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New insights on the interaction mechanism between tau protein and oleocanthal, an extra-virgin olive-oil bioactive component
Abstract
Oleocanthal (OLC) is a phenolic component of extra-virgin olive oil, recently supposed to be involved in the modulation of some human diseases, such as inflammation and Alzheimer. In particular, OLC has been shown to abrogate fibrillization of tau protein, one of the main causes of Alzheimer neurodegeneration. A recent interpretation of this mechanism has been attempted on the basis of OLC reactivity with the fibrillogenic tau hexapeptide VQIVYK and SDS-PAGE of OLC/tau incubation mixtures, suggesting that covalent modification events modulate tau fibrillization. In this paper we report a detailed mass spectrometric investigation of the OLC reactive profile with both tau protein fibrillogenic fragment K18 and propylamine in biomimetic conditions. We show that K18 is prone to be covalently modified by OLC through Schiff base formation between the ε-amino group of lysine residues and OLC aldehyde carbonyls. Moreover, as expected from its de-structured conformation, K18 shows a non-selective modification profile, reacting with several lysine residues to give cyclic pyridinium-like stable adducts. These data give new insights on the mechanism of inhibition of tau fibrillization mediated by OLC.
... Epidemiological and clinical studies compellingly documented the Mediterranean diet ability to reduce the incidence of breast and colon cancers and cardiovascular diseases, slow the decline of cognitive functions with aging, and slow the Alzheimer's disease progression. [40][41][42][43][44][45][46][47][48][49][50] Olive oil is a key ingredient of the Mediterranean diet, wherein ...
... it represents the main fat source. [41][42][43][44][45][46][47][48][49][50][51][52][53] The antiinflammatory activity of the phenolic secoiridoid S-(−)-oleocanthal (OC, Fig. 57.3) is well documented and proven to target in vitro and in vivo COX1-3,5-lipoxygenase, NO, iNOS, IL-6, and macrophage inflammatory protein 1-α (MIP-1α) expression and activation. [54][55][56][57][58][59] Thus OC proved to show NSAID-like activity comparable to ibuprofen. ...
... 38,61,65 Unlike other phenolic natural products, OC tends to spontaneously interact in vivo with lysine and other amino acids-containing protein forming highly stable Schiff's bases, rendering the prediction of its oral bioavailability highly challenging. 47 Based on its anticancer activities, (−)-oleocanthal was virtually screened for binding ability and mode against the crystal structures of several cell survival and motility controlling kinases including CDK1, CDK2, PKA, PKC, EGFR, GSK-3β, MEK1, JNK1, KIT, and c-MET using the SYBYL-X package program Surflex-Dock. 38 The dock ing results showed high binding scores for OC toward the c-MET's ATP binding site in multiple crystal structures, including the protein database (PDB) numbers 3I5N, 1R0P, and 2RFS (Fig. 57.2). 38 Oleocanthal showed hydrogen bond (HB) interactions between its phenolic hydroxyl group and both of the c-MET hinge region Pro1158 and Met1160 in PDB 3I5N (Fig. 57.2). 38 Additional HB interactions noted between the OC's C-1 aldehydic group with the activation loop Tyr1230 and Arg1086 (Fig. 57.2). ...
Breast cancer (BC) represents the second most cancer killer in the US after lung cancer. The Mediterranean extra-virgin olive oil (EVOO)-rich diet reduce the incidence of breast and colon cancers. S-(-)-Oleocanthal (OC) is a natural phenolic exclusively occurring in EVOO. HGF/MET pathway, a validated major OC molecular target, is involved in escaping the therapeutic effects of multiple targeted and chemotherapies and initiating aggressive and recurrent BC. The intake of OC in EVOO over human history and the lack of other safe therapeutic alternatives qualify this bioactive natural product for long-term translational use to synergize with targeted and chemotherapies and prevent c-MET-dependent breast cancer recurrence in patients and survivors. The use of OC as first-in-class anti-BC c-MET inhibitor has numerous advantages including cost-effectiveness with its sustained plant supply and a readily scalable preparation procedure and ease of its use as a nutraceutical without the need for FDA approval.
... Specifically, OC was able to cross-link and abrogate fibrillization of tau T40 and K18 construct protein via covalent modification in an in vitro assay [103]. The mass spectrometric investigation revealed that OC covalently modified tau K18 protein through Schiff base formation between the ε-amino groups of lysine residues and OC's aldehyde carbonyl moiety in 1:1 stoichiometry [104]. OC modified tau K18 protein in a temperature-and time-dependent manner [104]. ...
... The mass spectrometric investigation revealed that OC covalently modified tau K18 protein through Schiff base formation between the ε-amino groups of lysine residues and OC's aldehyde carbonyl moiety in 1:1 stoichiometry [104]. OC modified tau K18 protein in a temperature-and time-dependent manner [104]. The cross-linking of OC with lysine residues of tau K18 protein formed a stable cyclic pyridinium-like adduct after the rearrangement of the OC dialdehyde carbonyl moiety [104]. ...
... OC modified tau K18 protein in a temperature-and time-dependent manner [104]. The cross-linking of OC with lysine residues of tau K18 protein formed a stable cyclic pyridinium-like adduct after the rearrangement of the OC dialdehyde carbonyl moiety [104]. Despite the presence of the reactive dialdehyde moiety, OC exerted low or no binding reactivity towards nucleophilic amino acids, such as lysine and arginine [105]. ...
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.
... In Alzheimer's disease, tau aggregates into NFTs. In vitro, oleocanthal inhibits the polymerization of tau protein through a covalent mechanism [147,148]. This aspect was first investigated by Li et al. [147] that showed that oleocanthal forms an adduct with the lysine residue corresponding to K311 in tau protein, which is a critical site for tau fibrillization, via initial Schiff base formation and thereby inhibiting tau fibrillization. ...
... This study has some limitations as it was carried out using the fibrillogenic short hexapeptide PHF6 which cannot be representative of a complex protein system and it is not fully adequate to deduce the exact mechanism of action of oleocanthal. Monti et al. [148] demonstrated that oleocanthal is capable of altering the fibrillization of tau protein reacting with the lysine ε-amino groups of the tau fragment K18 in an unspecific fashion. Subsequently, the same authors investigated the recognition process and the reaction profile between oleocanthal and the wild-type tau protein demonstrating that oleocanthal interact with tau-441, inducing stable conformational modifications of the protein secondary structure and also interfering with tau aggregation [149]. ...
... Oleuropein Counteraction of LDL oxidations [85] Counteraction of oxidative stress at brain level [88,91] Induction of autophagy at micromolar concentration [100] Inhibition of autophagy at picomolar concentration [103,104] Reduction of cerebral infarct volume after cerebral ischemia/reperfusion injury in mice [115] Reduction of inflammatory biomarkers (TNF-α, IL-1α, iNOS, COX-2) after spinal cord injury (animal model) [122][123][124] interference with amyloid aggregation (in vitro) [32,138] Reduction of Aβ42 deposition and plaque deposit (animal models) [3,139] Counteraction of pE3-Aβ production [39,140] Reduction of oxidative stress and apoptosis induced by 6-OHDA (in vitro) [103,178] Oleocanthal Inhibition of COX activity [46] Anti-aggregation activities on tau protein (in vitro) [147][148][149] Enhancement of Aβ clearance from the brain (animal model) [38] Reduction of astrocytes activation and IL-1β levels in AD model [31,150] Hydroxytyrosol Inhibition of COX activity [84] Counteraction of oxidative stress at brain level [86,91] Counteraction of hypoxic brain damage (ex-vivo model) [111] Attenuates Aβ induced inflammation (animal model) [145] Beneficial effects on insulin resistance associated with AD [146] Protection against DA-or 6-OHDA-induce cell death (in vitro) [179] Inhibition of COMT activity, leading to increased intracellular DA levels (animal model) [156] Tyrosol Counteraction of hypoxic brain damage [111] Attenuation of mitochondrial dysfunction and ATP depletion induced by MPP+ (in vitro) [177] Counteraction of Cys-DA induced cytotoxicity (in vitro) [182] ...
Neurological disorders such as stroke, Alzheimer’s and Parkinson’s diseases are associated with high morbidity and mortality, and few or no effective options are available for their treatment. These disorders share common pathological characteristics like the induction of oxidative stress, abnormal protein aggregation, perturbed Ca2+ homeostasis, excitotoxicity, inflammation and apoptosis. A large body of evidence supports the beneficial effects of the Mediterranean diet in preventing neurodegeneration. As the Mediterranean diet is characterized by a high consumption of extra-virgin olive oil it has been hypothesized that olive oil, and in particular its phenols, could be responsible for the beneficial effect of the Mediterranean diet. This review provides an updated vision of the beneficial properties of olive oil and olive oil phenols in preventing/counteracting both acute and chronic neurodegenerative diseases.
... Findings from additional in vitro studies on OC have highlighted the significant role of OC in combating hallmarks of AD and related tauopathies [71,72]. Treatment with OC induced changes in the secondary structure of the tau-441 protein and disrupted its aggregation process [73], which suggests the potential of OC to reduce NFT formation. To clarify the mechanism, further investigation into the interaction between OC and the tau protein's fibrillogenic fragment K18 under biomimetic conditions showed that OC can covalently modify K18 by forming a Schiff base with lysine residues. ...
... To clarify the mechanism, further investigation into the interaction between OC and the tau protein's fibrillogenic fragment K18 under biomimetic conditions showed that OC can covalently modify K18 by forming a Schiff base with lysine residues. This modification inhibits the fibrillization of tau [73]. These findings were further confirmed by Li and colleagues (2009), who extended these findings by demonstrating that OC maintains tau protein in a naturally unfolded state, thereby inhibiting its fibrillization [72]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by several pathological hallmarks, including the deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier (BBB) dysfunction, increased oxidative stress, and neuroinflammation. Current treatment options include monoclonal antibody drugs, acetylcholinesterase, and n-methyl-d-aspartate (NMDA) antagonists. Although those treatments provide some improvements in patients’ quality of life, they fail to prevent or cure AD. Current research aims to identify novel targets and tools for AD prevention and modification. In this context, several studies showed the beneficial effect of the Mediterranean diet in the prevention and treatment of AD. One integral component of the Mediterranean diet is olive oil and extra-virgin olive oil (EVOO), which is high in phenolic compounds. EVOO and other olive-related phenolic compounds have been shown to reduce the risk of developing mild cognitive impairment (MCI) and AD. In this review, we discuss the mechanisms by which EVOO and phenolic compounds exert neuroprotective effects, including modulation of AD pathologies and promotion of cognitive health. Findings indicate that EVOO and its phenolic constituents influence key pathological processes of AD, such as Aβ aggregation, tau phosphorylation, and neuroinflammation, while also enhancing BBB integrity and reducing oxidative stress. The human studies cited reveal a consistent trend where the consumption of olive oil is associated with cognitive benefits and a decreased risk of AD and related dementias. In conclusion, EVOO and its phenolic compounds hold promising potential for the prevention and treatment of AD, representing a significant shift towards more effective strategies against this complex neurodegenerative disorder.
... By enhancing autophagy, OO could mitigate the effects of toxic vascular agents, favoring the prevention of late-onset AD [29]. Specifically, oleocanthal could reduce tau protein polymerization [138]. The interaction between oleocanthal and tau proteins induces a tau rearrangement that may explain the antifibrillogenic effect of oleocanthal [139]. ...
... Further, the phenolic components of EVOO (oleocanthal or oleuropein), with antioxidant and anti-inflammatory effects, could play a relevant role in neurodegenerative diseases such as AD [253][254][255]. Specifically, tauopathy was associated with astrocyte or microglia senescence [256,257] and oleocanthal-reduced tau protein polymerization [138]. In addition, the Aβ peptide was identified as a potent inducer of cellular senescence [258][259][260][261][262]. The intervention with oleocanthal in mice showed increased performance in the activity of blood-brain barrier transporter proteins in charge of eliminating Aβ peptides (P-glycoprotein and low-density lipoprotein receptor-related protein 1), with the percentage of degraded Aβ peptides being higher in the treated group. ...
The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologies that are associated with aging, in order to increase the quality of life of the aging population. In this review we analyze the influence of the Mediterranean diet on the molecular pathways and the microbiota associated with more favorable aging patterns, as well as its possible role as an anti-aging treatment.
... High-resolution methods include: (i) microscopy, 57,59,61,62,64,66,69,71,[73][74][75][80][81][82][83]85,86,[91][92][93][94] whereby electron microscopes provide high-resolution images of punctual protein structures. For tau protein, this technique provides structure information for aggregated states (notably fibrils); (ii) NMR spectroscopy 58,60,65,69,81,83,95 and solid-state NMR spectroscopy. 96 Globally, NMR spectroscopy is a reference method in structural biology for the elucidation of structures that do not need any crystal acquisition; (iii) electrophoresis 59,69,71,80,97 is a convenient and well-known technique for size and weightbased protein structure separation; and (iv) X-ray crystallography. ...
... Similar to kinetic studies, structural studies of small molecules, 61,62,65,66,69,71,[73][74][75]78,80,81,92,95 peptides, 58-60,82-85,93 antibodies, 90,91,98 or plant extracts 86 can provide evidence of their potential anti-aggregation effects (Fig. 2) on either truncated or full-length tau protein. ...
Tauopathies are neurodegenerative disorders associated with the accumulation of abnormal tubulin associated unit (tau) protein in the brain. Tau pathologies include a broad spectrum of diseases, with Alzheimer’s disease (AD) being the most common tauopathy. The pathophysiological mechanisms of AD are still only partially understood. As a consequence, attempts to establish therapeutic approaches have led to numerous clinical trial failures and, to date, no curative treatment is available for AD despite the considerable number of research programs. Therefore, over the past decade, the aggregation of the tau protein in AD has become a therapeutic target of interest. In this review, we gather in silico, in vitro, and in vivo methodologies that are relevant to assess compounds targeting tau aggregation, from early drug design to clinical trials.
... 16 In these in vitro studies, oleocanthal disrupted Aβ and tau aggregation by altering soluble Aβ 42 oligomerization state that was associated with significantly reduced synaptic loss, 26 and by locking tau into the unfolded form preventing its aggregation. 27,28 Aβ deposition in brain parenchyma, and in and around cerebral blood vessels play a central role in a series of response mechanisms that lead to compromises in BBB integrity and AD pathology. 29À32 However, the underlying mechanisms for Aβ accumulation are not well understood. ...
... 26,28 In these studies the authors mixed oleocanthal with the hexapeptide within the third repeat of tau, which is important for tau fibrillization, and demonstrated that oleocanthal through its aldehyde groups formed an adduct with the lysine residue via Schiff base reaction locking tau into its naturally unfolded form and thereby inhibiting tau fibrillization. 27,28 When tested in vivo in TgSwDI mouse model of CAA and AD fed with oleocanthal-rich EVOO for 3 months, oleocanthal significantly reduced total tau and tau phosphorylation at amino acid threonine position 231. While additional studies are necessary to explain the mechanism of such reduction in tau and its phosphorylated form in mice brains, enhanced autophagy and lysosomal degradation could contributed to this effect. ...
Studies from our laboratory and others reported that oleocanthal has a therapeutic potential against Alzheimer’s disease (AD) and related disorders, including cerebral amyloid angiopathy (CAA) and tauopathy. Oleocanthal is a naturally occurring phenolic secoiridoid isolated from extra-virgin olive oil (EVOO). Findings from in vitro and in vivo studies demonstrated that oleocanthal and oleocanthal-rich EVOO possess neuroprotective effects by targeting several pathological processes. Oleocanthal increased amyloid-β clearance by multiple pathways, improved blood–brain barrier function and integrity, and reduced neuroinflammation and oxidative stress, which collectively improved memory function in AD and CAA mouse models. In addition, oleocanthal-inhibited tau aggregation by locking tau into the unfolded form and reduced tau hyperphosphorylation. These findings suggest oleocanthal as a novel molecule that could provide neuroprotective effect and thus has the potential to prevent, hold progression, and/or treat AD and related disorders.
... On the other hand, OC exhibited nonspecific covalent interaction with isomer 441 of the tau protein (tau-441), inducing a conformational rearrangement that could explain the antifibrillogenic ability of OC and could also account for a downregulation of the abnormal hyperphosphorylation of tau proteins [66]. A detailed analysis of the reactive profile of OC towards the tau protein-specifically, to fragment K18 of the tau protein-has been performed under biologically relevant conditions, giving new insights into the mechanism of interaction at the molecular level, such as the dependency of the temperature reaction and time of contact between the OC and tau [67]. On the other hand, OC exhibited nonspecific covalent interaction with isomer 441 of the tau protein (tau-441), inducing a conformational rearrangement that could explain the antifibrillogenic ability of OC and could also account for a downregulation of the abnormal hyperphosphorylation of tau proteins [66]. ...
... On the other hand, OC exhibited nonspecific covalent interaction with isomer 441 of the tau protein (tau-441), inducing a conformational rearrangement that could explain the antifibrillogenic ability of OC and could also account for a downregulation of the abnormal hyperphosphorylation of tau proteins [66]. A detailed analysis of the reactive profile of OC towards the tau proteinspecifically, to fragment K18 of the tau protein-has been performed under biologically relevant conditions, giving new insights into the mechanism of interaction at the molecular level, such as the dependency of the temperature reaction and time of contact between the OC and tau [67]. ...
The broad number of health benefits which can be obtained from the long-term consumption of olive oil are attributed mainly to its phenolic fraction. Many olive oil phenolics have been studied deeply since their discovery due to their bioactivity properties, such as Hydroxytyrosol. Similarly, in the last decade, the special attention of researchers has been addressed to Oleocanthal (OC). This olive oil phenolic compound has recently emerged as a potential therapeutic agent against a variety of diseases, including cancer, inflammation, and neurodegenerative and cardiovascular diseases. Recently, different underlying mechanisms of OC against these diseases have been explored. This review summarizes the current literature on OC to date, and focuses on its promising bioactivities against different disease-targets.
... The formation of neurofibrillary tangles, has a main role in the neurological devastation of Alzheimer's disease (AD). Another protective property of EVOOLS, and more specifically oleocanthal, involves inhibition of the formation of neurofibrillary aggregates, through direct interaction with the fibrillogenic group [62] of the TAU microtubule associated proteins [63]. In particular, through circular dichroism and surface plasma resonance studies, it was observed that oleocanthal is able to induce a conformational rearrangement of TAU from random coil to alpha helix [62]. ...
... Another protective property of EVOOLS, and more specifically oleocanthal, involves inhibition of the formation of neurofibrillary aggregates, through direct interaction with the fibrillogenic group [62] of the TAU microtubule associated proteins [63]. In particular, through circular dichroism and surface plasma resonance studies, it was observed that oleocanthal is able to induce a conformational rearrangement of TAU from random coil to alpha helix [62]. ...
Different phenolic compounds are present in extra-virgin olive oil (EVOO), i.e. phenolic acids, phenolic alcohols, hydroxy-isochromans, flavonoids, lignans and secoiridoids. The biological effects of the more characterizing for EVOO, i.e. oleuropein, and some of its derivatives, have been extensively studied so far, so that their health beneficial properties, that go beyond merely antioxidant activities, are well recognized. In fact, a significant number of preclinical studies have clearly demonstrated the protective effects of such molecules on metabolic and cardiovascular disorders, and that their regular consumption counteracts cell aging and is associated with a decreased risk of Parkinson’s and Alzheimer’s diseases incidence.
Obviously the actual effect of EVOO on the consumers’ health directly depends on the quality and the quantity of phenolic compounds that are formed and retained in the oil during the extraction. In fact, several biochemical transformations occur to olive during oil extraction and deeply influence the fate of oleuropein derivatives in the final resulting oil, affecting oil’s beneficial properties. Such transformations depend on both chemical and enzymatic processes, that are influenced by the technological approaches used for oil production (crushing, malaxation, decanting). Importantly, olive enzymes have a precise location in the tissue, with important implications that have to be considered in the production: in fact, while the lipoxygenase are found all over the fruit, peroxidases and lipases are found in hazel and polyphenol oxidase are located almost exclusively in the pulp.
This review summarizes the knowledge on individual oil phenolic compounds on human health, taking into consideration the relationships between technological approaches and the biological aspects of olive tissues.
... Higher olive oil intake is also associated with low incidence of various types of cancer, indicating that olive oil may contain potent anti-cancer agents [19,20]. (-)-Oleocanthal, a phenolic compound in virgin olive oil (VOO), is thought to have anti-oxidative, anti-bacterial, and antiinflammatory activities [21][22][23][24][25]. It is also effective in ...
... (-)-Oleocanthal is a phenolic compound first discovered in VOO in the early 90's. Previous studies have reported that (-)-oleocanthal has anti-oxidation, anti-bacterial, and anti-inflammation effects and acts as a COX inhibitor [21][22][23][24][25]. (-)-Oleocanthal exerts anti-tumor effects by regulating key tumor-related signal pathways [29][30][31]. ...
We explored the anti-cancer capacity of (-)-oleocanthal in human hepatocellular carcinoma (HCC). (-)-Oleocanthal inhibited proliferation and cell cycle progression and induced apoptosis in HCC cells in vitro and suppressed tumor growth in an orthotopic HCC model. (-)-Oleocanthal also inhibited HCC cell migration and invasion in vitro and impeded HCC metastasis in an in vivo lung metastasis model. ( )-Oleocanthal acted by inhibiting epithelial-mesenchymal transition (EMT) through downregulation Twist, which is a direct target of STAT3. (-)-Oleocanthal also reduced STAT3 nuclear translocation and DNA binding activity, ultimately downregulating its downstream effectors, including the cell cycle protein Cyclin D1, the anti-apoptotic proteins Bcl-2 and survivin, and the invasion-related protein MMP 2. Overexpression of constitutively active STAT3 partly reversed the anti cancer effects of (-)-oleocanthal, which inhibited STAT3 activation by decreasing the activities of JAK1 and JAK2 and increasing the activity of SHP-1. These data suggest that (-)-oleocanthal may be a promising candidate for HCC treatment.
... Indeed, authors revealed that oleocanthal forms an adduct with the lysine residues through initial Schiff base formation and subsequently inhibits tau fibrillization [74], which is one of the main causes of neurodegeneration in Alzheimer's disease and related tauopathies [61]. Afterwards, Monti et al. [75] conducted a mass spectrometric investigation of the oleocanthal reactive profile with tau protein fibrillogenic fragment K18 and propylamine, documenting that K18 was prone to be covalently modified by oleocanthal via Schiff base formation between the oleocanthal aldehyde carbonyls and the ε-amino group of lysine residues. The same research group subsequently showed that oleocanthal interacts with tau-441 isoform, causing stable conformational changes in the protein secondary structure and counteracting tau aggregation [76]. ...
Dietary consumption of olive oil represents a key pillar of the Mediterranean diet, which has been shown to exert beneficial effects on human health, such as the prevention of chronic non-communicable diseases like cancers and neurodegenerative diseases, among others. These health benefits are partly mediated by the high-quality extra virgin olive oil (EVOO), which is produced mostly in Mediterranean countries and is directly made from olives, the fruit of the olive tree (Olea europaea L.). Preclinical evidence supports the existence of antioxidant and anti-inflammatory properties exerted by the polyphenol oleocanthal, which belongs to the EVOO minor polar compound subclass of secoiridoids (like oleuropein). This narrative review aims to describe the antioxidant and anti-inflammatory properties of oleocanthal, as well as the potential anticancer and neuroprotective actions of this polyphenol. Based on recent evidence, we also discuss the reasons underlying the need to include the concentrations of oleocanthal and other polyphenols in the EVOO’s nutrition facts label. Finally, we report our personal experience in the production of a certified organic EVOO with a “Protected Designation of Origin” (PDO), which was obtained from olives of three different cultivars (Rotondella, Frantoio, and Leccino) harvested in geographical areas located a short distance from one another (villages’ names: Gorga and Camella) within the Southern Italy “Cilento, Vallo di Diano and Alburni National Park” of the Campania Region (Province of Salerno, Italy).
... Decreases tau aggregation and tau filament formation (Campora et al., 2021;Paranjape et al., 2014) Prevents tau hyperphosphorylation (Tyagi et al., 2022) oleocanthal forms imines when it interacts with lysine residues of the hexapeptide VQIVYK to generate a covalent adduct via Schiff base production (Li et al., 2009;Monti et al., 2012;Monti et al., 2011). Oleocanthal suppresses the production of tau amyloid and prevents beta-sheet secondary structural alterations in tau in a concentration-dependent manner (Li et al., 2009). ...
Tau aggregation is a hallmark of several neurodegenerative disorders, such as Alzheimer's disease (AD), frontotemporal dementia, and progressive supranuclear palsy. Hyperphosphorylated tau is believed to contribute to the degeneration of neurons and the development of these complex diseases. Therefore, one potential treatment for these illnesses is to prevent or counteract tau aggregation. In recent years, interest has been increasing in developing nature-derived tau aggregation inhibitors as a potential treatment for neurodegenerative disorders. Researchers have become increasingly interested in natural compounds with multifunctional features, such as flavonoids, alkaloids, resveratrol, and curcumin, since these molecules can interact simultaneously with the various targets of AD. Recent studies have demonstrated that several natural compounds can inhibit tau aggregation and promote the disassembly of pre-formed tau aggregates. Nature-derived tau aggregation inhibitors hold promise as a potential treatment for neurodegenerative disorders. However, it is important to note that more research is needed to fully understand the mechanisms by which these compounds exert their effects and their safety and efficacy in preclinical and clinical studies. Nature-derived inhibitors of tau aggregation are a promising new direction in the research of neurodegenerative complexities. This review focuses on the natural products that have proven to be a rich supply for inhibitors in tau aggregation and their uses in neurodegenerative complexities, including AD.
... Specifically, tau protein which is a microtubule-associated protein that promotes microtubule assembly and stability is fibrillated and aggregated into neurofibrillary tangles in AD and related taupathies. OC abolished fibrillization of tau by locking tau into the naturally unfolded state [24,25]. ...
Proper dietary habits pave the way for a good and healthy life in order to maintain and prolong the quality of life. It is well known that quality of life in the elderly can be achieved by non-pharmacological approaches such as performing physical activity, cognitive training, or adhering to a Mediterranean Diet (MedDiet). The MedDiet is suggested as the prevalent dietary regimen and is strongly correlated with prevention of degenerative diseases and longevity. The most distinguished and beneficial ingredient of MedDiet is extra virgin olive oil (EVOO). Indeed, numerous epidemiological studies have proved that the consumption of olive oil was associated with better overall health. The foremost component of EVOO is polyphenolic compounds which are under investigation for its biological and pharma-nutritional properties. In this review we recorded several representative in vitro and in vivo studies performed in culture cell lines, in animal or clinical trials, indicating that the regular intake of EVOO is associated with enhanced neuroprotective, antioxidant, anti-inflammatory, anti-atherosclerotic, anti-cancer and anti-microbial properties. Furthermore, it is emerged the demand of more randomized controlled or longitudinal observational studies to be performed to confirm the efficacy of the beneficial health effect of EVOO.
... Extra virgin olive oil contains neuroprotective phenolic compounds, including oleocanthal and hydroxytyrosol, that have been shown to have anti-amyloid and anti-tau properties [103][104][105][106]. Such compounds may also impact pathways specifically impaired in ApoE4 carriers. ...
The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.
... Long-term intake of small oleocanthal quantities was proposed that may contribute partially for the preservation of low occurrence of heart diseases and AD, connected with MeDi [663,664]. Oleocanthal has recently earned the interest of the scientific community, after it has been demonstrated that it can disturb Aβ and tau aggregation in vitro [665] and enhance Aβ clearance from mice brains [666]. ...
... Oleocanthal (OC) is a phenolic compound found mostly in EVOO which is responsible for its bitter taste, having strong anti-inflammatory properties based on the inhibition of cyclooxygenase (COX) [12]. For this reason, OC is recognized as a natural non-steroidal anti-inflammatory agent [13][14][15][16]. ...
Extra virgin olive oil (EVOO) intake is associated with reduced cardiovascular risk, and its phenolic compound oleocanthal (OC) has anti-oxidant and anti-inflammatory properties. The cardiometabolic effects of EVOO with a high OC concentration have not been fully elucidated. We administered EVOO with a high OC concentration daily to 23 subjects with the metabolic syndrome (MetS) and hepatic steatosis (15 men and 8 women, age: 60 ± 11 years) for 2 months. Anthropometric data, metabolic parameters, hepatic steatosis (by fatty liver index, FLI), abdominal fat distribution (by ultrasound), and pro- and anti-inflammatory cytokines were assessed before and after the intervention. EVOO supplementation was associated with a reduction in body weight, waist circumference, body mass index (BMI), alanine transaminase and FLI, as well as interleukin (IL)-6, IL-17A, tumor necrosis factor-α and IL-1B, while IL-10 increased. Maximum subcutaneous fat thickness (SFT max) also increased, with a concomitant decrease in the ratio of visceral fat layer thickness/SFT max. Correlation analysis revealed positive associations between changes in body weight and BMI and those in SFT max, along with an inverse association between changes in IL-6 and those in SFT max. In conclusion, ingestion of EVOO with a high OC concentration had beneficial effects on metabolic parameters, inflammatory cytokines and abdominal fat distribution in MetS subjects with hepatic steatosis, a category of patients at high cardiometabolic risk.
... While most of the experimental studies have been focusing on the ability of EVOO to enhance Aβ clearance and reduce its deposition (Abuznait, Qosa, Busnena, El Sayed, & Kaddoumi, 2013;Qosa et al., 2015), only fewer research groups have been investigating the tau-modifying ability of EVOO. On this regard, studies reported that some natural phenolic derivatives from olives, as well as oleocanthal, can prevent tau fibrillization in vitro (Daccache et al., 2011;Monti, Margarucci, Tosco, Riccio, & Casapullo, 2011). More recently, we have shown that chronic administration of an EVOO-rich diet modulates positively several aspects of the AD-like pathology in a transgenic mouse model with plaques and tangles, the 3×Tg mice (Lauretti Iuliano, & Praticò, 2017;Lauretti, Li, Di Meco, & Praticò, 2017). ...
In recent years, increasing evidence has accumulated supporting the health benefits of extra virgin olive oil (EVOO). Previous studies showed that EVOO supplementation improves Alzheimer's disease (AD)‐like amyloidotic phenotype of transgenic mice. However, while much attention has been focused on EVOO‐mediated modulation of Aβ processing, its direct influence on tau metabolism in vivo and synaptic function is still poorly characterized. In this study, we investigated the effect of chronic supplementation of EVOO on the phenotype of a relevant mouse model of tauopathy, human transgenic tau mice (hTau). Starting at 6 months of age, hTau mice were fed chow diet supplemented with EVOO or vehicle for additional 6 months, and then the effect on their phenotype was assessed. At the end of the treatment, compared with control mice receiving EVOO displayed improved memory and cognition which was associated with increased basal synaptic activity and short‐term plasticity. This effect was accompanied by an upregulation of complexin 1, a key presynaptic protein. Moreover, EVOO treatment resulted in a significant reduction of tau oligomers and phosphorylated tau at specific epitopes. Our findings demonstrate that EVOO directly improves synaptic activity, short‐term plasticity, and memory while decreasing tau neuropathology in the hTau mice. These results strengthen the healthy benefits of EVOO and further support the therapeutic potential of this natural product not only for AD but also for primary tauopathies. Chronic administration of extra‐virgin olive oil increases synaptic activity and short‐term plasticity, improves memory, and reduces tau neuropathology.
... Due to the implication of oxidative stress and generation of reactive oxygen species in the aggregation of beta-amyloid peptide and tau protein, it is proposed that HT may offer a protective or therapeutic alternative against Alzheimer's disease [27] and other neurodegenerative diseases, such as Huntington's Disease [28], multiple scleroses [29], and Parkinson's Disease [30]. ...
Hydroxytyrosol and two other polyphenols of olive tree, hydroxytyrosol acetate and 3,4-dihydroxyphenylglycol, are known for a wide range of beneficial activities in human health and prevention from diseases. The inability to isolate high, pure amounts of these natural compounds and the difficult and laborious procedures for the synthesis of them led us to describe herein an efficient, easy, cheap, and scaling up synthetic procedure, from catechol, via microwave irradiation.
... Oleocanthal treatment in cultured mice brain endothelial cells and in the C57BL/6 wild-type mice model of Alzheimer disease [212,213] confirmed that oleocanthal enhances Ab clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDLreceptor-related protein-1 (LRP 1) across the BBB and decreases Ab toxicity in neural cells. Oleocanthal has positive effects against tP by inhibiting tau fibrillization [214][215][216]. Other effects mitigating microglia-mediated neuroinflammation have also been reported [217][218][219]. ...
Observational epidemiological studies provide valuable information regarding naturally occurring protective factors observed in populations with very low prevalences of vascular disease. Between 1935 and 1965, the Italian-American inhabitants of Roseto (Pennsylvania, USA) observed a traditional Italian diet and maintained half the mortality rates from myocardial infarction compared with neighboring cities. In the Seven Countries Study, during 40years (1960-2000) Crete maintained the lowest overall mortality rates and coronary heart disease fatalities, which was attributed to strict adherence to the Mediterranean diet. In the French Three-City Study, a ten-year follow-up (2000-2010) showed that higher consumption of olive oil was associated with lower risk of death, as well as protection from cognitive decline and stroke. A large number of population-based studies and intervention trials have demonstrated that the Mediterranean diet is associated with lower prevalence of vascular disease, obesity, arthritis, cancer, and age-associated cognitive decline. Many of these effects are the result of consumption of fruits, seeds, legumes and vegetables but olive oil is the chief dietary fat in Mediterranean countries and the main source of monounsaturated fatty acids, as well as an important source of beneficial polyphenols and other antioxidants. Considering the critical role of vascular factors in the pathogenesis of late-onset Alzheimer disease it seems appropriate to focus on disease modification through proven dietary therapy. The authors base their hypothesis on meta-analyses of epidemiological data, numerous experimental studies, and a comprehensive review of the mechanisms of action of extra-virgin olive oil and its components in the prevention of vascular disease. In addition, extra-virgin olive oil has had positive effects on experimental animal models of Alzheimer disease. We therefore propose that extra-virgin olive oil is a promising tool for mitigating the effects of adverse vascular factors and may be utilized for potential prevention of late-onset Alzheimer disease.
... The oleocanthal (OLC) is a phenolic component responsible for the bitter taste of extra virgin olive oil. It has a strong anti-inflammatory activity similar to that of ibuprofen; this property could also play an important role in the prevention of Alzheimer's disease [27,28]. In our samples, its contents varied between 10 and 81 mg/kg. ...
This study aimed at investigating the quality indices, phenolic and tocopherols compounds, antioxidant potential and antibacterial activity against six bacteria of oils extracted from fruits of tree oleasters (1, 2, 3) (Olea europaea L. var. Oleaster) and cultivated variety (var. Chemlal). Results show that oils from oleasters were richer in phenolic compounds and tocopherols than the oil of Chemlal variety. The antioxidant capacity of the samples followed the same order as the amount of antioxidant. The oil of the three oleasters had a better antibacterial activity, particularly against Gram-positive compared to the oil of Chemlal variety. The highest antibacterial activity was observed against methicilin-resistant Staphylococcus aureus, whereas Klebsiella pneumoniae had the highest resistance. Globally, this study showed that oleaster oils are interesting for their nutritional and protective effect against foodborne pathogens, and this opens the way to their valorisation. © 2018, Innovhub Stazione Sperimentale per le Industrie. All Rights Reserved.
... Oleocanthal is responsible for the bitter and pungent taste of extra virgin olive oil, and has anti-inflammatory properties similar to the nonsteroidal anti-inflammatory drug ibuprofen [24]. In vitro, it has been shown that oleocanthal is effective on the key mediators of AD pathogenesis, amyloid-β and hyper-phosphorylated tau proteins [25][26][27][28], which contribute significantly to neurodegeneration and memory loss [29]. Moreover, oleocanthal reduces astrocyte activation and interleukin-1β levels in vivo [21]. ...
Neurodegenerative diseases represent a heterogeneous group of disorders that share common features like abnormal protein aggregation, perturbed Ca2+ homeostasis, excitotoxicity, impairment of mitochondrial functions, apoptosis, inflammation, and oxidative stress. Despite recent advances in the research of biomarkers, early diagnosis, and pharmacotherapy, there are no treatments that can halt the progression of these age-associated neurodegenerative diseases. Numerous epidemiological studies indicate that long-term intake of a Mediterranean diet, characterized by a high consumption of extra virgin olive oil, correlates with better cognition in aged populations. Olive oil phenolic compounds have been demonstrated to have different biological activities like antioxidant, antithrombotic, and anti-inflammatory activities. Oleocanthal, a phenolic component of extra virgin olive oil, is getting more and more scientific attention due to its interesting biological activities. The aim of this research was to characterize the neuroprotective effects of oleocanthal against H2O2-induced oxidative stress in neuron-like SH-SY5Y cells. Moreover, protein expression profiling, combined with pathways analyses, was used to investigate the molecular events related to the protective effects. Oleocanthal was demonstrated to counteract oxidative stress, increasing cell viability, reducing reactive oxygen species (ROS) production, and increasing reduced glutathione (GSH) intracellular level. Proteomic analysis revealed that oleocanthal significantly modulates 19 proteins in the presence of H2O2. In particular, oleocanthal up-regulated proteins related to the proteasome, the chaperone heat shock protein 90, the glycolytic enzyme pyruvate kinase, and the antioxidant enzyme peroxiredoxin 1. Moreover, oleocanthal protection seems to be mediated by Akt activation. These data offer new insights into the molecular mechanisms behind oleocanthal protection against oxidative stress.
... Oleocanthal, another polyphenol present in olive oil, appears to increase Ab clearance from the mouse brain through the up regulation of two important Ab transporter proteins, LRP1 (Lipoprotein receptor-related protein 1) and p-glycoprotein, at the blood brain barrier (Abuznait et al. 2013). It also chemically alters the lysine residue K18 that is part of the fibrillogenic tau hexapeptide VQIVYK sequence via Schiff base formation (Monti et al. 2011) and interacts with tau-441, thereby stabilizing the protein secondary structure and preventing its aggregation (Monti et al. 2012). Interestingly, OLE also protects against aggregated Ab toxicity in transgenic mouse models of AD since its administration to the CL2600 strain of C. elegans constitutively expressing Ab 3-42 results in a significant reduction of plaque deposits and oligomer in the muscle apparatus, with a significant decrease in severity of paralysis and an increase in worm life span (Diomede et al. 2013). ...
Alzheimer's disease (AD) is characterized by a massive neuronal death causing memory loss, cognitive impairment and behavioral alteration that ultimately lead to dementia and death. AD is a multi-factorial pathology controlled by molecular events such as oxidative stress, protein aggregation, mitochondrial dysfunction and neuro inflammation. Nowadays, there is no efficient disease-modifying treatment for AD and epidemiological studies have suggested that diet and nutrition have a significant impact on the development of this disorder. Indeed, some nutrients can protect all kind of cells, including neurons. As prevention is better than cure, life style improvement, with a special emphasis on diet, should seriously be considered as an anti-AD track and intake of nutrients promoting neuronal health is the need of the hour. Diets rich in unsaturated fatty acids, polyphenols and vitamins have been shown to protect against AD, whereas saturated fatty acids-containing diets deprived of polyphenols promote the development of the disease. Thus, Mediterranean diets, mainly composed of fruits, vegetables and omega-3 fatty acids, stand as valuable, mild and preventive anti-AD agents. This review focuses on our current knowledge in the field and how one can fight this devastating neurodegenerative disorder through the simple proper modification of our life style.
... Long-term intake of small oleocanthal quantities was proposed that may contribute partially for the preservation of low occurrence of heart diseases and AD, connected with MeDi [663,664]. Oleocanthal has recently earned the interest of the scientific community, after it has been demonstrated that it can disturb Aβ and tau aggregation in vitro [665] and enhance Aβ clearance from mice brains [666]. ...
Neurodegenerative diseases (NDs) have a serious impact on global health with no effective treatments yet available. Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder, considered to be the most common cause of dementia. There is increasing evidence for the infectious/inflammatory etiology of AD. Although brain is assumed to be an immunologically isolated organ, many bacteria (Helicobacter pylori), viruses (Herpes simplex virus, influenza, CMV etc.), fungi, toxoplasma, are associated with AD. The presence of immune-related antigens around amyloid plaques, activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients, led to the concept of “neuro-inflammation”. Persistent or acute neuronal and peripheral inflammatory response to infectious agents is gradually gaining more attention, as a risk factor for someone to develop sporadic AD. The human microbiome (HM) has a pivotal role in nutrition, health and disease. About 100 trillion bacteria from up to 1000 bacterial species inhabit the gastrointestinal (GI) tract, contributing, at least in part, to what is known as the “human-biochemical” or “genetic-individuality” and resistance to disease. Several pathologies, including AD and inflammatory bowel disease, are associated with alterations in gut microbiome. Microbes of the gut microbiota or of extracorporeal origin possess the ability of producing functional amyloid proteins. These amyloids, via lymphatic and systemic transport to the Central Nervous System (CNS), seem to have an important role in the expression of neurologic and psychiatric disorders, such as schizophrenia, anxiety and AD. Cross-seeding of the neurodegenerative disorder proteins may be induced by these amyloids. Moreover, chronic inflammatory response to these immune-reactive proteins can also be an important risk factor for CNS well-being. Therapeutic/preventive options for halting CNS disorders’ onset, could include: (a) Anti-inflammatory, anti-amyloid drugs (β-sheet breakers and other inhibitors of amyloid fibrillization), monoclonal antibodies, nanoparticles, which target pathological components of AD, or other medical interventions to remove infectious agents or to ameliorate their biochemical influence on GI-CNS tract, (b) Prebiotics to enhance the growth of desired organisms and reduce oxidative stress - a cause that has been implicated with AD, (c) Probiotics to provide both the desired bacteria, which increase the competitive effects with pathogens, and essential metabolic products, and to modulate the host immune system to resist in infection (d) The consumption of natural products, and the dedication to the Mediterranean (MeDi) and Asian (AsDi) Diets, abundant in bioactive compounds, are capable to prevent AD or reduce danger of AD, and strengthen the host's ability to confront infections. The significance of diet diversity leading to the microbiota diversity is a new clinically important concept. Finally, and (e) preventive medical and/or other therapies to alter the amyloids produced by bacteria, to decrease their production or stimulate their removal. This chapter is addressed to, and urges the excellent cooperation between experts of neurology/psychiatry, microbiology, biochemistry, dietary and nutritional sciences, in order to confront AD.
... There are many studies that have demostrated the effects of phenolic compounds on neurodegenerative diseases. Olive oil phenols have neuro-protective effects against brain hypoxia-reoxigenation (González-Correa et al., 2007;, cerebral ischemia (Bu et al., 2007;Mohagheghi et al., 2010), brain damage after hypoxia-reoxygenation in diabetic rats (De La Cruz et al., 2010), Alzheimer's diseases (Monti et al., 2011;Parkinson and Keast, 2014), Huntington's disease (Tasset et al., 2011), Parkinson's disease (Jones, 2011), peripheral neuropathy (Ristagno et al., 2012), and spinal cord injury (Khalatbary and Ahmadvand, 2012;Impellizzeri et al., 2012). ...
... In primary hippocampal neuronal cultures low doses of OLC were able to interact with Alzheimer'sassociated A oligomers, altering their structure and reducing their synaptotoxicity [101]. OLC has also been shown to inhibit Tau fibrillization, a process responsible for the formation of paired helical filaments through the formation of different types of chemical bonds with Tau peptides [102,103]. Some reports have shown interactions between oleuropein and -amyloid: oleuropein interacts in solution with the 28-amino acid residue N-terminal fragment of the -amyloid peptide [104] and with the A (1-40) peptide [105], and oleuropein aglycone disrupts A aggregation and reduces early A oligomer toxicity in cell cultures [106]. ...
Human studies indicate that consumption of olive oil is associated with decreased mortality, reduced cardiovascular risk and improved cognitive function in the elderly. Many of these benefits are thought to be due to the phenolic content of olive oil. In support of this, intervention studies in humans indicate that olive oil phenols protect blood lipids from oxidation and improve blood parameters of inflammation, hemostasis and vascular function, all risk factors for cardiovascular disease. The aim of this review is to evaluate the experimental evidence that olive oil phenols are beneficial to the aging process. Animal studies suggest that olive oil phenols have preventive actions on age-related cognitive and motor dysfunction, an important cause of disability in the elderly. Supporting mechanistic in vitro studies indicate that olive oil phenols may inhibit inflammatory pathways and associated proteins, induce pathways related to cell protection and survival, and modulate pathways related to energy metabolism similar to anti-aging substances. Furthermore, they can interact with beta-amyloid peptide and Tau protein to inhibit the formation of protein aggregates, a hallmark of Alzheimer’s disease. However, caution should be expressed in interpreting these in vitro data are as they are based on experiments carried out mainly using un-physiological concentrations of native olive phenols rather than phenolic metabolites. In conclusion, while in vivo data for the beneficial effects of olive oil phenols in aging are growing, a mechanistic explanation for these effects requires much additional research on the effects of metabolites at relevant concentrations.
... Further evidence suggests that oleocanthal may be a potent pharmacological agent in the treatment of neurogenerative disease, as this compound exhibits neuroprotective properties, in addition to attenuating markers of inflammation implicated in Alzheimer's disease [50][51][52][53]. However, it must be considered that results from in vitro models may not extend to in vivo models of disease due to the inability of some compounds to cross the blood-brain barrier. ...
Virgin olive oil (VOO) is credited as being one of the many healthful components associated with the Mediterranean diet. Mediterranean populations experience reduced incidence of chronic inflammatory disease states and VOO is readily consumed as part of an everyday Mediterranean dietary pattern. VOO is rich in phenolic compounds and the health promoting benefits of these phenolics are now established. Recent studies have highlighted the biological properties of VOO phenolic compounds elucidating their anti-inflammatory activities. This paper will review current knowledge on the anti-inflammatory and nutrigenomic, chemoprotective and anti-atherosclerotic activities of VOO phenolics. In addition the concentration, metabolism and bioavailability of specific phenolic compounds will be discussed. The evidence presented in the review concludes that oleurepein, hydroxytyrosol and oleocanthal have potent pharmacological activities in vitro and in vivo; however, intervention studies with biologically relevant concentrations of these phenolic compounds are required.
... Olive oil is the main source of dietary fat in the Mediterranean diet, the consumers of which have a low incidence of cardiovascular disease, age related cognitive disease, and cancer (17,18). (-)-Oleocanthal (OC), a main ingredient contained in virgin olive oil (VOO), has been reported to possess various biological activities such as anti-oxidative, anti-bacterial and anti-inflammatory activities (19)(20)(21)(22)(23). In addition, OC exhibits potent antitumor abilities in many malignant tumors, including breast carcinoma, prostate carcinoma and multiple myeloma (24)(25)(26)(27). ...
Tumor angiogenesis, growth and metastasis are three closely related processes. We therefore explored the effects of (-)-oleocanthal (OC) on the three processes in melanoma and investigated underlying mechanisms. In vitro, OC suppressed proliferation, migration, invasion and induced apoptosis in melanoma cells. In addition, OC inhibited proliferation, migration, invasion and tube formation in human umbilical vascular endothelial cells. In vivo, it exhibited potent activity in suppressing tumor growth in a subcutaneous xenograft model. Furthermore, OC suppressed proliferation and angiogenesis as measured by immunohistochemical staining of Ki-67 and CD31. In addition, OC was found to inhibit metastasis of melanoma in a lung metastasis model. Mechanistically, OC significantly suppressed signal transducer and activator of transcription 3 (STAT3) phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. OC also downregulated STAT3 target genes, including Mcl-1, Bcl-xL, MMP-2, MMP-9, VEGF, which are involved in apoptosis, invasion and angiogenesis of melanoma. These results support further investigation of OC as a potential anti-melanoma drug.
... For example, it has been reported that OLE favors α-secretase cleavage of the amyloid precursor protein (APP) thus promoting the non-amyloidogenic pathway and skipping the production of the most aggregating peptides [42]. Oleocanthal also appears to enhance Aβ clearance from the mouse brain via upregulation of two major Aβ transport proteins, P-glycoprotein and LRP1, at the blood-brain barrier [13]; it also chemically modifies K18 in the fibrillogenic tau hexapeptide VQIVYK through Schiff base formation [43] and interacts with tau-441, inducing stable conformational modifications of the protein secondary structure thus interfering with its aggregation [15]. The latter data provide insights on the mechanism of oleocanthal-mediated inhibition of tau fibrillization. ...
Introduction: Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). Olive leaves and EVOO contain many phenolics effective against several aging and lifestyle-related diseases, including neurodegeneration, both in animal models and in humans. Recent research has shown that such protection stems from several effects, including (i.) the interference with the aggregation of peptides/proteins found in amyloid diseases, particularly in Alzheimer’s and Parkinson’s diseases; (ii.) the protection of cells and tissues against aging-associated functional derangement (ion/redox homeostasis, aberrant cell signaling, etc.); (iii.) the transcriptional modulation through epigenetic modifications.
Area covered: We used MEDLINE for literature reference; we also searched ClinicalTrials.gov to select clinical trials with olive oil and/or its polyphenols that suggested their potential particularly for what neuroprotective therapy is concerned.
Expert commentary: We focus the relation between diet components, particularly olive polyphenols, and protection against the occurrence of the most widespread neurodegenerative conditions associated with aging. The need of more clinical studies in humans to confirm the results obtained in animal and cell models to definitely support the utility of these molecules to combat or to delay the symptoms associated to aging-associated neurodegeneration is also stressed.
... This evidence is in line with the findings of Hamdi and Castellon (35) who demonstrated that oleuropein treatment disrupted the organization of actin filaments thus altering the shape of cancer cells and their ability to proliferate. These data are also in line with the findings of Monti et al (36), who evidenced an interaction between oleocanthal and tau (τ) protein, a protein involved in the stabilization of microtubules, thereby modulating the plasticity of the cytoskeleton. ...
Epidemiological data indicate that the daily consumption of extra‑virgin olive oil (EVOO), a common dietary habit of the Mediterranean area, lowers the incidence of certain types of cancer, in particular bladder neoplasm. The aim of the present study was to evaluate the antiproliferative activity of polyphenols extracted from EVOO on bladder cancer (BCa), and to clarify the biological mechanisms that trigger cell death. Furthermore, we also evaluated the ability of low doses of extra‑virgin olive oil extract (EVOOE) to modulate the in vitro activity of paclitaxel or mitomycin, two antineoplastic drugs used in the management of different types of cancer. Our results showed that EVOOE significantly inhibited the proliferation and clonogenic ability of T24 and 5637 BCa cells in a dose‑dependent manner. Furthermore, cell cycle analysis after EVOOE treatment showed a marked growth arrest prior to mitosis in the G2/M phase for both cell lines, with the subsequent induction of apoptosis only in the T24 cells. Notably, simultaneous treatment of mitomycin C and EVOOE reduced the drug cytotoxicity due to inhibition of ROS production. Conversely, the co‑treatment of T24 cells with paclitaxel and the polyphenol extract strongly increased the apoptotic cell death at each tested concentration compared to paclitaxel alone. Our results support the epidemiological evidence indicating that olive oil consumption exerts health benefits and may represent a starting point for the development of new anticancer strategies.
Oleocanthal, OC, 2‐(4‐Hydroxyphenyl)ethyl(3S,4E)‐4‐formyl‐3‐(2‐oxoethyl)hex‐4‐enoate, is a natural organic compound exclusively found in Olea europaea L. (Oleoaceae), such as extra virgin olive oil (EVOO). Chemically, it is considered a monophenolic secoiridoid, taking part of the validated antioxidants naturally occurring in some plant-based foods. In this review, the aim is to summarize the identity and characteristics of this molecule, where it can be obtained (isolation from the natural source or chemical synthesis), as well as the use as food component. Then, the bioavailability, safety and studies aiming to demonstrate the potential health benefits, including in vitro and in vivo animal and human studies were also discussed.
Over 55 million people globally are living with dementia and, by 2050, this number is projected to increase to 131 million. This poses immeasurable challenges for patients and their families and a significant threat to domestic and global economies. Given this public health crisis and disappointing results from disease-modifying trials, there has been a recent shift in focus toward primary and secondary prevention strategies. Approximately 40% of Alzheimer's disease (AD) cases, which is the most common form of dementia, may be prevented or at least delayed. Success of risk reduction studies through addressing modifiable risk factors, in addition to the failure of most drug trials, lends support for personalized multidomain interventions rather than a “one-size-fits-all” approach. Evolving evidence supports early intervention in at-risk patients using individualized interventions directed at modifiable risk factors. Comprehensive risk stratification can be informed by emerging principals of precision medicine, and include expanded clinical and family history, anthropometric measurements, blood biomarkers, neurocognitive evaluation, and genetic information. Risk stratification is key in differentiating subtypes of dementia and identifies targetable areas for intervention. This article reviews a clinical approach toward dementia risk stratification and evidence-based prevention strategies, with a primary focus on AD.
Background: Alzheimer's disease (AD) is the most common form of dementia in older people and is a progressive disease of the brain that
leads to shrinkage of the brain tissue and irreversible loss of neurons.
Results: The aim of this study was to evaluate the effects of olive oil on brain aging in rat and to verify whether these antioxidant and anti�inflammatory activities were involved. A rat was fed with extra-virgin olive oil (Coratina (C) and Koroneiki (K) olive oils (0.3 ml/kg of
body weight/ day). Behavioral tests were employed to assess object recognition test and Morris Water Maze apparatus in treated animals.
Parameters of oxidative status and inflammation were measured in different brain areas at the same time and evaluated for correlation with
behavioral changes. The present study was designed to evaluate the neuroprotective properties of olive oil in an aluminum chloride (AlCl3)-
induced model of AD in Wistar rats. Wistar rats were administered with dietary oils for 60 days before induction of Alzheimer's disease
(AD) using AlCl3. Spatial memory was assessed using Brain antioxidant parameters such as lactate dehydrogenase (LDH) activity
malondialdehyde MDA levels (lipid peroxidation product) and nitrite levels were determined. In addition, tau protein and amyloid precursor
protein (APP) - Amyloid (β1-42) expression mRNA expression and the levels of acetylcholinesterase in serum biochemical.
Conclusion: This work points out that natural extra-virgin olive oil can improve some age-related dysfunctions by differentially affecting
different brain areas. Such a modulation can be obtained with an olive oil intake that is normal in the Mediterranean area, provided that the
oil has a sufficiently high polyphenols content.
There is a wide variety of neurodegenerative diseases, among which frontotemporal dementia stands out. These are the second most frequent cause of dementia in the world and demand the search for an effective treatment. This disease is linked to the abnormal behavior of proteins, which group together to form insoluble aggregates. It has been shown that the tau protein and TDP-43 are the main proteins involved in these pathologies. This article details 11 compounds already used in different neuropathologies, which may serve as potential drugs against these proteins. The mechanism of how most of these molecules inhibited the tau and TDP-43 aggregation process was highlighted. Importantly is to mention that Curcumin, Proanthocyanidin B2, Oleocanthal, Oleuropein Aglycone, Thionine, Resveratrol had been reported as direct inhibitors of tau. While 4-aminoquinoline, Dimethoxycurcumin, and Auranofin directly inhibited TDP-43. Epigallocatechin-3- gallate and Methylene Blue were described as tau and TDP-43 inhibitors. In this review, it is proposed that future research could elucidate the detailed inhibition mechanisms of these compounds to obtain relevant data to advance in treatments search for these coexisting proteins in frontotemporal dementia.
Alzheimer’s disease (AD), a major form of dementia, has been reported to affect more than 50 million people worldwide. It is characterized by the presence of amyloid-β (Aβ) plaques and hyperphosphorylated Tau-associated neurofibrillary tangles in the brain. Apart from AD, microtubule (MT)-associated protein Tau is also involved in other neurodegenerative diseases called tauopathies, including Pick’s disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration. The recently unsuccessful phase III clinical trials related to Aβ-targeted therapeutic drugs indicated that alternative targets, such as Tau, should be studied to discover more effective and safer drugs. Recent drug discovery approaches to reduce AD-related Tau pathologies are primarily based on blocking Tau aggregation, inhibiting Tau phosphorylation, compensating impaired Tau function with MT-stabilizing agents, and targeting the degradation pathways in neuronal cells to degrade Tau protein aggregates. Owing to several limitations of the currently-available Tau-directed drugs, further studies are required to generate further effective and safer Tau-based disease-modifying drugs. Here, we review the studies that focused on medicinal plant-derived compounds capable of modulating the Tau protein, which is significantly elevated and hyperphosphorylated in AD and other tauopathies. We mainly considered the studies that focused on Tau protein as a therapeutic target. We reviewed several pertinent papers retrieved from PubMed and ScienceDirect using relevant keywords, with a primary focus on the Tau-targeting compounds from medicinal plants. These compounds include indolines, phenolics, flavonoids, coumarins, alkaloids, and iridoids, which have been scientifically proven to be Tau-targeting candidates for the treatment of AD.
Aim
To develop, characterise, and optimise SNEDDS formulation to enhance organoleptics, bioavailability, physical & oxidative-stability, and extend shelf-life of pure Ω-3-fatty acids oil for use in the food fortification industry as nutraceuticals.
Methods
SNEDDS formulations were prepared using a simple stirring technique and optimised based on in-vitro characterisation.
Results
The optimised SNEDDS formulation (F3) had a mean diameter of 52.9 ± 0.4 nm, PDI of 0.229 ± 0.02, zeta potential of −17.3 ± 0.1 mV, cloud temperature of 92 ± 0.2 °C, self-emulsification time of 50 ± 0.2 sec, and stable under accelerated stability conditions. Intestinal permeability study on rat ileum depicted absorption of 88.5 ± 0.2% DHA at 5 h for F3 formulation in comparison to 61.5 ± 0.2% for commercial counterpart. F3 formulation exhibited better therapeutics for melamine-induced cognitive dysfunction.
Conclusions
The developed Ω-3-loaded SNEDDS heralds the future for an efficacious, safer, and higher strength formulation intended as a better substitute for currently available formulations.
Older people are increasing in number worldwide and they are affected by neurodegenerative disorders. Tauopathies are neurodegenerative disorders that involve diseases such as progressive supranuclear palsy (PSP), frontotemporal dementia linked to chromosome 17 (FTD-17), corticobasal degeneration, and Alzheimer's disease (AD) among others. Other neurodegenerative disorders such as Parkinson's disease is characterized for inclusion denominated as Lewis bodies conformed by hyperphosphorylated alpha-synuclein protein (α-syn). However, there are some neurodegenerative disorders that overlap each other such as dementia with Lewy bodies (DLB), Lewy body variant of AD and Parkinson's disease with dementia (PDD). Moreover, there is an increase in the number of patients of PD with dementia and patients with AD with Lewy body's inclusions in post mortem samples. Thus, we find pertinent to discuss both covalent and noncovalent inhibitors targeting alpha-synuclein and tau.
Carrot (Daucus carota L.) is an important vegetable source of bioactive compounds having significant health-promoting properties beyond basic nutrition. Higher intakes of carotenoids are associated with an enhancement of the immune system, and decreased risk of various cancers and degenerative diseases. Further, the presence of phenolic compounds is responsible for the aroma and bitterness of carrots, as well as strong antioxidant potential. Carrot processing generates wastes in the form of peels and pomaces, which can create serious nutritional, economic, and environmental problems. Carrot waste contains high amounts of residual bioactives, with currently little commercial values. These phytochemicals could be profitably utilized for the fortification and development of functional foods, pharmaceuticals, and medicines. This review describes carrot waste as a source of natural bioactive compounds, with health-promoting properties and potential applications in the food and pharmaceutical industries.
Cancer is among the leading causes of mortality worldwide. Current cancer therapies are associated with serious side effects, which further damage patients' health. Therefore, the search for new anticancer agents with no toxic effects on normal and healthy cells is of great interest. Recently, we and other groups have demonstrated that oleocanthal (OLC), a phenolic compound from extra virgin olive oil, exhibits antitumor activity in various tumor models. However, the underlying mechanisms and intracellular targets of OLC remain to be completely elucidated. This review summarizes the current advancers concerning the anticancer activity of OLC, with particular emphasis on the molecular signaling pathways modulated by this compound in different tumor cell types. The major mechanisms of action of OLC include modulation of the apoptotic pathway, the HGF/c‐Met pathway, and the signal transducer and activator of transcription 3 signaling pathway, among others. Furthermore, OLC has synergistic effects with anticancer drugs in vitro. Also discussed are OLC bioavailability and its concentration in olive oil. Data summarized here will represent a database for more extensive studies aimed at providing information on molecular mechanisms against cancer induced by OLC.
The present study was designed to investigate the role of the canonical and noncanonical inflammasome, MAPKs and NRF-2/HO-1, signaling pathways involved in the antioxidant and anti-inflammatory activities of oleocanthal in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. Isolated cells were treated with oleocanthal in the presence or absence of LPS (5 μg mL-1) for 18 h. Oleocanthal showed a potent reduction of reactive oxygen species (ROS) (25 μM, 50. 612 ± 0.02; 50 μM, 53. 665 ± 0.09; 100 μM, 52. 839 ± 0.02), nitrites (25 μM, 0.631 ± 0.07; 50 μM, 0.652 ± 0.07; 100 μM, 0.711 ± 0.08), and pro-inflammatory cytokines levels when compared with LPS-DMSO-treated control cells. In terms of enzymes protein expression, oleocanthal was able to downregulate iNOS (25 μM, 0.173 ± 0.02; 50 μM, 0.149 ± 0.01; 100 μM, 0.150 ± 0.01; p < 0.001), COX-2 (25 μM, 0.482 ± 0.08; 50 μM, 0.469 ± 0.05; 100 μM, 0.418 ± 0.06; p < 0.001), and mPGES-1 (25 μM, 0.185 ± 0.11; 50 μM, 0.218 ± 0.13; 100 μM, 0.161 ± 0.15; p < 0.001) as well as p38 (25 μM, 0.366 ± 0.11; 50 μM, 0.403 ± 0.13; 100 μM, 0.362 ± 0.15; p < 0.001), JNK (25 μM, 0.443 ± 0.11; 50 μM, 0.514 ± 0.13; 100 μM, 0.372 ± 0.15; p < 0.001), and ERK (25 μM, 0.294 ± 0.01; 50 μM, 0.323 ± 0.01; 100 μM, 0.274 ± 0.01; p < 0.001) protein phosphorylation, which was accompanied by an upregulation of Nrf-2 (25 μM, 1.57 ± 0.01; 50 μM, 1.54 ± 0.01; 100 μM, 1.63 ± 0.05; p < 0.05) and HO-1(25 μM, 2.12 ± 0,03; 50 μM, 2.24 ± 0.01; 100 μM, 1.92 ± 0.05; p < 0.01) expression in comparison with LPS-DMSO cells. Moreover, oleocanthal inhibited canonical and noncanonical inflammasome signaling pathways. Thus, oleocanthal might be a promising natural agent for future treatment of immune-inflammatory diseases.
Extra virgin olive oil (EVOO) is the main source of fat in the Mediterranean diet. Phenolic compounds of EVOO, in particular, secoiridoids, are minor components that have generated special interest due to their positive effects on human health, supported by several clinical trials. This review summarizes the most recent findings on the pharmacological properties and action's mechanisms of secoiridoid oleocanthal focusing attention on inflammation, oxidative stress, cancer, neurodegenerative processes, and rheumatic diseases. Being of relevance to the clinical effects of EVOO intake, the bioavailability and biotransformation of EVOO polyphenols are addressed. Moreover, this review summarizes the factors that may influence the oleocanthal concentration in EVOO. With the growing incidence of age- and lifestyle-related diseases, the current data indicated that the administration of EVOO rich in secoiridoids may be helpful in the prevention or treatment of different pathologies with an inflammatory component. Although promising, the future raises several questions and challenges, that are discussed here. The real beneficial effects of olive oil phenols on human health need to be clarified in new well-designed clinical studies.
Background:
There is accumulating evidence that a polyphenol present in olive oil, oleuropein, has antioxidant, anti-inflammatory and anti-apoptotic effects. This study aimed at determining the anti-apoptotic effect of Oleuropein (Ole) on dexamethasone-induced apoptosis of mouse thymocytes.
Method:
Mice were randomly divided to four groups as follow: Dexamethasone (Dex)-treated group (20 mg/kg; single dose), Ole-treated group (20 mg/kg per day), Dex plus Ole-treated group, and vehicle group. Sections of thymus were taken 16 hours after dexamethasone injection and studied for histopathological and immunohistochemistry assessment.
Result:
Further characteristics of degeneration in thymocytes were observed in the Dex group compared with the Dex plus Ole group. Compared with the Dex group (10.94±3.35), positive staining for Bax in thymocytes decreased in Dex plus Ole group (2.64±1.26), but remained higher than the Ole (0.65±0.30) and vehicle (0.67±0.29) groups. Compared with the Dex group (2.94±0.42), positive staining for Bcl-2 in thymocytes increased in Dex plus Ole group (12.24±1.84) yet was lower than the Ole (14.94±1.54) and vehicle (18.93±3.54) groups.
Conclusion:
Our results suggest that dexamethasone-induced apoptosis is subsided by oleuropein.
We present a short synthesis of a suitably functionalized enantioselective dihydropyran core of Secoiridoids using N-heterocyclic carbene (NHC) catalyzed Coates-Claisen rearrangment mechanism. Key steps of the synthesis are (i) the highly enantioselective NHC catalyzed Coates-Claisen rearrangment for dihydropyran core (ii) the highly diastereoselective exocyclic trans alkene for the assembly of the target dihydropyran core structure of Oleuropein (iii) highly stereoselective assembly of monoterpene elenolide core structure
Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive-or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive-or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/μl) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARγ expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive-and fish-oil-rich diets exert neuroprotective effects.
Clinical Alzheimer’s disease (AD), for the purposes of this volume, includes mild cognitive impairment due to AD, mild AD, moderate AD, and severe AD. Likely implicated in these stages of AD, in addition to the pathogenic hallmarks already identified, are impaired synaptic function, tau hyperphosphorylation, tau aggregation, impaired tau clearance, aberrant neuroinflammation, and AD-related oxidative stress. This chapter reports that a simple combination of three polyphenolic compounds—curcumin (and two other curcuminoids), resveratrol, and epigallocatechin-gallate, an extract of green tea—possess an ability to favorably influence each of these pathogenic hallmarks of AD; that is, to upregulate alpha-secretase activity, downregulate beta-secretase and gamma-secretase activity, inhibit amyloid beta aggregation, protect against amyloid beta toxicity, enhance amyloid beta clearance, protect synaptic function, inhibit tau hyperphosphorylation, reduce tau aggregation, enhance tau clearance, reduce neuroinflammation, and reduce AD-related oxidative stress. These findings exemplify the range of pleiotropic capabilities of these polyphenolic compounds.
This chapter describes olives and olive oil composition and their functionality. Olive fruit and olive oil contain a variety of both lipophilic and non-lipophilic compounds with a specific effect on their quality and functional value. The olive oil constituents are primarily triacylglycerols (TAGs) (∼99%) and secondly free fatty acids (FAs), monoacylglycerols (MAGs), and diacylglycerols (DAGs). Triterpenoids are present in high concentrations in the epicarp of olive fruit, forming part of the waxes that cover them, and in other parts of olive fruit. Several studies have shown that triterpenoids seem to play a role in the prevention of cancer. It is clear that triterpenoids affect tumorigenesis and key factors for its development, such as angiogenesis. Aroma and flavor, which are distinctive features of olive oil compared to other edible oils, are generated by a number of volatile compounds present at extremely low concentrations.
Background: There is accumulating evidence that a polyphenol present in olive oil, oleuropein, has antioxidant, anti-inflammatory and anti-apoptotic effects. This study aimed at determining the anti-apoptotic effect of Oleuropein (Ole) on dexamethasone-induced apoptosis of mouse thymocytes.
Method: Mice were randomly divided to four groups as follow: Dexamethasone (Dex)-treated group (20 mg/kg; single dose), Ole-treated group (20 mg/kg per day), Dex plus Ole-treated group, and vehicle group. Sections of thymus were taken 16 hours after dexamethasone injection and studied for histopathological and immunohistochemistry assessment.
Result: Further characteristics of degeneration in thymocytes were observed in the Dex group compared with the Dex plus Ole group. Compared with the Dex group (10.94±3.35), positive staining for Bax in thymocytes decreased in Dex plus Ole group (2.64±1.26), but remained higher than the Ole (0.65±0.30) and vehicle (0.67±0.29) groups. Compared with the Dex group (2.94±0.42), positive staining for Bcl-2 in thymocytes increased in Dex plus Ole group (12.24±1.84) yet was lower than the Ole (14.94±1.54) and vehicle (18.93±3.54) groups.
Conclusion: Our results suggest that dexamethasone-induced apoptosis is subsided by oleuropein.
Extra-virgin olive oil (EVOO) is a major component of the traditional Mediterranean diet. EVOO and its phenolic constituents, including oleocanthal and oleuropein aglycone, have several health-promoting effects that protect against the development of Alzheimer's disease (AD). Findings from in vitro and in vivo studies performed by us and others have shown EVOO and its phenolic constituents to exert their positive effect via multiple mechanisms, including: reduce amyloid beta (Aβ) production, enhanced Aβ clearance, reduced Aβ aggregation, decreased tau hyperphosphorylation, and anti-inflammatory effects. In this chapter, we review the evidence for the neuroprotective effects of EVOO and its phenolic constituents, and discuss the mechanisms by which EVOO and its constituents provide such effects.
The two histopathological hallmarks that characterize Alz- heimers disease (AD) are the extracellular amyloid plaques that are formed by b-amyloid fragments of the amyloid precursor protein (APP), and intracellular neurofibrillary tangles and neuropil threads, which consist of the micro- tubule-associated protein tau forming paired helical filaments with highly ordered structures, as recently corroborated by X- ray microcrystallography.(1) In addition, tau deposits similar to those of AD occur in several "tauopathies".(2, 3) The normal function of tau is to stabilize the microtubule network for the transport of vesicles and organelles in nerve cells, which is necessary for the communication between cells and thus for brain activity. When tau aggregates, it is thought that the tracks for transport (microtubules) break down and the transport is interrupted.(4-6) Moreover, the relevance of tau for neurodegeneration induced by b amyloid has been demon- strated in a mouse model.(7, 8) It would therefore be highly desirable to find methods to keep tau in a functional state and prevent or reverse abnormal aggregation. The quest for cures for Alzheimers disease is very intense. Available therapies to date make use of cholinesterase inhibitors and NMDA receptor antagonists,(9, 10) and newer approaches focus, for
In vitro, olive phenols exert potent antioxidant and enzyme-modulating activities.
We comparatively evaluate, in mildly dyslipidemic patients, the vasoprotective potential of extra virgin olive oil.
22 patients were administered 40 mL/day of either extra-virgin, i. e. phenol rich, or refined, i. e. phenol poor, olive oils (EVOO or ROO, respectively, with nearly identical fatty acid composition), with a crossover design. Each treatment was carried out for seven weeks, with four weeks of washout in between. Plasma antioxidant capacity, serum thromboxane B2 (TXB2) formation, and urinary isoprostane excretion were evaluated as surrogate markers of cardioprotective potential and vascular function.
No effects on plasma lipid/lipoprotein profile were observed. Conversely, EVOO consumption was associated with favorable effects on circulating markers. Namely, decreased serum TXB2 production and increased plasma antioxidant capacity were observed when EVOO was administered in both treatment arms. Neither treatment had any significant effect on isoprostane excretion.
EVOO consumption by mildly dyslipidemic patients is associated with favorable changes in circulating markers of cardiovascular condition. Based on current knowledge, these effects may be associated with cardioprotection.
The abnormal aggregation of tau protein into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease.
Aggregation takes place in the cytoplasm and could therefore be cytotoxic for neurons. To find inhibitors of PHF aggregation
we screened a library of 200,000 compounds. The hits found in the PHF inhibition assay were also tested for their ability
to dissolve preformed PHFs. The results were obtained using a thioflavin S fluorescence assay for the detection and quantification
of tau aggregation in solution, a tryptophan fluorescence assay using tryptophan-containing mutants of tau, and confirmed
by a pelleting assay and electron microscopy of the products. Here we demonstrate the feasibility of the approach with several
compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit
PHF formation with IC50 values of 1–5 μm and to disassemble preformed PHFs at DC50 values of 2–4 μm. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere
with the stabilization of microtubules by tau. Tau-inducible neuroblastoma cells showed the formation of tau aggregates and
concomitant cytotoxicity, which could be prevented by inhibitors. Thus, small molecule inhibitors could provide a basis for
the development of tools for the treatment of tau pathology in AD and other tauopathies.
The aggregation of the microtubule-associated tau protein and formation of "neurofibrillary tangles" is one of the hallmarks of Alzheimer disease. The mechanisms underlying the structural transition of innocuous, natively unfolded tau to neurotoxic forms and the detailed mechanisms of binding to microtubules are largely unknown. Here we report the high-resolution characterization of the repeat domain of soluble tau using multidimensional NMR spectroscopy. NMR secondary chemical shifts detect residual beta-structure for 8-10 residues at the beginning of repeats R2-R4. These regions correspond to sequence motifs known to form the core of the cross-beta-structure of tau-paired helical filaments. Chemical shift perturbation studies show that polyanions, which promote paired helical filament aggregation, as well as microtubules interact with tau through positive charges near the ends of the repeats and through the beta-forming motifs at the beginning of repeats 2 and 3. The high degree of similarity between the binding of polyanions and microtubules supports the hypothesis that stable microtubules prevent paired helical filament formation by blocking the tau-polyanion interaction sites, which are crucial for paired helical filament formation.
Newly pressed extra-virgin olive oil contains oleocanthal--a compound whose pungency induces a strong stinging sensation in the throat, not unlike that caused by solutions of the non-steroidal anti-inflammatory drug ibuprofen. We show here that this similar perception seems to be an indicator of a shared pharmacological activity, with oleocanthal acting as a natural anti-inflammatory compound that has a potency and profile strikingly similar to that of ibuprofen. Although structurally dissimilar, both these molecules inhibit the same cyclooxygenase enzymes in the prostaglandin-biosynthesis pathway.
We generated several cell models of tauopathy in order to study the mechanisms of neurodegeneration in diseases involving abnormal changes of tau protein. N2a neuroblastoma cell lines were created that inducibly express different variants of the repeat domain of tau (tau(RD)) when exposed to doxycycline (Tet-On system). The following three constructs were chosen: (i) the repeat domain of tau that coincides with the core of Alzheimer paired helical filaments; (ii) the repeat domain with the deletion mutation DeltaK280 known from frontotemporal dementia and highly prone to spontaneous aggregation; and (iii) the repeat domain with DeltaK280 and two proline point mutations that inhibit aggregation. The comparison of wild-type, pro-aggregation, and anti-aggregation mutants shows the following. (a) Aggregation of tau(RD) is toxic to cells. (b) The degree of aggregation and toxicity depends on the propensity for beta-structure. (c) Soluble mutants of tau(RD) that cannot aggregate are not toxic. (d) Aggregation is preceded by fragmentation. (e) Fragmentation of tau(RD) in cells is initially due to a thrombin-like protease activity. (f) Phosphorylation of tau(RD) (at KXGS motifs) precedes aggregation but is not correlated with the degree of aggregation. (g) Aggregates of tau(RD) disappear when the expression is silenced, showing that aggregation is reversible. (h) Aggregation can be prevented by drugs and even pre-formed aggregates can be dissolved again by drugs. Thus, the cell models open up new insights into the relationship between the structure, expression, phosphorylation, aggregation, and toxicity of tau(RD) that can be used to test current hypotheses on tauopathy and to develop drugs that prevent the aggregation and degeneration of cells.
The goal of this study was to evaluate the effects of the phenolic content of virgin olive oil on endothelial reactivity.
Endothelial-dependent vasodilatation is impaired during the postprandial state, and oxidative stress could play a key role in its development.
Twenty-one hypercholesterolemic volunteers received two breakfasts, using a randomized sequential crossover design. Both arms received the same olive oil, but one had its phenolic acid content reduced from 400 to 80 ppm. Ischemic reactive hyperemia (IRH) was measured with a laser-Doppler procedure at baseline and 2 h and 4 h after oil intake. Postprandial plasma concentrations of lipid fractions, lipoperoxides (LPO), 8-epi prostaglandin-F(2alpha), and nitrates/nitrites (NO(x)) were obtained at baseline and after 2 h of the fat meal.
The intake of the polyphenol-rich breakfast was associated with an improvement in endothelial function, as well as a greater increase in concentrations of NO(x) (p < 0.001) and a lower increase in LPO (p < 0.005) and 8-epi prostaglandin-F2alpha (p < 0.001) than the ones induced by the low polyphenol fat meal. A positive correlation was found to exist between NO(x) and enhanced endothelial function at the second hour (r = 0.669; p < 0.01). Furthermore, a negative correlation was found between IRH and LPO (r = -0.203; p < 0.05) and 8-epi prostaglandin-F2alpha levels (r = -0.440; p < 0.05).
A meal containing high-phenolic virgin olive oil improves ischemic reactive hyperemia during the postprandial state. This phenomenon might be mediated via reduction in oxidative stress and the increase of nitric oxide metabolites.
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development.
Studies in human, animal and cellular systems suggest that phenols from virgin olive oil are capable of inhibiting several stages in carcinogenesis, including metastasis. The invasion cascade comprises cell attachment to extracellular matrix components or basement membrane, degradation of basement membrane by proteolytic enzymes and migration of cells through the modified matrix. In the present study, we investigated the effect of phenolics extracted from virgin olive oil (OVP) and its main constituents: hydroxytyrosol (3,4-dihydroxyphenylethanol), tyrosol (p-hydroxyphenylethanol), pinoresinol and caffeic acid. The effects of these phenolics were tested on the invasion of HT115 human colon carcinoma cells in a Matrigel invasion assay. OVP and its compounds showed different dose-related anti-invasive effects. At 25 microg/ml OVP and equivalent doses of individual compounds, significant anti-invasive effects were seen in the range of 45-55% of control. Importantly, OVP, but not the isolated phenolics, significantly reduced total cell number in the Matrigel invasion assay. There were no significant effects shown on cell viability, indicating the reduction of cell number in the Matrigel invasion assay was not due to cytotoxicity. There were also no significant effects on cell attachment to plastic substrate, indicating the importance of extracellular matrix in modulating the anti-invasive effects of OVP. In conclusion, the results from this study indicate that phenols from virgin olive oil have the ability to inhibit invasion of colon cancer cells and the effects may be mediated at different levels of the invasion cascade.
Breaking up the crowd: The pathological aggregation of tau protein correlates closely with the progression of Alzheimer's disease. Rhodanine-based inhibitors of tau aggregation (e.g. 1) have been identified, and it has been shown that tau aggregation in a cell model is reversible and can be inhibited by small molecules at nanomolar concentrations (see SEM images). (Chemical Equation Presented)
Phenolic compounds are important in relation to nutritional and sensory characteristics and the shelflife of virgin olive oil. Four new phenolic compounds have been separated by HPLC. The compounds are two (3,4-dihydroxyphenyl)ethanol derivatives and two (p-hydroxyphenyl)ethanol derivatives. This paper reports the NMR, IR, and UV characterization of three of these phenolic compounds. The compounds identified are an isomer of oleuropeine aglycon, the dialdehydic form of elenolic acid linked to (3,4-dihydroxyphenyl)ethanol, and the dialdehydic form of elenolic acid linked to (p-hydroxyphenyl)-ethanol.
Phenolic compounds have a fundamental importance in the nutritional and sensory characteristics of virgin olive oil. Problems regarding their qualitative and quantitative evaluation have not been completely solved; hence, in this paper the extractive and HPLC methods of analysis are examined and some modifications are presented. By means of these techniques, elenolic acid and four unknown compounds having phenolic behavior were separated from virgin olive oil. Four of them were correlated with total phenols evaluated by means of the Folin-Ciocalteu reagent, and two of them were correlated with olive oil autoxidation stability.
The traditional Mediterranean diet is thought to represent a healthy lifestyle; especially given the incidence of several cancers including colorectal cancer is lower in Mediterranean countries compared to Northern Europe. Olive oil, a central component of the Mediterranean diet, is believed to beneficially affect numerous biological processes. We used phenols extracted from virgin olive oil on a series of in vitro systems that model important stages of colon carcinogenesis. The effect the extract on DNA damage induced by hydrogen peroxide was measured in HT29 cells using single cell microgel-electrophoresis. A significant anti-genotoxic linear trend (p = 0.011) was observed when HT29 cells were pre-incubated with olive oil phenols (0, 5, 10, 25, 50, 75, 100 μg/ml) for 24 hr, then challenged with hydrogen peroxide. The olive oil phenols (50, 100 μg/ml) significantly (p = 0.004, p = 0.002) improved barrier function of CACO2 cells after 48 hr as measured by trans-epithelial resistance. Significant inhibition of HT115 invasion (p < 0.01) was observed at olive oil phenols concentrations of 25, 50, 75, 100 μg/ml using the matrigel invasion assay. No effect was observed on HT115 viability over the concentration range 0, 25, 50 75, 100 μg/ml after 24 hr, although 75 and 100 μg/ml olive oil phenols significantly inhibited HT115 cell attachment (p = 0.011, p = 0.006). Olive oil phenols had no significant effect on metastasis-related gene expression in HT115 cells. We have demonstrated that phenols extracted from virgin olive oil are capable of inhibiting several stages in colon carcinogenesis in vitro. © 2005 Wiley-Liss, Inc.
Hydroxytyrosol, the major representative phenolic compound of virgin olive oil, is a dietary component. Its possible protective effect on hydrogen peroxide (H(2)O(2))-induced oxidative alterations was investigated in human erythrocytes. Cells were pretreated with micromolar hydroxytyrosol concentrations and then exposed to H(2)O(2) over different time intervals. Subsequently, erythrocytes were analyzed for oxidative hemolysis and lipid peroxidation. Our data demonstrate that hydroxytyrosol prevents both oxidative alterations, therefore, providing protection against peroxide-induced cytotoxicity in erythrocytes. The effect of oxidative stress on erythrocyte membrane transport systems, as well as the protective role of hydroxytyrosol, also were investigated in conditions of nonhemolytic mild H(2)O(2) treatment. Under these experimental conditions, a marked decrease in the energy-dependent methionine and leucine transport is observable; this alteration is quantitatively prevented by hydroxytyrosol pretreatment. On the other hand, the energy-independent glucose transport is not affected by the oxidative treatment. The reported data give new experimental support to the hypothesis of a protective role played by nonvitamin antioxidant components of virgin olive oil on oxidative stress in human systems.
Tau isoforms constitute a family of microtubule-associated proteins that are mainly expressed in neurons of the central nervous system. They promote the assembly of tubulin monomers into microtubules and modulate their stability, thus playing a key structural role in the distal portion of axons. In Alzheimer's disease and related tauopathies, Tau aggregation into fibrillary tangles contributes to intraneuronal and glial lesions. We report herein the ability of three natural phenolic derivatives obtained from olives and derived food products to prevent such Tau fibrillization in vitro, namely hydroxytyrosol, oleuropein, and oleuropein aglycone. The latter was found to be more active than the reference Tau aggregation inhibitor methylene blue on both wild-type and P301L Tau proteins, inhibiting fibrillization at low micromolar concentrations. These findings might provide further experimental support for the beneficial nutritional properties of olives and olive oil as well as a chemical scaffold for the development of new drugs aiming at neurodegenerative tauopathies.
It now appears likely that soluble oligomers of amyloid-beta1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Abeta oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Abeta species, when assayed with both sequence- and conformation-specific Abeta antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Abeta-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.
Tau is a microtubule-associated protein that promotes microtubule assembly and stability. In Alzheimer's disease and related tauopathies, tau fibrillizes and aggregates into neurofibrillary tangles. Recently, oleocanthal isolated from extra virgin olive oil was found to display non-steroidal anti-inflammatory activity similar to ibuprofen. As our unpublished data indicates an inhibitory effect of oleocanthal on amyloid beta peptide fibrillization, we reasoned that it might inhibit tau fibrillization as well. Herein, we demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. Using PHF6 consisting of the amino acid residues VQIVYK, a hexapeptide within the third repeat of tau that is essential for fibrillization, we show that oleocanthal forms an adduct with the lysine via initial Schiff base formation. Structure and function studies demonstrate that the two aldehyde groups of oleocanthal are required for the inhibitory activity. These two aldehyde groups show certain specificity when titrated with free lysine and oleocanthal does not significantly affect the normal function of tau. These findings provide a potential scheme for the development of novel therapies for neurodegenerative tauopathies.
We report an analysis of the mechanism of human group IIA secretory phospholipase A(2) (sPLA(2)-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a gamma-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA(2)-IIA Lys67 residue, located near the enzyme-membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of sPLA(2)-IIA through several van der Waals/electrostatic complementarities. The two events cannot co-occur on a single PLA(2) molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA(2) supramolecular complexes. These insights could suggest new PLA(2)-inhibition-based therapeutic strategies.
My concern about diet as a public health problem began in the early 1950s in Naples, where we observed very low incidences of coronary heart disease associated with what we later came to call the "good Mediterranean diet." The heart of this diet is mainly vegetarian, and differs from American and northern European diets in that it is much lower in meat and dairy products and uses fruit for dessert. These observations led to our subsequent research in the Seven Countries Study, in which we demonstrated that saturated fat is the major dietary villain. Today, the healthy Mediterranean diet is changing and coronary heart disease is no longer confined to medical textbooks. Our challenge is to persuade children to tell their parents to eat as Mediterraneans do.
In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.
Mutagenic heterocyclic amines (HAs) are formed at low levels during cooking of meat and fish, and some of them are considered to be possible human carcinogens. The formation of HAs may be affected by the presence of synthetic or naturally occurring antioxidants. In the present study the effect of virgin olive oil (VOO) phenolic compounds, identified and quantified by LC-MS, on the formation of HAs in a model system was evaluated. An aqueous solution of creatinine, glucose, and glycine was heated in the presence of two samples of VOO differing only in the composition of phenolic compounds. The addition of VOO to the model system inhibited the formation of 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) by between 30 and 50% compared with the control. Fresh-made olive oil, which contained a high amount of dihydroxyphenylethanol derivatives, inhibited HA formation more than a 1-year-old oil did. The inhibition of HA formation was also verified using phenolic compounds extracted from VOO.
Olive oil is the principal source of fats in the Mediterranean diet, which has been associated with a lower incidence of coronary heart disease and certain cancers. Phenolic compounds, e.g., hydroxytyrosol and oleuropein, in extra-virgin olive oil are responsible for its peculiar pungent taste and for its high stability. Recent findings demonstrate that olive oil phenolics are powerful antioxidants, both in vitro and in vivo, and possess other potent biological activities that could partially account for the observed healthful effects of the Mediterranean diet.
A combined strategy to obtain a partial NMR assignment of the neuronal Tau protein is presented. Confronted with the extreme spectral degeneracy that the spectrum of this 441 amino acid long unstructured protein presents, we have introduced a graphical procedure based on residue type-specific product planes. Combining this strategy with the search for pairwise motifs, and combining the spectra of different Tau isoforms and even of peptides derived from the native sequence, we arrive at a partial assignment that is sufficient to map the interactions of Tau with its molecular partners. The obtained assignments equally confirm the absence of regular secondary structure in the isolated protein.
25-Acetyl-petrosaspongiolide M (PMAc) (1), a mild non-covalent PLA(2) inhibitor, unexpectedly recovers, after incubation with bvPLA(2), the ability to covalently modify the enzyme target. This study demonstrates the catalytic effect of bvPLA(2) in converting 1 in its deacetylated congener petrosaspongiolide M (PM) (2), a strong covalent PLA(2) inhibitor whose molecular mechanism of inhibition has already been clarified. Moreover, our findings outline the potential role of PMAc as anti-inflammatory pro-drug, by virtue of its ability of delivering the active PM agent at the site of inflammation, functioning as a suicide inhibitor.
A high-performance liquid chromatography (HPLC) method was developed to quantitatively analyze oleocanthal in extra virgin olive oils. Oleocanthal, a deacetoxy ligstroside aglycone, is known to be responsible for the back of the throat irritation of olive oils and to have probated antiinflamatory activity. Oleocanthal was isolated from small amounts of olive oil sample (1 g) by liquid-liquid extraction. Hexane-acetonitrile was found to be the best solvent system to extract oleocanthal from the oil matrix. The solvent extract was analyzed by reversed-phase HPLC with UV detection at 278 nm. Chromatogaphic separation of oleocanthal from other extracted compounds and of the two geometric isomers of oleocanthal was achieved by an elution gradient with acetonitrile and water. Both the external standard calibration curve and the internal standard calibration curve were established, and quantitation using both calibration curves gave essentially the same result. The reproducibility (RSD = 4.7%), recovery (> 95%), and limit of quantitation (< 1 microg/g) were also determined. Concentrations of oleacanthal in 10 selected throat-burning extra virgin olive oils were determined using the method (ranged from 22 to 190 microg/g) with external standard calibration.
The molecular basis of the inactivation of bee venom PLA2 by the marine natural product bolinaquinone (BLQ) was studied by several spectral techniques (CD, fluorescence, and NMR spectroscopy, mass spectrometry), biomimetic reactions, and molecular modeling. Our data suggest competitive inhibition based on a BLQ-PLA2 noncovalent molecular recognition. However, BLQ is also able to react selectively with Lys133 through conjugate addition followed by a beta elimination. The biological implications of both the covalent and noncovalent molecular events are discussed.
In 1906, Alzheimer described the clinical and neuropathological characteristics of the disease that was subsequently named after him. Although the paired helical filament was identified as the major component of the neurofibrillary pathology of Alzheimer's disease in 1963, its molecular composition was only uncovered in the 1980s. In 1988, work at the MRC Laboratory of Molecular Biology in Cambridge (UK) provided direct proof that tau protein is an integral component of the paired helical filament. The paper highlighted here [Goedert M., Wischik C.M., Crowther R.A., Walker J.E. and Klug A. (1988) Cloning and sequencing of a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85, 4051-4055] also reported the first sequerce of a human tau isoform and paved the way for the identification of the six brain tau isoforms that are expressed by alternative mRNA splicing from a single gene. By the early 1990s, it was clear that tau protein is the major component of the paired helical filament and that the latter is made of all six tau isoforms, each full-length and hyperphosphorylated.
Tau proteins are building blocks of the filaments that form neurofibrillary tangles of Alzheimer's disease (AD) and related neurodegenerative tauopathies. It was recently reported that two VQIXXK motifs in the microtubule (MT) binding region, named PHF6 and PHF6*, are responsible for tau fibrillization. However, the exact role each of these motifs plays in this process has not been analyzed in detail. Using a recombinant human tau fragment containing only the four MT-binding repeats (K18), we show that deletion of either PHF6 or PHF6* affected tau assembly but only PHF6 is essential for filament formation, suggesting a critical role of this motif. To determine the amino acid residues within PHF6 that are required for tau fibrillization, a series of deletion and mutation constructs targeting this motif were generated. Deletion of VQI in either PHF6 or PHF6* lessened but did not eliminate K18 fibrillization. However, removal of the single K311 residue from PHF6 completely abrogated the fibril formation of K18. K311D mutation of K18 inhibited tau filament formation, while K311A and K311R mutations had no effect. These data imply that charge change at position 311 is important in tau fibril formation. A similar requirement of nonnegative charge at this position for fibrillization was observed with the full-length human tau isoform (T40), and data from these studies indicate that the formation of fibrils by T40K311D and T40K311P mutants is repressed at the nucleation phase. These findings provide important insights into the mechanisms of tau fibrillization and suggest targets for AD drug discovery to ameliorate neurodegeneration mediated by filamentous tau pathologies.
A library of approximately 51,000 compounds was interrogated by high throughput screening (HTS) using a heparin-induced tau fibrillization assay. HTS was conducted with bacterially expressed recombinant tau fragment K18 and the reaction was monitored by thioflavine T fluorescence. Hits meeting criteria set for selection in HTS were further evaluated in a panel of assays designed (a) to confirm the initial results and (b) to identify possible false positives arising from non-specific mechanisms or assay-dependent artifacts. Two 2,3-di(furan-2-yl)-quinoxalines were confirmed as inhibitors of tau fibrillization with IC(50)s in the low micromolar range (l-3 microM). Among false positive hits, members of the pyrimidotriazines, benzofurans, porphyrins, and anthraquinone, inhibited tau fibrillization by generating peroxides via catalytic redox cycles due to the reducing agent dithiothreitol (DTT) in the assay. This study delineates focused strategies for HTS of tau fibrillization inhibitors that are relevant to drug discovery for Alzheimer's disease and related tauopathies.
Several marine terpenoids that contain at least one reactive aldehyde group, such as manoalide and its congeners, possess interesting anti-inflammatory activities that are mediated by the covalent inactivation of secretory phospholipase A(2) (sPLA(2)). Scalaradial, a 1,4-dialdehyde marine terpenoid that was isolated from the sponge Cacospongia mollior, is endowed with a relevant anti-inflammatory profile, both in vitro and in vivo, through selective sPLA(2) inhibition. Due to its peculiar dialdehyde structural feature, it has been proposed that scalaradial exerts its enzymatic inactivation by means of an irreversible covalent modification of its target. In the context of our on-going research on anti-PLA(2) natural products and their interaction at a molecular level, we studied scalaradial in an attempt to shed more light on the molecular mechanism of its PLA(2) inhibition. A detailed analysis of the reaction profile between scalaradial and bee venom PLA(2), a model sPLA(2) that shares a high structural homology with the human synovial enzyme, was performed by a combination of spectroscopic techniques, chemical reactions (selective modifications, biomimetic reactions), and classical protein chemistry (such as proteolytic digestion, HPLC and mass spectrometry), along with molecular modeling studies. Unexpectedly, our data clearly indicated the noncovalent forces to be the leading event in the PLA(2) inactivation process; thus, the covalent modification of the enzyme emerges as only a minor side event in the ligand-enzyme interaction. The overall picture might be useful in the design of SLD analogues as new potential anti-inflammatory compounds that target sPLA(2) enzymes.
Epidemiological studies demonstrate that the Mediterranean diet, in which olive oil is the major source of fat, reduces the risk of coronary heart disease and cancer. It has been proposed that the beneficial effects of olive oil not only depend on oleic acid, but are also associated with minor polar compounds (MPC). A positive correlation between inflammation and cardiovascular diseases has long been described, monocyte/macrophages and NF-kappaB playing a pivotal role. The aim of this work was to investigate the effects of an extra-virgin olive oil extract (MPC-OOE), particularly rich in MPC and prepared by some of us, on NF-kappaB translocation in monocytes and monocyte-derived macrophages (MDM) isolated from healthy volunteers. In a concentration-dependent manner, MPC-OOE inhibited p50 and p65 NF-kappaB translocation in both un-stimulated and phorbol-myristate acetate (PMA)-challenged cells, being particularly effective on the p50 subunit. Interestingly, this effect occurred at concentrations found in human plasma after nutritional ingestion of virgin olive oil and was quantitatively similar to the effect exerted by ciglitazone, a PPAR-gamma ligand. However, MPC-OOE did not affect PPAR-gamma expression in monocytes and MDM. These data provide further evidence of the beneficial effects of extra-virgin olive oil by indicating its ability to inhibit NF-kappaB activation in human monocyte/macrophages.