and the various interactions with two bioactive constituents, are presented and discussed. The choice of the appropriate delivery system for a given molecule depends on whether the drug is incorporated in an aqueous or hydrophobic environment. With this in mind, the aim of this evaluation was focused on two case studies, one representative of hydrophobic phenolic compounds and the other of hydrophilic ones. In particular, hydroxytyrosol was selected as a bioactive phenol with a hydrophilic character, while curcumin was selected as typical representative hydrophobic molecules.

Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP+ Model of Parkinson's Disease.

3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP+) in rats. Rats were administered intravenously (i.v.) in the tail with 1 mL saline solution or polyphenol compound (1.5 mg/kg) 5 min before intrastriatal infusion of 10 µg MPP+/8 µL. We found that rats injured with MPP+, pretreatment with HTy, HTyA or HTyN significantly decreased ipsilateral turns. This result was consistent with a significant preservation of striatal dopamine levels and decreased lipid fluorescence products (LFP), a marker of oxidative stress. Brain GSH/GSSG ratio, from rats pretreated with HTy or HTyN showed a significant preservation of that marker, decreased as a consequence of MPP+-induced oxidative damage. These results show an antioxidant effect of HTy, HTyA and HTyN in the MPP+ model of Parkinson's disease in the rat.

EVOO Polyphenols Relieve Synergistically Autophagy Dysregulation in a Cellular Model of Alzheimer's Disease.

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aß1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aß1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.

3,4-Dihydroxyphenethyl nitrate with nitric oxide releasing, antioxidant, hypoglycemic and hypolipidemic effects.

Nitric oxide (NO) dysfunction, oxidative stress, and dyslipidemia are main risk factors associated with the pathophysiology of diabetic complications. In this study, 3,4-dihydroxyphenethyl nitrate (HT-ONO2) was designed, synthesized and evaluated, which incorporated hydroxytyrosol (HT) and nitrate. HT-ONO2 significantly exhibited hypoglycemic activity after oral administration to diabetic mice induced by streptozocin (STZ). HT-ONO2 also potently decreased plasma triglyceride (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR 1339. Meanwhile, HT-ONO2 displayed NO-releasing and antioxidant activity both in diabetic and hyperlipidemia mice and in vitro. Moreover, HT-ONO2 shown definite vasodilation and α-glucosidase inhibition activity in vitro. The results suggested that the hybrid hydroxytyrosol-based nitrate with NO supplement, antioxidant, hypoglycemia and hypolipidemia provided a potential multi-target agent to ameliorate the diabetes mellitus and its complications.

The protective effect of extra-virgin olive oil in the experimental model of multiple sclerosis in the rat.

This study has evaluated the effect of EVOO (Extra-Virgin olive oil), OA (oleic acid) and HT (hydroxytyrosol) in an induced model of MS through experimental autoimmune encephalomyelitis (EAE).Dark Agouti 2-month old rats (25 males) were divided into five groups: (i) control group, (ii) EAE group, (iii) EAE+EVOO, (iv) EAE+HT, and (v) EAE+OA. At 65 days, the animals were sacrificed and the glutathione redox system and bacterial lipopolysaccharide (LPS) and LPS-binding protein (LBP) products of the microbiota in brain, spinal cord, and blood were evaluated.Gastric administration of EVOO, OA, and HT reduced the degree of lipid and protein oxidation, and increased glutathione peroxidase, making it a diet-based mechanism for enhancing protection against oxidative damage. In addition, it reduced the levels of LPS and LBP, which appeared as being increased in the EAE correlated with the oxidative stress produced by the disease.

Safety assessment of a newly synthesized copolymer for micellar delivery of hydrophobic caffeic acid phenethyl ester.

Caffeic acid phenethyl ester (CAPE), a major pharmacologically active component of poplar type propolis, is known for its proapoptotic, anti-inflammatory, antioxidant, antiviral, and enzyme inhibiting activities. The aim of this study was to perform an in vitro and in vivo safety assessment of a micellar system based on a newly synthesized copolymer, consisting of polyglycidol and poly(allyl glycidyl ether) (C12-PAGE-PG) as a drug delivery platform for CAPE. The in vitro studies on HepG2 and L929 cells by MTT and LDH assays after treatment with the empty and CAPE-loaded micelles showed no cytotoxic effects of the empty micelles and retained cytotoxic activity of CAPE loaded in the micelles. No hemolysis or stimulation of mouse lymphocytes or macrophages was observed in vitro. In vivo hematological, biochemical, and histological assays on rats, treated with the empty (2580 and 5160 µg/kg) or CAPE-loaded (375 and 750 µg CAPE/kg) micelles did not reveal pathological changes of any of the parameters assayed after 14-days' treatment. In conclusion, initial toxicological data characterize C12-PAGE-PG as a non-toxic and promising copolymer for development of micellar drug delivery systems, particularly for a hydrophobic active substance as CAPE.

Protective Effects of Caffeic Acid Phenethyl Ester (CAPE) and Novel Cape Analogue as Inducers of Heme Oxygenase-1 in Streptozotocin-Induced Type 1 Diabetic Rats.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease resulting in the destruction of insulin producing ß-cells of the pancreas, with consequent insulin deficiency and excessive glucose production. Hyperglycemia results in increased levels of reactive oxygen species (ROS) and nitrogen species (RNS) with consequent oxidative/nitrosative stress and tissue damage. Oxidative damage of the pancreatic tissue may contribute to endothelial dysfunction associated with diabetes. The aim of the present study was to investigate if the potentially protective effects of phenethyl ester of caffeic acid (CAPE), a natural phenolic compound occurring in a variety of plants and derived from honeybee hive propolis, and of a novel CAPE analogue, as heme oxygenase-1 (HO-1) inducers, could reduce pancreatic oxidative damage induced by excessive amount of glucose, affecting the nitric oxide synthase/dimethylarginine dimethylaminohydrolase (NOS/DDAH) pathway in streptozotocin-induced type 1 diabetic rats. Our data demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and DDAH dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as CAPE or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions.

Acrolein-induced atherogenesis by stimulation of hepatic flavin containing monooxygenase 3 and a protection from hydroxytyrosol.

Acrolein, a highly toxic α, ß-unsaturated aldehyde, promotes the progression of atherosclerosis in association with inflammatory signaling pathway and reverse cholesterol transport (RCT) process. Additionally, hepatic flavin containing monooxygenase 3 (FMO3) is involved in the pathogenesis of atherosclerosis by regulating cholesterol metabolism. Hydroxytyrosol (HT), as a major phenolic compound in olive oil, exerts anti-inflammatory and anti-atherogenic activities in vitro and animal models. The current study was designed to evaluate whether FMO3 participated in pro-atherogenic process by acrolein and HT showed protective effect during this process. Here, endothelial cells and macrophage Raw264.7 cells were used as the cell models. Following oxidized low-density lipoprotein (OX-LDL) treatment, acrolein exposure promoted foam cells formation in macrophage Raw264.7 cells. The expression of FMO3 and inflammatory makers such as phospho-NF-κB, IL-1ß, TNFα as well as IL-6 were significantly increased. However, ATP-binding cassette transporters subfamily A member 1 (ABCA1), a major transporter in RCT process, was repressed by acrolein. In addition, FMO3 knockdown could suppress inflammatory markers and promote ABCA1 expression. Hydroxytyrosol (HT) was observed to reduce lipid accumulation, FMO3 expression as well as inflammatory response. Moreover, it promoted ABCA1 expression. Therefore, our findings indicated that acrolein-enhanced atherogenesis by increasing FMO3 which increased inflammatory responses and decreased ABCA1 in vitro can be alleviated by HT, which may have a therapeutic potential for the treatment of atherosclerosis.

Influence of Airflow Rate and Stimulus Concentration on Olfactory Event-Related Potentials (OERP) in Humans.

Although the association between odor concentration and olfactory event-related potential (OERP) has been studied, less is known about the influence of airflow on OERP. The aim of this study was to investigate the influence of airflow rate and stimulus concentration on OERP in humans. Electroencephalogram data were collected from young healthy volunteers (n = 17) in separate sessions where 2-phenylethanol (PEA) was delivered in the following conditions: 8 L/min 50% v/v, 8 L/min 30% v/v, 4 L/min 100% v/v, and 4 L/min 60%v/v. Odor concentrations are referred to the %v/v achieved with air dilution and was not measured in the nose. Odor intensity ratings were recorded immediately after stimulus presentation. Data recorded at 5 electrodes (Fz, Cz, Pz, C3, and C4) were pooled and analyzed using both time-domain averaging and single-trial time-frequency domain approaches. Higher airflow rate significantly increased intensity ratings (F = 10.98, P < 0.01), and improved the signal-to-noise-ratio (F = 5.42, P = 0.025). Results from time-frequency analysis showed higher concentration versus lower concentration increased brain oscillations in the slow frequency band (1-3 Hz) at 0-600 ms; while higher airflow rates versus lower airflow rate increased theta-band oscillations (300-600 ms and 5-9 Hz) and decreased delta-band oscillations at 900-1500 ms after stimulus onset. In conclusion, compared to stimulus concentration, airflow rate was associated with improved OERP quality and more pronounced responses. The results suggest that intensity ratings and OERP are strongly related to the steepness of stimulus onset. High airflow rates are suggested for odor delivery in order to record OERP.

Olfactory and Trigeminal Systems Interact in the Periphery.

The olfactory and trigeminal systems are intimately connected as most odorants stimulate both sensory systems. They interact by mutually suppressing and enhancing each other. However, the location and the degree of their interaction remain unclear. One method to test sensitivity in the trigeminal system is the odor localization task: when an odorant is presented to one nostril, we are able to localize the stimulated nostril only if the odorant stimulates the trigeminal nerve. Our objective was to evaluate the interaction between olfactory and trigeminal system by measuring the effect of an olfactory co-stimulation on the ability to localize a trigeminal stimulus. More specifically, we evaluated the influence of an olfactory co-stimulation with pure odors (phenyl ethanol, vanillin), presented either ipsilaterally or contralaterally, on the localization of predominantly trigeminal stimuli (mustard oil, eucalyptol). The ipsilateral, but not the contralateral, olfactory co-stimulation with a pure odorant increased the capacity to localize a trigeminal stimulus. These results suggest an interaction between the olfactory and trigeminal systems at peripheral, that is, mucosal, levels.

A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects.

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p < 0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.

Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells.

Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases. N-myc downstream regulated gene 1 (NDRG1) is demonstrated as a tumor suppressor gene in several cancers. Our result showed that CAPE treatment could repress NPC cell growth, through induction of S phase cell cycle arrest, and invasion. CAPE treatment stimulated NDRG1 expression in NPC cells. NDRG1 knockdown increased NPC cell proliferation and invasion and rendered NPC cells less responsive to CAPE growth-inhibiting effect, indicating CAPE repressed NPC cell growth partly through NDRG1indcution. CAPE treatment increased phosphorylation of ERK, JNK, and p38 in a dose- and time-dependent manner. Pre-treatments by inhibitors of ERK (PD0325901), JNK (SP600125), or p38 (SB201290), respectively, all could partly inhibit the CAPE effect on NDRG1 induction in NPC cells. Further, STAT3 activity was also repressed by CAPE in NPC cells. In summary, CAPE attenuates NPC cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CAPE could be a promising agent against NPC.

Gender differences in plasma and urine metabolites from Sprague-Dawley rats after oral administration of normal and high doses of hydroxytyrosol, hydroxytyrosol acetate, and DOPAC.

PURPOSE: To date, several in vitro and in vivo studies have shown phenolic compounds occurring naturally in olives and olive oil to be beneficial to human health due to their interaction with intracellular signaling pathways. However, the bioavailability of the most important of these compounds, hydroxytyrosol (HT), and its transformation into derivatives within the organism after oral intake are still not completely understood, requiring further in vivo research. This study deals with the differential bioavailability and metabolism of oral HT and its derivatives in rats. METHODS: Hydroxytyrosol (HT), hydroxytyrosol acetate (HTA), and 2,3-dihydroxyphenylacetic acid (DOPAC) were administered at doses of 1 and 5 mg/kg to Sprague-Dawley rats (n = 9 per treatment) by oral gavage. Their plasma kinetics and absorption ratio, assessed as their excretion in 24-h urine, were determined by UHPLC/MS/MS. RESULTS: Plasma and urine levels indicated that although the three compounds are efficiently absorbed in the gastrointestinal tract and show similar metabolism, the bioavailability is strongly dependent on the derivative considered, dosage, and gender. Inter-conversion among them has been described also, suggesting an interaction with internal routes. Microbiota metabolites derived from these phenolics were also taken into account; thereby, homovanillic alcohol and tyrosol were identified and quantified in urine samples after enzymatic de-conjugation, concluding the metabolic profile of HT. CONCLUSIONS: Our results suggest that different dosages of HT, HTA, and DOPAC do not provide a linear, dose-dependent plasma concentration or excretion in urine, both of which can be affected by the saturation of first-phase metabolic processes and intestinal transporters.

Differential effects of the combination of tyrosol with chlorhexidine gluconate on oral biofilms.

OBJECTIVE: This study assessed the effect of tyrosol and chlorhexidine gluconate in combination against Candida albicans, Candida glabrata, and Streptococcus mutans in the planktonic state or forming biofilms in vitro. MATERIALS AND METHODS: Checkerboard assays were performed for determination of minimum inhibitory concentration. Biofilms were cultivated during 24 h on specimens of acrylic resin and hydroxyapatite and treated with the drugs alone or in combination twice a day for 1 min, during 3 days. The antibiofilm effect was determined by quantification of the metabolic activity and cultivable cells. The drug combination was also applied on C. albicans to investigate its action on the number of hyphae. Data were statistically examined by two-way ANOVA and Holm-Sidak test (P < 0.05). RESULTS: The effect of drug combination on planktonic cells was classified as antagonistic for C. albicans and indifferent for the other strains. Also, the drugs were ineffective against the tested biofilms. However, the drug combination showed a synergistic effect in reducing the number of hyphae by C. albicans. CONCLUSION: The combination of tyrosol with chlorhexidine gluconate was only effective in reducing the number of hyphae by C. albicans, a relevant virulence factor of this species.

Transdermal anti-inflammatory activity of bilayer film containing olive compound hydroxytyrosol: physical assessment, in vivo dermal safety and efficacy study in Freund's adjuvant-induced arthritic rat model.

Previous studies have shown that hydroxytyrosol (HT) can be a potential alternative therapeutic agent for the treatment of rheumatoid arthritis (RA). However, HT is extensively metabolized following oral administration, which leads to formulating HT in a topical vehicle to prolong drug action as well as to provide a localized effect. Hidrox-6 is a freeze-dried powder derived from fresh olives and contains a high amount of HT (∼3%) and other polyphenols. Alginate bilayer films containing 5% and 10% Hidrox-6 were formulated. The films were characterized with respect to their physical, morphology, rheological properties; drug content uniformity; and in vitro drug release. Acute dermal irritancy tests and a skin sensitization study were carried out in rats. An efficacy study of the bilayer films for RA was conducted using Freund's adjuvant-induced polyarthritis rats. Animal data showed that the bilayer film formulations did not cause skin irritancy. The efficacy in vivo results showed that the Hidrox-6 bilayer films lowered the arthritic scores, paw and ankle circumference, serum IL-6 level and cumulative histological scores compared with those measured for controls. The topical Hidrox-6 bilayer films improve synovitis and inflammatory symptoms in RA and can be a potential alternative to oral RA therapy.

Effect of superoxide dismutase supplementation on sperm DNA fragmentation.

BACKGROUND: antioxidants supplementation improves sperm quality, but few trials have analyzed the effects on sperm DNA fragmentation (SDF). This study compares the effectiveness of SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol in reducing SDF with other antioxidants without SOD, hydroxytyrosol, and carnosol. MATERIALS AND METHODS: men with high SDF at baseline were selected in our clinical database. The patients taken into account had a 2-month control. SDF was measured by Sperm Chromatin Dispersion test (SCD). Untreated men were used as a control group. The remaining subjects received some oral antioxidant supplements (12 different combinations of both hydrophilic and lipophilic antioxidants), with some of them receiving nutritional support with a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol. RESULTS: 118 men were selected for a retrospective study. Mean age 39.3 ± 5.4 years. Fifteen had no treatment, 55 were treated with a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol, and 48 took some antioxidant supplements for 2 months. Clinically, variations of at least 10% in baseline values of classic semen parameters and sperm DNA fragmentation were taken into consideration. Classic seminal parameters did not vary significantly in the three groups, with the exception of viability (p = 0.001). We assessed which of the active substances (no. 19) in different formulations were associated with variations in SDF. In the multivariable analysis of the 7 active substances that passed the univariable analysis, only the SOD molecule appeared to be linked to an improvement in SDF (< 0.0001). In detail, only one patient in the control group showed a spontaneous improvement in SDF (6%), compared to 16/48 (33%) of those taking various oral antioxidant supplements, and 31/55 (56%) of those taking a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol. CONCLUSIONS: SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol seems to provide a better chance of improving sperm DNA integrity than other classical antioxidant molecules.

Beneficial effects of tyrosol on altered glycoprotein components in streptozotocin-induced diabetic rats.

CONTEXT: Olive oil is the major source of tyrosol which is a natural phenolic antioxidant. Olive oil constitutes a major component of the Mediterranean diet that is linked to a reduced incidence of chronic diseases. OBJECTIVE: This study evaluates the effects of tyrosol on altered glycoprotein components in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Diabetes mellitus was induced in male Wistar rats by streptozotocin (40 mg/kg body weight). These rats were administered tyrosol (20 mg/kg body weight) and glibenclamide (600 µg/kg body weight) orally daily for 45 days. Plasma glucose, plasma insulin, glycoprotein components such as hexose, hexosamine, sialic acid and fucose in the plasma, liver and kidney, and histopathogy of tissues were analyzed. RESULTS: Diabetic rats revealed significant (p < 0.05) increase in the levels of glucose, hexose, hexosamine, sialic acid and fucose (277.17, 152.45, 100.43, 79.69 and 49.29 mg/dL) in the plasma; decrease in the levels of palsma insulin (6.12 µU/mL) and sialic acid (4.36 and 5.03 mg/g) in the liver and kidney; significant (p < 0.05) increase in hexose (49.33 and 46.82 mg/g), hexosamine (22.68 and 33.20 mg/g) and fucose (31.63 and 32.44 mg/g) in the liver and kidney. Further, periodic acid-Schiff staining of tissues revealed positive-stain accumulation in diabetic rats. Tyrosol treatment showed significant (p < 0.05) effects on all the biochemical parameters and histopathology studied in streptozotocin- nduced diabetic rats. Also, the in vitro study revealed the antioxidant effect of tyrosol. DISCUSSION AND CONCLUSIONS: Thus, tyrosol protects streptozotocin-induced diabetic rats from the altered glycoprotein components. Further, this study can be extrapolated to humans.

Tyrosol, an olive oil polyphenol, inhibits ER stress-induced apoptosis in pancreatic ß-cell through JNK signaling.

Dysfunction of pancreatic ß-cell is a major determinant for the development of type 2 diabetes. Because of the stimulated insulin secretion in metabolic syndrome, endoplasmic reticulum (ER) stress plays a central mediator for ß-cell failure. In this study, we investigated whether an antioxidant phenolic compound, tyrosol protects against ß-cell dysfunction associated with ER stress. To address this issue, we exposed pancreatic ß cells, NIT-1 to tunicamycin with tyrosol. We found tyrosol diminished tunicamycin-induced cell death in a dose-dependent manner. We also detected tyrosol decreased the expressions of apoptosis-related markers. Exposure to tunicamycin evoked UPR response and co-treatment of tyrosol led to reduction of ER stress. These effects of tyrosol were mediated by the phosphorylation of JNK. Moreover, we confirmed supplement of tyrosol ameliorated ß-cell loss induced by high fat feeding. Taken together, our study provides a molecular basis for signaling transduction of protective effect of tyrosol against ER stress-induced ß-cell death. Therefore, we suggest tyrosol could be a potential therapeutic candidate for amelioration of type 2 diabetes.

Could Caffeic Acid Phenethyl Ester Expand the Antitumor Effect of Tamoxifen in Breast Carcinoma?

Despite tamoxifen (TAM) is beneficial in treating a significant proportion of patients with breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis, with a plethora of important biological actions including anticancer activity. This study aimed to explore the cytotoxicity, the type of drugs interaction as well as the apoptotic and autophagic pathways of the combined treatment of TAM and CAPE in MCF-7 cells. Their antitumor activity and effect on survival of mice bearing Ehrlich tumor were also analyzed. The results showed synergistic cytotoxic effects, manifested by significant activation of apoptotic machinery, along with downregulation of protein levels of Bcl-2 and beclin-1, upon using the combination regimen. However, the ratio between microtubule-associated protein light chain 3-II and -I was not altered. Moreover, a decrease in vascular endothelial growth factor level was detected. Similarly, TAM + CAPE increased the life span of tumor-bearing animals and caused a marked regression in their tumor size and weight compared with those treated with either TAM or CAPE alone. In conclusion, CAPE relatively improved the anticancer activity of TAM in both in vitro and in vivo models via its apoptotic and angiostatic potentials.

Protective Effects of Intralipid and Caffeic Acid Phenethyl Ester (CAPE) on Hepatotoxicity and Pancreatic Injury Caused by Dichlorvos in Rats.

The present study was aimed to the investigate the protective effects of caffeic acid phenethyl ester (CAPE) and intralipid (IL) on hepatotoxicity and pancreatic injury caused by acute dichlorvos (D) intoxication in rats. Forty-eight Wistar rats were randomly divided into seven groups each containing seven rats except control groups. The groups included control, D, CAPE, IL, D + CAPE, D + IL, and D + CAPE + IL. Total antioxidant status and total oxidative stress levels were measured by automated colorimetric assay. Tissues were evaluated using hematoxylin and eosin (H&E) staining. Tissues were analyzed with hematoxylin and eosin by using standard protocols. Also, Bcl-2, Bax and caspase-3 were evaluated by immunohistochemical method in liver tissue. Total oxidant status in control, CAPE, and IL groups were significantly lower, and total antioxidant status in the D + CAPE, D + IL, and D + IL + CAPE groups were significantly higher compared to the D group. CAPE and IL treatment decreased the apoptotic and mitotic cell count in liver tissue. Parenchymal necrosis caused by dichlorvos is observed in pancreas tissues of rats. Mild congestion and edema formation occurred in pancreas tissues following D + CAPE and D + IL therapies. These results indicate that CAPE and IL have the potential to decrease oxidative stress and hepatic and pancreatic injuries caused by acute dichlorvos intoxication. These drugs can be considered as a new method for supportive and protective therapy against pesticide intoxication.