2-4-3--5--tetrahydroxystilbene and Disease-Models--Animal

Oleocanthal is a minor constituent of olive oil with strong anti-inflammatory activities. Since the pathogenesis of many chronic diseases involves inflammatory and oxidative components, oleocanthal is a promising agent to prevent these conditions. This review aimed to summarise the current beneficial health effects of oleocanthal and the molecular basis of its biological actions. The anti-inflammatory, antioxidative, antimicrobial, anticancer and neuroprotective activities of oleocanthal have been examined by previous studies. Of these, studies on the anticancer effects have been the most extensive. Oleocanthal was reported to suppress melanoma, breast, liver, and colon cancer cells. Neurological studies focused on the effects of oleocanthal against Alzheimer’s disease. Oleocanthal improved clearance of the amyloid beta protein from neurons and reduced the inflammation of astrocytes. Despite the positive results, validation of the biological effects of oleocanthal in animal disease models is limited and should be emphasized in the future. As a conclusion, oleocanthal may act together with other bioactive compounds in olive oil to achieve its therapeutic potential. The use of oleocanthal alone as a single therapeutic measure awaits validation from future studies.

Topics: Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Astrocytes; Cell Line, Tumor; Cyclopentane Monoterpenes; Disease Models, Animal; Humans; Inflammation; Neoplasms; Neurons; Neuroprotective Agents; Olive Oil; Phenols

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Mice; Mice, Transgenic; Phenotype

Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid

Topics: Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cyclopentane Monoterpenes; Dietary Supplements; Disease Models, Animal; Dosage Forms; Female; Mice; Mice, Transgenic; Olive Oil; Phenols; Plaque, Amyloid; Powders; Spectroscopy, Fourier Transform Infrared

Triple negative breast cancer (TNBC) heterogeneity and limited therapeutic options confer its phenotypic aggressiveness. The discovery of anti-TNBC natural products with valid molecular target(s) and defined pharmacodynamic profile would facilitate their therapeutic nutraceutical use by TNBC patients. The extra-virgin olive oil (EVOO) is a key Mediterranean diet ingredient.

Topics: Aldehydes; Animals; Cell Line, Tumor; Cyclopentane Monoterpenes; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Olive Oil; Phenols; Triple Negative Breast Neoplasms

Topics: Aging; Aldehydes; Alzheimer Disease; Animals; Brain; Cell Line; Cell Respiration; Cyclopentane Monoterpenes; Disease Models, Animal; Female; Glucosides; Humans; Mice; Mitochondria; Neurons; Neuroprotective Agents; Phenols; Pyrans

Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options. Dysregulation of the mesenchymal epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) initiates aggressive LC profile in a subset of patients. The Mediterranean extra-virgin olive oil (EVOO)-rich diet already documented to reduce multiple malignancies incidence. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid exclusively occurring in EVOO and showed documented anti-breast and other cancer activities via targeting c-MET. This study shows the novel ability of OC to suppress LC progression and metastasis through dual targeting of c-MET and COX-2. Western blot analysis and COX enzymatic assay showed significant reduction in the total and activated c-MET levels and inhibition of COX1/2 activity in the lung adenocarcinoma cells A549 and NCI-H322M, in vitro. In addition, OC treatment caused a dose-dependent inhibition of the HGF-induced LC cells migration. Daily oral treatment with 10 mg/kg OC for 8 weeks significantly suppressed the LC A549-Luc progression and prevented metastasis to brain and other organs in a nude mouse tail vein injection model. Further, microarray data of OC-treated lung tumors showed a distinct gene signature that confirmed the dual targeting of c-MET and COX2. Thus, the EVOO-based OC is an effective lead with translational potential for use as a prospective nutraceutical to control LC progression and metastasis.

Topics: Adenocarcinoma; Aldehydes; Animals; Brain Neoplasms; Cell Line, Tumor; Cyclooxygenase 2 Inhibitors; Cyclopentane Monoterpenes; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice, Nude; Olive Oil; Phenols; Phytotherapy; Proto-Oncogene Proteins c-met

Primary dysmenorrhea is a common occurrence in adolescent women and is a type of chronic inflammation. Dysmenorrhea is due to an increase in oxidative stress, which increases cyclooxygenase-2 (COX-2) expression, increases the concentration of prostaglandin F2α (PGF2α), and increases the calcium concentration in uterine smooth muscle, causing excessive uterine contractions and pain. The polyphenolic compound oleocanthal (OC) in extra virgin olive oil (EVOO) has been shown to have an anti-inflammatory and antioxidant effect. This study aimed to investigate the inhibitory effect of extra virgin olive oil and its active ingredient oleocanthal (OC) on prostaglandin-induced uterine hyper-contraction, its antioxidant ability, and related mechanisms. We used force-displacement transducers to calculate uterine contraction in an ex vivo study. To analyze the analgesic effect, in an in vivo study, we used an acetic acid/oxytocin-induced mice writhing model and determined uterus contraction-related signaling protein expression. The active compound OC inhibited calcium/PGF2α-induced uterine hyper-contraction. In the acetic acid and oxytocin-induced mice writhing model, the intervention of the EVOO acetonitrile layer extraction inhibited pain by inhibiting oxidative stress and the phosphorylation of the protein kinase C (PKC)/extracellular signal-regulated kinases (ERK)/ myosin light chain (MLC) signaling pathway. These findings supported the idea that EVOO and its active ingredient, OC, can effectively decrease oxidative stress and PGF2α-induced uterine hyper-contraction, representing a further treatment for dysmenorrhea.

Topics: Abdominal Pain; Aldehydes; Animals; Anti-Inflammatory Agents; Antioxidants; Calcium; Cyclooxygenase 2; Cyclopentane Monoterpenes; Dinoprost; Disease Models, Animal; Dysmenorrhea; Female; Mice; Olive Oil; Oxidative Stress; Oxytocin; Phenols; Prostaglandins; Signal Transduction; Uterine Contraction; Uterus

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple hallmarks including extracellular amyloid (Aβ) plaques, neurofibrillary tangles, dysfunctional blood-brain barrier (BBB), neuroinflammation, and impaired autophagy. Thus, novel strategies that target multiple disease pathways would be essential to prevent, halt, or treat the disease. A growing body of evidence including our studies supports a protective effect of oleocanthal (OC) and extra-virgin olive oil (EVOO) at early AD stages before the onset of pathology. In addition, we reported previously that OC and EVOO exhibited such effect by restoring the BBB function; however, the mechanism(s) by which OC and EVOO exert such an effect and whether this effect extends to a later stage of AD remain unknown. In this work, we sought first to test the effect of OC-rich EVOO consumption at an advanced stage of the disease in TgSwDI mice, an AD mouse model, starting at the age of 6 months for 3 months treatment, and then to elucidate the mechanism(s) by which OC-rich EVOO exerts the observed beneficial effect. Overall findings demonstrated that OC-rich EVOO restored the BBB function and reduced AD-associated pathology by reducing neuroinflammation through inhibition of NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome and inducing autophagy through activation of AMP-activated protein kinase (AMPK)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway. Thus, diet supplementation with OC-rich EVOO could provide beneficial effect to slow or halt the progression of AD.

Topics: Administration, Oral; Aldehydes; Alzheimer Disease; Animals; Autophagy; Blood-Brain Barrier; Brain; Cyclopentane Monoterpenes; Disease Models, Animal; Inflammasomes; Mice; Mice, Transgenic; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Olive Oil; Phenols

To evaluate the neuroprotective effects of deocanthal OC in a rat model of traumatic brain injury (TBI).. Twenty-six adult male, Wistar albino rats were used. The rats were divided into 4 groups. Group 1 was the sham group (n=5). Group 2 was the trauma group (n=5) where rats were treated with 10 mg/kg saline intraperitoneally (IP) twice a day. Groups 3 and 4, rats were treated with 10 (group 3, n=8) or 30 (group 4, n=8) mg/kg OC IP twice a day. For each group, brain samples were collected 72 hours after injury. Brain samples and blood were evaluated with histopathological and biochemical methods.. Histopathological evaluation revealed a significant difference between Group 2 and Group 4. Biochemical findings demonstrated that the oxidative stress index was highest in Group 2 and lowest in Group 4.. OC has a protective effect on neural cells after TBI. This effect is achieved by reducing oxidative stress and apoptosis.

Topics: Aldehydes; Animals; Apoptosis; Brain; Brain Injuries, Traumatic; Cyclopentane Monoterpenes; Disease Models, Animal; Male; Neuroprotective Agents; Olive Oil; Oxidative Stress; Phenols; Rats; Rats, Wistar

Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-β (Aβ) pathology and improving cognitive function in Alzheimer's disease (AD) mouse models. In addition, we recently reported the beneficial effect of oleocanthal, a phenolic compound in EVOO, against AD pathology. Currently, medications available to target AD pathology are limited. Donepezil is an acetylcholine esterase inhibitor approved for use for all AD stages. Donepezil has been reported to have limited Aβ-targeting mechanisms beside its acetylcholine esterase inhibition. The aim of this study was to investigate the consumption of EVOO rich with oleocanthal (hereafter EVOO) as a medical food on enhancing the effect of donepezil on attenuating Aβ load and related toxicity in 5xFAD mouse model of AD. Our results showed that EVOO consumption in combination with donepezil significantly reduced Aβ load and related pathological changes. Reduced Aβ load could be explained, at least in part, by enhancing Aβ clearance pathways including blood-brain barrier (BBB) clearance and enzymatic degradation, and shifting amyloid precursor protein processing toward the nonamyloidogenic pathway. Furthermore, EVOO combination with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Aβ pathology. In conclusion, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the noncholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Aβ-related pathology in AD patients.

Topics: Acetylcholine; Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antioxidants; ATP Binding Cassette Transporter 1; Blood-Brain Barrier; Brain; Cyclopentane Monoterpenes; Disease Models, Animal; Donepezil; Female; Male; Mice, Inbred Strains; Neuroprotective Agents; Olive Oil; Phenols; PPAR gamma

Fungi of the genus Penicillium produce unique and chemically diverse biologically active secondary metabolites, including indole alkaloids. The role of dysregulated hepatocyte growth factor (HGF) and its receptor, c-Met, in the development and progression of breast carcinoma is documented. The goal of this work is to explore the chemistry and bioactivity of the secondary metabolites of the endophytic Penicillium chrysogenum cultured from the leaf of the olive tree Olea europea, collected in its natural habitat in Egypt. This fungal extract showed good inhibitory activities against the proliferation and migration of several human breast cancer lines. The CH2Cl2 extract of P. chrysogenum mycelia was subjected to bioguided chromatographic separation to afford three known indole alkaloids; meleagrin (1), roquefortine C (2) and DHTD (3). Meleagrin inhibited the growth of the human breast cancer cell lines MDA-MB-231, MDA-468, BT-474, SK BR-3, MCF7 and MCF7-dox, while similar treatment doses were found to have no effect on the growth and viability of the non-tumorigenic human mammary epithelial cells MCF10A. Meleagrin also showed excellent ATP competitive c-Met inhibitory activity in Z-Lyte assay, which was further confirmed via molecular docking studies and Western blot analysis. In addition, meleagrin treatment caused a dose-dependent inhibition of HGF-induced cell migration, and invasion of breast cancer cell lines. Meleagrin treatment potently suppressed the invasive triple negative breast tumor cell growth in an orthotopic athymic nude mice model, promoting this unique natural product from hit to a lead rank. The indole alkaloid meleagrin is a novel lead c-Met inhibitory entity useful for the control of c-Met-dependent metastatic and invasive breast malignancies.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line; Cell Movement; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial Cells; Female; Humans; Indole Alkaloids; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Neoplasm Invasiveness; Olea; Ovomucin; Penicillium chrysogenum; Proto-Oncogene Proteins c-met; Structure-Activity Relationship

Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer's disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD.

Topics: Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Astrocytes; ATP Binding Cassette Transporter 1; Blood-Brain Barrier; Brain; Cyclopentane Monoterpenes; Disease Models, Animal; Male; Mice, Transgenic; Neuroprotective Agents; Phenols; Phosphorylation; PPAR gamma; tau Proteins

The Mediterranean diet rich in fruits, vegetables and olive oil has been related to a lower osteoporosis incidence and accordingly to a reduced fracture risk. These observations might be mediated by the active constituents of extra virgin olive oil, and especially polyphenols. In the context of exploring the features of olive oil active constituents on postmenopausal osteoporosis, an extra virgin olive oil total polyphenolic fraction (TPF) was isolated and its effect on the bone loss attenuation was investigated.. Female Lewis rats were ovariectomized and fed a diet enriched with a total phenolic extract of extra virgin olive oil in a concentration of 800 mg/kg diet.. Oleocanthal, one compound of the polyphenolic fraction, showed a higher relative estrogen receptor binding affinity to the ERα compared to the ERβ. While the TPF only slightly induced the uterine wet weight (490.7 ± 53.7 vs. 432.7 ± 23, p = 0.058), TPF regulated estrogen response genes in the uterus (progesterone receptor, antigen identified by monoclonal antibody Ki67, complement C3). Comparing the quantified bone parameters, the oral TPF substitution did not attenuate the ovariectomy-induced bone loss.. The administration of extra virgin olive oil polyphenols regulated uterine estrogen response marker genes in an E2-agonistic manner. The bone loss induced by estrogen ablation was not mitigated by treatment with the polyphenolic extract.

Topics: Aldehydes; Animals; Bone and Bones; Cyclopentane Monoterpenes; Disease Models, Animal; ERRalpha Estrogen-Related Receptor; Female; Humans; Olive Oil; Organ Size; Osteoporosis, Postmenopausal; Ovariectomy; Phenols; Plant Extracts; Plant Oils; Polyphenols; Rats; Rats, Inbred Lew; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; Uterus