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The olive tree ( Olea europaea ) and olive oil hold significant cultural and historical importance in Europe. The health benefits associated with olive oil consumption have been well documented. This paper explores the mechanisms of the anti-cancer effects of olive oil and olive leaf, focusing on their key bioactive compounds, namely oleocanthal, oleacein, and oleuropein. The chemopreventive potential of oleocanthal, oleacein, and oleuropein is comprehensively examined through this systematic review. We conducted a systematic literature search to identify eligible articles from Scopus, PubMed, and Web of Science databases published up to 10 October 2023. Among 4037 identified articles, there were 88 eligible articles describing mechanisms of chemopreventive effects of oleocanthal, oleacein, and oleuropein. These compounds have the ability to inhibit cell proliferation, induce cell death (apoptosis, autophagy, and necrosis), inhibit angiogenesis, suppress tumor metastasis, and modulate cancer-associated signalling pathways. Additionally, oleocanthal and oleuropein were also reported to disrupt redox hemostasis. This review provides insights into the chemopreventive mechanisms of O. europaea -derived secoiridoids, shedding light on their role in chemoprevention. The bioactivities summarized in the paper support the epidemiological evidence demonstrating a negative correlation between olive oil consumption and cancer risk. Furthermore, the mapped and summarized secondary signalling pathways may provide information to elucidate new synergies with other chemopreventive agents to complement chemotherapies and develop novel nutrition-based anti-cancer approaches.

Sickle cell disease (SCD) is the most common genetic disorder, affecting millions of people worldwide. Aromatic aldehydes, which increase the oxygen affinity of human hemoglobin to prevent polymerization of sickle hemoglobin and inhibit red blood cell (RBC) sickling, have been the subject of keen interest for the development of effective treatment against SCD. However, the aldehyde functional group metabolic instability has severly hampered their development, except for voxelotor, which was approved in 2019 for SCD treatment. To improve the metabolic stability of aromatic aldehydes, we designed and synthesized novel molecules by incorporating Michael acceptor reactive centers into the previously clinically studied aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF). Eight such derivatives, referred to as MMA compounds were synthesized and studied for their functional and biological activities. Unlike 5-HMF, which forms Schiff-base interaction with αVal1 nitrogen of hemoglobin, the MMA compounds covalently interacted with βCys93, as evidenced by reverse-phase HPLC and disulfide exchange reaction, explaining their RBC sickling inhibitory activities, which at 2 mM and 5 mM, range from 0% to 21% and 9% to 64%, respectively. Additionally, the MMA compounds showed a second mechanism of sickling inhibition (12%-41% and 13%-62% at 2 mM and 5 mM, respectively) by directly destabilizing the sickle hemoglobin polymer. In vitro studies demonstrated sustained pharmacologic activities of the compounds compared to 5-HMF. These findings hold promise for advancing SCD therapeutics., (© 2023 John Wiley & Sons Ltd.)

Gabapentinoids are effective drugs in most animal models of pain and inflammation with variable effects in humans. The current study evaluated the pharmacological activity of gabapentin (GBP) and its salicylaldehyde derivative (gabapentsal; [2-(1-(((2-hydroxybenzylidene) amino) methyl) cyclohexyl) acetic acid]; GPS) in well-established mouse models of nociceptive pain, inflammatory edema, and pyrexia at doses of 25-100 mg/kg. GPS allayed tonic visceral pain as reflected by acetic acid-induced nociception and it also diminished thermally induced nociception as a mimic of phasic thermal pain. Antagonism of GPS-induced antinociceptive activities by naloxone (NLX, 1.0 mg/kg, subcutaneously, s.c), beta-funaltrexamine (β-FNT, 5.0 mg/kg, s.c), naltrindole (NT, 1.0 mg/kg, s.c), and nor-binaltorphimine (NOR-BNI, 5.0 mg/kg, s.c), and pentylenetetrazole (PTZ-15 mg/kg, intraperitoneally, i.p) implicated an involvement of both opioidergic and GABAergic mechanisms. Tail immersion test was conducted in order to delineate the mechanistic insights of antinociceptive response. Inflammatory edema induced by carrageenan, histamine, or serotonin was also effectively reversed by GPS in a fashion analogous to aspirin (150 mg/kg, i.p), chlorpheniramine (1.0 mg/kg, i.p), and mianserin (1.0 mg/kg, i.p), respectively. Additionally, yeast-induced pyrexia was decreased by GPS in a comparable manner to acetaminophen (50 mg/kg, i.p). These observations suggest that GPS possesses ameliorative properties in tonic, phasic, and tail immersion tests of nociception via opioidergic and GABAergic mechanisms, curbs inflammatory edema, and is antipyretic in nature., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To assess the post-acute activity and clinical utility of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, versus vehicle in patients with seasonal allergic conjunctivitis., Design: Parallel-group, double-masked, randomized Phase 3 trial., Methods: Two topical ocular reproxalap concentrations (0.25% and 0.5%) were evaluated versus vehicle in patients with allergic conjunctivitis randomized 1:1:1 and treated with test article 10 minutes prior to conjunctival seasonal allergen challenge. The primary endpoint was area under the post-acute ocular itching score (range = 0-4) curve from 10 to 60 minutes after challenge. The key secondary endpoint was the proportion of subjects with ≥2 points improvement from their peak ocular itching score at baseline., Results: A total of 318 patients were randomized at 11 US sites. Both concentrations of reproxalap (0.25% and 0.5%) achieved the primary endpoint (P < .0001 and P = .003, respectively) and the key secondary endpoint (P = .0005 and P = .02, respectively). Time to complete resolution of ocular itching was statistically faster for both reproxalap concentrations than for vehicle (P < .0001 and P = .001, respectively). No safety or tolerability concerns were noted. The most common adverse event was mild and transient instillation site irritation., Conclusion: Reproxalap was effective at reducing ocular itching in patients with allergic conjunctivitis. Reproxalap activity was clinically relevant, as assessed by responder-based and distributional analyses. ALLEVIATE represents one of the first allergic conjunctivitis Phase 3 trials of a novel mechanism of action in decades, and is unique among conjunctival allergen challenge trials in assessing clinical relevance with standard and validated techniques., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed., Competing Interests: All authors declare they have no conflicts of interest.

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., (© 2020 John Wiley & Sons, Ltd.)

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

Friedreich's ataxia (FA) is due to deficiency of the mitochondrial protein, frataxin, which results in multiple pathologies including a deadly, hypertrophic cardiomyopathy. Frataxin loss leads to deleterious accumulations of redox-active, mitochondrial iron, and suppressed mitochondrial bioenergetics. Hence, there is an urgent need to develop innovative pharmaceuticals. Herein, the activity of the novel compound, 6-methoxy-2-salicylaldehyde nicotinoyl hydrazone (SNH6), was assessed in vivo using the well-characterized muscle creatine kinase (MCK) conditional frataxin knockout (KO) mouse model of FA. The design of SNH6 incorporated a dual-mechanism mediating: (1) NAD + -supplementation to restore cardiac bioenergetics; and (2) iron chelation to remove toxic mitochondrial iron. In these studies, MCK wild-type (WT) and KO mice were treated for 4-weeks from the asymptomatic age of 4.5-weeks to 8.5-weeks of age, where the mouse displays an overt cardiomyopathy. SNH6-treatment significantly elevated NAD + and markedly increased NAD + consumption in WT and KO hearts. In SNH6-treated KO mice, nuclear Sirt1 activity was also significantly increased together with the NAD + -metabolic product, nicotinamide (NAM). Therefore, NAD + -supplementation by SNH6 aided mitochondrial function and cardiac bioenergetics. SNH6 also chelated iron in cultured cardiac cells and also removed iron-loading in vivo from the MCK KO heart. Despite its dual beneficial properties of supplementing NAD + and chelating iron, SNH6 did not mitigate cardiomyopathy development in the MCK KO mouse. Collectively, SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD + and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

3,4-Dihydroxyphenylacetaldehyde (DOPAL), the monoamine oxidase (MAO) metabolite of dopamine, plays a role in pathogenesis of Parkinson disease, inducing α-synuclein aggregation. DOPAL generates discrete α-synuclein aggregates. Inhibiting this aggregation could provide therapy for slowing Parkinson disease progression. Primary and secondary amines form adducts with aldehydes. Rasagiline and aminoindan contain these amine groups. DOPAL-induced α-synuclein aggregates were resolved in the presence and absence of rasagiline or aminoindan using quantitative Western blotting. DOPAL levels in incubation mixtures, containing increased rasagiline or aminoindan concentrations, were determined by high pressure liquid chromatography (HPLC). Schiff base adducts between DOPAL and rasagiline or aminoindan were determined using mass spectrometry. A neuroprotective effect of rasagiline and aminoindan against DOPAL-induced toxicity was demonstrated using PC-12 cells. Rasagiline and aminoindan significantly reduced aggregation of α-synuclein of all sizes in test tube and PC-12 cells experiments. Dimethylaminoindan did not reduce aggregation. DOPAL levels in incubation mixtures were reduced with increasing rasagiline or aminoindan concentrations but not with dimethylaminoindan. Schiff base adducts between DOPAL and either rasagiline or aminoindan were demonstrated by mass spectrometry. A neuroprotective effect against DOPAL-induced toxicity in PC-12 cells was demonstrated for both rasagiline and aminoindan. Inhibiting DOPAL-induced α-synuclein aggregation through amine adducts provides a therapeutic approach for slowing Parkinson disease progression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Photodynamic therapy (PDT) is an effective treatment against skin field cancerization. Its main side effect is local inflammation in the treated area. The phenolic compound oleocanthal (decarboxy methyl ligstroside aglycone), which is present in extra virgin olive oil (EVOO), has anti-inflammatory properties. The purpose of this study was to evaluate the topical efficacy of an oily fluid enriched with oleocanthal (OC) extract, in comparison with a conventional oily fluid, in reducing the degree of inflammatory reaction after conventional PDT., Methods: Quasi-experimental pilot study, before-after with a control group, performed with a cohort of consecutive patients diagnosed with actinic keratosis/field cancerization (AK/FC) in the forehead and/or scalp, treated by PDT. The study was carried out from April 2016 to November 2017 at a speciality hospital in southern Spain. A group of 24 consecutive patients received the topical application, three times daily for one week, of an emollient oily fluid in the area treated with PDT. Subsequently, another group, of 23 consecutive patients, received the same treatment pattern with an oily fluid enriched with OC extract. The post-PDT inflammatory reaction was measured by an independent member of the hospital's dermatology department, using the following visual scale of erythema (from 0 to 4).The assessment was conducted at 30 min and at 48 h post-PDT., Results: In the assessment at 48 h after treatment, the inflammation had improved more among the patients treated with OC (median: 25%, 95%CI: -5.3 to 28.5) than in the non-OC group (median: 0%; 95%CI: -45.2 to -6.2). The difference was statistically significant (p<0.01), and the Cohen's d value was 0.89 (large effect). At three months after PDT, a complete response had been obtained by 60.9% of the patients treated with OC compared to 29.2% of the non-OC group, and the difference was close to statistical significance (p=0.059)., Conclusions: The topical application of an oily fluid enriched with OC extract achieved a greater reduction in post-PDT cutaneous inflammation and a better treatment response, in comparison with the application of a conventional oily fluid., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cardiac fibrosis contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Antifibrotic therapies are likely to be a crucial strategy in curbing many fibrosis-related cardiac diseases. In our previous study, an ethyl acetate extract of a traditional Chinese medicine Aristolochia yunnanensis Franch. was found to have a therapeutic effect on myocardial fibrosis in vitro and in vivo. However, the exact chemicals and their mechanisms responsible for the activity of the crude extract have not been illustrated yet. In the current study, 10 sesquiterpenoids (1-10) were isolated from the active extract, and their antifibrotic effects were systematically evaluated in transforming growth factor β 1 (TGFβ1)-stimulated cardiac fibroblasts and NIH3T3 fibrosis models. (+)-Isobicyclogermacrenal (1) and spathulenol (2) were identified as the main active components, being more potent than the well-known natural antifibrotic agent oxymatrine. Compounds 1 and 2 could inhibit the TGFβ1-induced cardiac fibroblasts proliferation and suppress the expression of the fibrosis biomarkers fibronectin and α-smooth muscle actin via down-regulation of their mRNA levels. The mechanism study revealed that 1 and 2 could inhibit the phosphorylation of TGFβ type I receptor, leading to the decrease of the phosphorylation levels of downstream Smad2/3, then consequently blocking the nuclear translocation of Smad2/3 in the TGFβ/Smad signaling pathway. These findings suggest that 1 and 2 may serve as promising natural leads for the development of anticardiac fibrosis drugs., (© 2018 John Wiley & Sons, Ltd.)

Metabolic syndrome is a cluster of medical conditions that increases the risk of developing cardiovascular disease and type 2 diabetes. Numerous studies have shown that inflammation is directly involved in the onset of metabolic syndrome and related pathologies. In this study, in silico techniques were applied to a natural products database containing molecules isolated from mushrooms from the Catalan forests to predict molecules that can act as human nuclear-factor κβ kinase 2 (IKK-2) inhibitors. IKK-2 is the main component responsible for activating the nuclear-factor κβ transcription factor (NF-κβ). One of these predicted molecules was o-orsellinaldehyde, a molecule present in the mushroom Grifola frondosa. This study shows that o-orsellinaldehyde presents anti-inflammatory and pro-apoptotic properties by acting as IKK-2 inhibitor. Additionally, we suggest that the anti-inflammatory and pro-apoptotic properties of Grifola frondosa mushroom could partially be explained by the presence of o-orsellinaldehyde on its composition.

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.

Inflammation plays an important role in maintaining the body's homeostasis. It repairs the damaged tissues of the body resulting from injury or infection. In addition, a diverse array of diseases like hepatitis, arthritis and colitis has been reported and described to be associated with inflammatory processes. Some autoimmune diseases like inflammatory bowel disease (IBD) emerge by the influence of numerous genes in complex environmental situations belong to inflammation. The currently available processes for curing inflammation and related disorders facilitate the use of non steroidal antiinflammatory drugs (NSAIDs). Moreover, intolerable side effects are also associated with the consumption of these medications. It is well known that phenolic compounds, largely present in vegetables and fruits, serve as an integral part of normal human diet besides having great medicinal value. These are considered to reflect a variety of anti-inflammatory properties, and can be used as an alternate natural source for the prevention of chronic inflammatory disorders. This mini-review summarized the antiinflammatory benefits of plants derived very prominent dietary polyphenolic compounds particularly, Oleocanthal, Curcumin, Resveratrol and Quercetin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aldehydes are continuously formed in biological systems through enzyme-dependent and spontaneous oxidation of lipids, glucose, and primary amines. These highly reactive, biogenic electrophiles can become toxic via covalent modification of proteins, lipids and DNA. Thus, agents that scavenge aldehydes through conjugation have therapeutic value for a number of major cardiovascular diseases. Several commonly-prescribed drugs (e.g., hydralazine) have been shown to have potent aldehyde-conjugating properties which may contribute to their beneficial effects. Herein, we briefly describe the major sources and toxicities of biogenic aldehydes in cardiovascular system, and provide an overview of drugs that are known to have aldehyde-conjugating effects. Some compounds of phytochemical origin, and histidyl-dipeptides with emerging therapeutic value in this area are also discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this perspective, we summarize and discuss critical advancements in the study of 4-hydroxy-2-nonenal (4-HNE) as it relates to diseases and clinical complications either caused or exacerbated by oxidative stress. Since its identification in 1980, 4-HNE has been extensively studied with an emphasis on its formation, its role in pathology, and its targets. As a reactive aldehyde, and a product of lipid peroxidation, studies corroborate its ability to disrupt signal transduction and protein activity, as well as induce inflammation and trigger cellular apoptosis in conditions of oxidative stress. Notably, we discuss the role of natural enzymes involved in the regulation of 4-HNE, and how they can be applied to its detoxification in various physiological conditions., (Copyright © 2016 the American Physiological Society.)

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., Competing Interests: The authors declare no conflicts of interest.

DNA damage is one of the leading causes of various pathological conditions including carcinogenesis. Crotonaldehyde is a 4-carbon unsaturated bifunctional aldehyde which is found ubiquitously and produced both exogenously and endogenously. It reacts with deoxyguanosine and form adducts with DNA. These adducts were detected and found involved in tumor formation in rats treated with crotonaldehyde. In the present study, structural changes in DNA by crotonaldehyde were evaluated by Fourier transform infrared (FTIR) spectroscopy, differential scanning colorimetry (DSC), dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), and atomic force microscopy (AFM). Enhanced binding was observed in cancer autoantibodies with the DNA modified by crotonaldehyde than the native counterpart. Immunological studies revealed enhanced binding of cancer autoantibodies with crotonaldehyde modified DNA, compared to the native form. Furthermore, lymphocyte DNA isolated from cancer patients demonstrated considerable recognition of anti-Cro-DNA IgG as compared to the DNA from healthy individuals. Therefore, we suggest that crotonaldehyde modified DNA presents unique epitopes, that may trigger autoantibody induction in cancer patients.

Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti-inflammatory and chemotherapeutic roles., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Citronella oil is one of the most famous Indonesian essential oils, having a distinctive aroma. As with other essential oils, it is crucial to explore the effects of inhalation of this oil. Therefore, the aim of this research was to elucidate the effects of inhalation of citronella oil and its components isolated from Cymbopogon nardus L. (Poaceae), Indonesian local name: "Sereh Wangi" on the body weight, blood lipid profile, and liver function of rats, as well as on the sympathetic nerve activity and temperature of brown adipose tissue. Sprague-Dawley male adult rats fed with high fat diet (HFD) were made to inhale citronella oil, R-(+)-citronellal, and β-citronellol for five weeks, and the observations were compared to those of HFD rats that were not subjected to inhalation treatment. The results showed that inhalation of β-citronellol decreased feed consumption. As a consequence, the percentage of weight gain decreased compared with that in control group and the blood cholesterol level in the β-citronellol group was significantly lowered. Concentration of liver function enzymes were not significantly different among the groups. In conclusion, inhalation of citronella oil, specifically β-citronellol, decreased body weight by decreasing appetite, without any marked changes in liver enzyme concentrations.

Epidemiological studies suggest that the cardioprotective properties of olive oil, particularly extra-virgin type, result from a positive influence of its components, such as phenolic compounds, on the cardiovascular system. One of the most abundant phenolic compounds of extra virgin olive oil is the dialdehydic form of elenolic acid conjugated with 3, 4-(dihydroxyphenyl)ethanol (3, 4- DHPEA-EDA), also known as oleacein. Due to its abundance in olive oil, it may play a special role in decreasing the progression of atherosclerosis. Some bioactivities of oleacein, such as antioxidant, anti-inflammatory, anti-proliferative and antimicrobial, were documented. There is also evidence of the bioavailability of oleacein in humans as well. However, due to the lack of clinical data, further studies are needed to provide information about the usefulness of this compound in antiatherosclerotic therapy.

Virgin olive oil (VOO) is credited as being one of many healthful components of the Mediterranean diet. Mediterranean populations experience reduced incidence of chronic inflammatory disease states and VOO is readily consumed as part of an everyday dietary pattern. A phenolic compound contained in VOO, named oleocanthal, shares unique perceptual and anti-inflammatory characteristics with Ibuprofen. Over recent years oleocanthal has become a compound of interest in the search for naturally occurring compounds with pharmacological qualities. Subsequent to its discovery and identification, oleocanthal has been reported to exhibit various modes of action in reducing inflammatory related disease, including joint-degenerative disease, neuro-degenerative disease and specific cancers. Therefore, it is postulated that long term consumption of VOO containing oleocanthal may contribute to the health benefits associated with the Mediterranean dietary pattern. The following paper summarizes the current literature on oleocanthal, in terms of its sensory and pharmacological properties, and also discusses the beneficial, health promoting activities of oleocanthal, in the context of the molecular mechanisms within various models of disease.

Background and Purpose: Products of Maillard reactions between aminoacids and reducing sugars are known to have anti-inflammatory properties. Here we have assessed the anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its possible mechanisms of action., Experimental Approach: We used cultures of LPS-activated macrophages (RAW264.7 cells) and human synoviocytes from patients with rheumatoid arthritis for in vitro assays and the collagen-induced arthritis model in mice. NO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities were measured in vitro and in joint tissues of arthritic mice, along with clinical scores and histopathological assessments. Binding of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal to STAT3 was evaluated by a pull-down assay and its binding site was predicted using molecular docking studies with Autodock VINA., Key Results: (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 μg·mL(-1) ) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities in macrophage and human synoviocytes. This compound also suppressedcollagen-induced arthritic responses in mice by inhibiting expression of iNOS and COX2, and NF-κB/IKK and STAT3 activities; it also reduced bone destruction and fibrosis in joint tissues. A pull-down assay showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal interfered with binding of ATP to STAT3. Docking studies suggested that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal bound to the DNA-binding interface of STAT3 possibly inhibiting ATP binding to STAT3 in an allosteric manner., Conclusions and Implications: (E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-κB/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease., (© 2014 The British Pharmacological Society.)

Context: Citronellal is a monoterpene present in the oil of many species, including Cymbopogon winterianus Jowitt (Poaceae)., Objective: The present study investigated the effect of citronellal on inflammatory nociception induced by different stimuli and examined the involvement of the NO-cGMP-ATP-sensitive K⁺ channel pathway., Materials and Methods: We used male Swiss mice (n = 6 per group) that were treated intraperitoneally with citronellal (25, 50 or 100 mg/kg) 0.5 h after the subplantar injection of 20 μl of carrageenan (CG; 300 µg/paw), tumor necrosis factor-α (TNF-α; 100 pg/paw), prostaglandin E₂ (PGE₂; 100 ng/paw) or dopamine (DA; 30 μg/paw). The mechanical nociception was evaluated at 0.5, 1, 2 and 3 h after the injection of the agents, using a digital analgesimeter (von Frey). The effects of citronellal were also evaluated in the presence of L-NAME (30 mg/kg) or glibenclamide (5 mg/kg)., Results: At all times, citronellal in all doses inhibited the development of mechanical nociception induced by CG (p < 0.001 and p < 0.01) and TNF-α (p < 0.001, p < 0.01, and p < 0.05). The citronellal was able to increase the pain threshold in the DA test (p < 0.001, p < 0.01, and p < 0.05) and in the PGE₂ test at all times (p < 0.001 and p < 0.05). L-NAME and glibenclamide reversed the antinociceptive effects of the citronellal at higher doses in the PGE₂ test., Discussion and Conclusion: These data suggest that citronellal attenuated mechanical nociception, mediated in part by the NO-cGMP-ATP-sensitive K⁺ channel pathway.

Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer's disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of (125)I-Aβ40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced (125)I-Aβ40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing (125)I-Aβ40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in (125)I-Aβ40 degradation as a result of the up-regulation of Aβ degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of Aβ clearance from the brain.

Background: Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) fibrils within the brain and activation of astrocytes and microglial cells. In this study, we examined anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal (HPB242), an anti-inflammatory compound produced by the tyrosine-fructose Maillard reaction., Methods: 12-month-old Tg2576 mice were treated with HPB242 (5 mg/kg) for 1 month and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, western blot analysis, Gel electromobility shift assay, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains of Tg2576 mice. The Morris water maze task was analyzed using two-way ANOVA with repeated measures. Otherwise were analyzed by one-way ANOVA followed by Dunnett's post hoc test., Results: Treatment of HPB242 (5 mg/kg for 1 month) significantly attenuated cognitive impairments in Tg2576 transgenic mice. HPB242 also prevented amyloidogenesis in Tg2576 transgenic mice brains. This can be evidenced by Aβ accumulation, BACE1, APP and C99 expression and β-secretase activity. In addition, HPB242 suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes and microglial cells. Furthermore, activation of nuclear factor-kappaB (NF-κB) and signal transducer and activator of transcription 1/3 (STAT1/3) in the brain was potently inhibited by HPB242., Conclusions: Thus, these results suggest that HPB242 might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.

The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [(123)I]-N-(2-diethylaminoethyl)benzamide ([(123)I]BZA) or [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([(125)I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC(50), 0.71 and 0.64 μM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Green odor (GO), a mixture of cis-3-hexenol and trans-2-hexenal, attenuates stress responses and anxiety to psychological stressors in rodents; however, it remains unknown whether GO affects behavioral and stress responses to risk-related olfactory stimuli and actual noxious stimuli. The present study investigated the effects of green odor on behavioral and plasma adrenocorticotropic hormone (ACTH) responses to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a component of fox feces, and electric footshock (FS) stress. When rats were simultaneously exposed to TMT and GO, they showed decreases in immobility and plasma ACTH levels compared with TMT alone. GO exposure after TMT increased immobility, but blocked the elevation of plasma ACTH levels compared with rats exposed to distilled water after TMT. This means that GO presentation during TMT attenuated the TMT-induced behavioral response and GO presentation during and after TMT inhibited TMT-induced elevation of plasma ACTH levels. Furthermore, electric FS-induced plasma ACTH elevations were attenuated by simultaneous GO and FS exposure. GO presentation after FS attenuated plasma ACTH elevations and fecal responses. These findings reveal that GO has alleviating effects on olfactory stimulus- and noxious stimulus-induced behavioral and endocrinal responses., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The anti-inflammatory and redox protective effects of the citronellal (CT) were evaluated using in vivo and in vitro tests. Intraperitoneal (i.p.) administration of CT (50, 100, and 200 mg/kg) inhibited (p < 0.05) the carrageenan-induced leukocyte migration to the peritoneal cavity. Additionally, the carrageenan- and arachidonic acid-induced rat hind paw edema was significantly inhibited (p < 0.05) by i.p. administration of 100 and 200 mg/kg of the compound. When the redox activity was evaluated, CT (200 mg/kg) significantly reduced hepatic lipoperoxidation (p < 0.001), as well as oxidation of plasmatic (p < 0.05) and hepatic (p < 0.01) proteins. The results of the present study support the hypothesis that CT possesses anti-inflammatory and redox protective activities. It is suggested that its effects are associated with the inhibition of the enzymes in the arachidonic acid pathway, which prevent cell migration by inhibiting leukotriene production, edema formation and the increase of reactive oxygen species in tissues. Therefore, CT is of potential benefit to manage inflammatory disorders and correlated damages caused by oxidant agents.

Chronic inflammation is a critical factor in the pathogenesis of many inflammatory disease states including cardiovascular disease, cancer, diabetes, degenerative joint diseases and neurodegenerative diseases. Chronic inflammatory states are poorly understood, however it is known that dietary habits can evoke or attenuate inflammatory responses. Popular methods to deal with inflammation and its associated symptoms involve the use of non steroidal anti-inflammatory drugs, however the use of these drugs are associated with severe side effects. Therefore, investigations concerned with natural methods of inflammatory control are warranted. A traditional Mediterranean diet has been shown to confer some protection against the pathology of chronic diseases through the attenuation of pro-inflammatory mediators and this has been partially attributed to the high intake of virgin olive oil accompanying this dietary regime. Virgin olive oil contains numerous phenolic compounds that exert potent anti-inflammatory actions. Of interest to this paper is the recently discovered phenolic compound oleocanthal. Oleocanthal is contained in virgin olive oil and possesses similar anti-inflammatory properties to ibuprofen. This pharmacological similarity has provoked interest in oleocanthal and the few studies conducted thus far have verified its anti-inflammatory and potential therapeutic actions. A review of the health benefits of the Mediterranean diet and anti-inflammatory properties of virgin olive oil is presented with the additional emphasis on the pharmacological and anti-inflammatory properties of the phenolic compound oleocanthal.

Immunizations belong to the most successful interventions in medicine. Like other drugs, vaccines undergo long periods of pre-clinical development, followed by careful clinical testing through study Phases I, II, and III before they receive licensure. A successful candidate vaccine will move on to be an investigational vaccine to undergo three phases of pre-licensure clinical trials in a stepwise fashion before it can be considered for approval, followed by an optional fourth phase of post-marketing assessment. The overall risk-benefit assessment of a candidate vaccine is very critical in making the licensure decision for regulatory authorities, supported by their scientific committees. It includes analyses of immunogenicity, efficacy, reactogenicity or tolerability, and safety of the vaccine. Public trust in vaccines is a key to the success of immunization programs worldwide. Maintaining this trust requires knowledge of the benefits and scientific understanding of real or perceived risks of immunizations. Under certain circumstances, pre- or post-exposure passive immunization can be achieved by administration of immunoglobulines. In terms of prevention of infectious diseases, disinfection can be applied to reduce the risk of transmission of pathogens from patient to patient, health-care workers to patients, patients to health-care workers, and objects or medical devices to patients.

Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive γ-ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of γ-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of γ-ketoaldehyde protein adducts in the cerebellum were not different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available γ-ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12-14 month old ApoE4 mice. These findings suggest that γ-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether γ-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD.

Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of alpha,beta-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). There is compelling evidence that high concentrations of aldehydes are responsible for much of the damage elicited by cardiac ischemia-reperfusion injury, while sublethal concentrations of aldehydes stimulate stress resistance pathways, to achieve cardioprotection. We investigated the mechanism of cardioprotection mediated by 4-HNE. For cultured cardiomyocytes, 4-HNE was cytotoxic at higher concentrations (>or=20 microM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5muM) of 4-HNE primed cardiomyocytes to become resistant to cytotoxic concentrations of 4-HNE. 4-HNE induced nuclear translocation of transcription factor NF-E2-related factor 2 (Nrf2), and enhanced the expression of gamma-glutamylcysteine ligase (GCL) and the core subunit of the Xc(-) high-affinity cystine transporter (xCT), thereby increasing 1.45-fold the intracellular GSH levels. Cardiomyocytes treated with either Nrf2-specific siRNA or the GCL inhibitor l-buthionine sulfoximine (BSO) were less tolerant to 4-HNE. Moreover, the cardioprotective effect of 4-HNE pretreatment against subsequent glucose-free anoxia followed by reoxygenation was completely abolished in these cells. Intravenous administration of 4-HNE (4 mg/kg) activated Nrf2 in the heart and increased the intramyocardial GSH content, and consequently improved the functional recovery of the left ventricle following ischemia-reperfusion in Langendorff-perfused hearts. This cardioprotective effect of 4-HNE was not observed for Nrf2-knockout mice. In summary, 4-HNE activates Nrf2-mediated gene expression and stimulates GSH biosynthesis, thereby conferring on cardiomyocytes protection against ischemia-reperfusion injury., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: New compounds with biological targets and less cytotoxicity to normal cells are necessary for cancer therapy. In this work ten synthetic chalcones derived from 2-naphtaldehyde were evaluated for their cytotoxic effect in murine acute lymphoblastic leukemia cells L-1210., Methods: A series of ten chalcones derived from 2-naphtaldehyde and corresponding acetophenones were prepared by aldolic condensation, using methanol as solvent under basic conditions, at room temperature for 24 h. The cell viability was determined by MTT colorimeter method. The cell cycle phase analysis was carried out by flow cytometry after propidium iodide staining. The apoptosis induction was assessed by exposure to phosphatidylserine (ANNEXIN V-FITC). Cytometric analysis was performed to evaluate the expression of p53, Bcl-2 and Bax protein. The caspase-3 expression was studied by immunoblotting analysis., Key Findings: A preliminary screening of a series of ten chalcones derived from 2-naphtaldehyde showed that chalcone 8, (2E)-3-(2-naphtyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one, had the highest cytotoxic effect (IC50 of 54 microM), but not in normal human lymphocytes. To better understand the cytotoxic mechanism of chalcone 8, its effect on cell cycle and apoptosis was assessed. Our results showed that chalcone 8 caused cell cycle arrest in the G2/M phase and a significant increase in the proportion of cells in the subG0/G1 phase. Our results also demonstrated that chalcone 8 promoted a modification in Bax:Bcl-2 ratio and increased p53 expression and caspase-3 activation., Conclusions: The studied chalcone 8 has cytotoxic effect against L-1210 lymphoblastic leukaemic cells, and this effect is associated with increase of p-53 and Bax expression.

Aims: To evaluate the antinociceptive effects of citronellal (CTL) on formalin-, capsaicin-, and glutamate-induced orofacial nociception in mice and to investigate whether such effects might involve a change in neural excitability., Methods: Male mice were pretreated with CTL (50, 100, and 200 mg/kg, ip), morphine (5 mg/kg, ip), or vehicle (distilled water plus one drop of Tween 80 0.2%) before formalin (20 microL, 2%), capsaicin (20 microL, 2.5 microg) or glutamate (40 microL, 25 microM) injection into the right vibrissa. Sciatic nerve recordings were made using the single sucrose gap technique in rats. The data obtained were analyzed by ANOVA followed by Dunnett's test for the behavioral analyses and by the Student t test for CAP evaluation., Results: Pretreatment with CTL was effective in reducing nociceptive face-rubbing behavior in both phases of the formalin test, which was also naloxone-sensitive. CTL produced significantly antinociceptive effect at all doses in the capsaicin- and glutamate- tests. Rota-rod testing indicated that such results were unlikely to be provoked by motor abnormality. Recordings using the single sucrose gap technique revealed that CTL (10 mM) could reduce the excitability of the isolated sciatic nerve through a diminution of the compound action potential amplitude by about 42.4% from control recordings., Conclusion: These results suggest that CTL might represent an important tool for management and/or treatment of orofacial pain.

Introduction: Thyroid autoregulation has been related to intraglandular content of an unknown putative iodocompound. The thyroid is capable of producing different iodolipids such as 6-iodo-deltalactone (ILdelta) and 2-iodohexadecanal (2-IHDA). Data from different laboratories have shown that these iodolipids inhibit several thyroid parameters. ILdelta has an antigoitrogenic action but no data about the action of 2-IHDA on this parameter has been published., Objectives: to study the action of 2-IHDA on methimazole (MMI)-induced goiter and analyze if this compound can cause the involution of preformed goiter., Results: Administration of MMI to rats during 10 days increased thyroid weight by 112%. This effect was significantly inhibited by the simultaneous injection of 20mug/day of 2-IHDA (51% vs. MMI) while iodine or non iodinated hexadecanal were without action. Thyroidal proliferating cell nuclear antigen (PCNA) content was increased by MMI while 2-IHDA decreased this value (control: 100%; MMI: 190+/-11; MMI+2-IHDA: 134+/-10). Serum TSH was increased after MMI administration and 2-IHDA did not modify this parameter (control: 1.89+/-0.10; MMI: 8.19+/-0.93ng/ml; MMI+2-IHDA: 7.38+/-0.72). Treatment with MMI increased thyroidal cAMP content (control: 16.1+/-0.82, MMI: 42.4+/-4.6 fmol/mg protein) while injection of 2-IHDA significantly decreased this value (22.3+/-2.0). Goiter prevention by 2-IHDA was also observed at 30 days of treatment reducing total number of cells (51% inhibition) and epithelial height (81% inhibition). Goiter involution was induced after withdrawal of MMI and injection with 2-IHDA, KI or saline. 2-IHDA led to a reduction of 74.5% in thyroid weight after 3 days while spontaneous involution (saline) was only of 32%. KI failed to alter this value. This significant involution was accompanied by a reduction in the number of cells (66%). Administration of the iodolipids did not produce significant changes in several serum parameters such as total T(3) and T(4), cholesterol, transaminases, urea and creatinine., Conclusion: 2-Iodohexadecanal, as 6-iodo-deltalactone, prevents goiter growth in rats and opens a potential therapeutic application of iodolipids.

Citronellal is a monoterpene reported to be a major component of the essential oils in various aromatic species of plants. The present study evaluated the central nervous system depressant and antinociceptive properties of citronellal through behavioral experimental models. Following intraperitoneal injection, citronellal induced the reduction of spontaneous activity, ataxia, analgesia, and sedation. In pentobarbital-induced hypnosis, CTL (citronellal) at 50, 100, and 200 mg/kg (i.p.) significantly increased sleeping time (88.0 +/- 11.4, 100.2 +/- 16.4, and 119.5 +/- 20.9 min) when compared to vehicle solution injections (43.0 +/- 6.1). Citronellal (100 and 200 mg/kg, i.p.) significantly reduced the number of writhes (66.4 and 81.9%) in a writhing test and the number of paw licks during phase 1 (47.0 and 66.8%) and phase 2 (71.1 and 79.2%) of a formalin test when compared to control group animals. In addition, the results of a hot plate test showed central analgesic properties for citronellal (p < 0.05). These results indicate depressant, hypnotic, and antinociceptive properties of this monoterpene.

A hallmark feature of monosodium urate (MSU) crystal-induced inflammation in gouty arthritis is the infiltration of activated neutrophils into the joint. Therefore inhibition of neutrophil superoxide production is a rational target for treating inflammation in gout. The natural product polygodial and related sesquiterpene dialdehyde analogs were tested in vitro and in vivo for their ability to inhibit neutrophil infiltration and superoxide production in response to MSU crystal stimulation. Polygodial and other sesquiterpene dialdehydes exhibited dose-dependent inhibition of MSU-induced superoxide production in the micromolar and submicromolar ranges. Inhibition of superoxide production was dependent on the presence of the dialdehyde functional groups and was sensitive to blockade with the thiol-containing amino acid cysteine. Polygodial, 6-hydroxypaxidal and sesquiterpene 2 inhibited both neutrophil infiltration and neutrophil superoxide production in an MSU crystal-induced mouse model of gouty inflammation. Together, these data highlight the potential of sesquiterpene dialdehydes for development as anti-inflammatory agents for the treatment of neutrophil-driven inflammatory diseases including gout.

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.

Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1(G37R) mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1(G37R) transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1(G37R) mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.

An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

A comprehensive focus on 4-hydroxynonenal (HNE) as candidate molecule in a variety of pathophysiological conditions occurring in humans is here provided. Despite an active, now well characterized, metabolism in most cells and tissues, HNE can be easily detected and quantified by means of several methods, although with different sensitivity. Measurements of HNE and/or stable metabolites in biological fluids are already applied as lipid peroxidation/oxidative stress markers in a huge number of human disease processes, often sustained by inflammatory reactions. A primary involvement of this aldehydic product of membrane lipid oxidation in inflammation-related events, as well as in regulation of cell proliferation and growth, in necrotic or apoptotic cell death, appears supported by its marked ability to modulate several major pathways of cell signaling and, consequently, gene expression. The actual knowledge of HNE reactivity, metabolism, signaling and modulatory effect in the various human organs should provide a solid background to the investigation of the aldehyde's contribution to the pathogenesis of human major chronic diseases and would likely promote advanced and oriented applications not only in diagnosis and prevention but also in molecular treatment of human diseases., ((c) 2007 Wiley Periodicals, Inc.)

A new pyran derivative, 6-hydroxy-2H-pyran-3-carbaldehyde, has been isolated from the methanolic extract of Crinum yemense along with the known alkaloid haemanthamine, benzoic acid and 1,1'-bis(1,1'-carboxyethyl) ether which is isolated from a natural source for the first time. Structure elucidation of these compounds based on spectroscopicevidences. The pyran derivative was found to be a tyrosinase inhibitor more potent than kojic acid.

Background: Reactive oxygen species (ROS) play an important role in several pathogenic processes, damaging various structural and functional cellular components. The endothelium is at major risk of radical-induced lesions and this damage is most manifest in microcirculation. It has been recently observed that ROS are implicated in the pathology of the inner ear and the peripheral and central pathways. In a previous study we detected high serum values of ROS in subjects with idiopathic tinnitus. The purpose of the present study was to evaluate the validity of antioxidant treatment in tinnitus sufferers with high ROS values., Methods: The study considered 31 consecutive patients with unilateral idiopathic tinnitus. The mean pure tone audiometric threshold (PTA), tinnitus loudness, subjective disturbance level [visual analogue scale (VAS) determination], and the indirect ROS dosage 48 h before and after medical treatment were evaluated. Patients underwent an 18-week oral treatment with a mix of phospholipids and vitamins (glycerophosphorylcholine, glycerophosphorylethanolamine, beta-carotene, vitamin C, vitamin E)., Results: ROS levels were significantly reduced following antioxidant treatment (malonaldehyde: 2.10 vs. 1.98 mumol/dL, p = 0.003; 4-hydroxynonenal: 2.36 vs. 2.16 mumol/dL, p = 0.002) In addition, great improvement was observed in the reduction of tinnitus (VAS and tinnitus loudness evaluations). No significant changes in audiometric threshold occurred., Conclusions: Oral antioxidant therapy in patients with idiopathic tinnitus seems to reduce the subjective discomfort and tinnitus intensity and may be considered as an additional treatment modality.

Idiopathic localized hyperhidrosis, called for hyperhidrosis, affects almost 3% of the US population. The most frequent anatomic sites of involvement include the axillae, palms, soles, and face. For those affected, this condition can be extremely socially debilitating and interfere with work activities. Until recently, frequently ineffective topical regimens or problematic surgical procedures have been the treatments of choice. Since 1996, intracutaneous injections of botulinum toxin have been used as a minimally invasive treatment for this condition with numerous studies documenting safety, efficacy, and extremely high levels of patient satisfaction. Botulinum toxin type A (Botox) was approved by the US Food and Drug Administration in 2004 for the treatment of axillary hyperhidrosis.

Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down's syndrome have been associated with several mitochondrial alterations. Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions, particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.

PEGylation of IFN-alpha has been used successfully to improve the pharmacokinetic properties and efficacy of the drug. To prepare a PEGylated form of human interferon-beta-1a (IFN-beta-1a) suitable for testing in vivo, we have synthesized 20 kDa mPEG-O-2-methylpropionaldehyde and used it to modify the N-terminal alpha-amino group of the cytokine. The PEGylated protein retained approximately 50% of the activity of the unmodified protein and had significantly improved pharmacokinetic properties following intravenous administration in rats. The clearance and volume of distribution at steady state were reduced approximately 30-fold and approximately 4-fold, respectively, resulting in a significant increase in systemic exposure as determined by the area under the curve. The elimination half-life of the PEGylated protein was approximately 13-fold greater than for the unmodified protein. The unmodified and PEGylated proteins were tested for their ability to inhibit the formation of radially oriented blood vessels entering the periphery of human SK-MEL-1 melanoma tumors in athymic nude homozygous (nu/nu) mice. In a single dose comparison study, administration of 1 x 10(6) units of unmodified IFN-beta-1a resulted in a 29% reduction in vessel number, while 1 x 10(6) units of PEGylated IFN-beta-1a resulted in a 58% reduction. Both treatments resulted in statistically significant reductions in mean vessel number as compared to the vehicle (control)-treated mice, with the PEGylated IFN-beta-1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared to the unmodified IFN-beta-1a-treated mice. In a multiple versus single dose comparison study, daily administration of 1 x 10(6) units of unmodified IFN-beta-1a for 9 days resulted in a 51% reduction in vessel number, while a single dose of 1 x 10(6) units of the PEGylated protein resulted in a 66% reduction. Both treatments resulted in statistically significant reductions in mean vessel number as compared to the vehicle-treated mice, with the PEGylated IFN-beta-1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared to the unmodified IFN-beta-1a-treated mice. Therefore, the improved pharmacokinetic properties of the modified protein translated into improved efficacy. Since unmodified IFN-beta is used for the treatment of multiple sclerosis and hepatitis C virus infection, a PEGylated form of the protein such as 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN-beta-1a may serve as a useful adjunct for the treatment of these diseases. In addition, the antiangiogenic effects of PEGylated IFN-beta-1a may be harnessed for the treatment of certain cancers, either as a sole agent or in combination with other antitumor drugs.

The true auklets (Genus Aethia) are small planktivorous seabirds of the Bering Sea and North Pacific. Two species, the crested and whiskered auklets produce volatile citrus-like odorants. We here show that the whiskered auklet odorant is composed predominantly of two odd-numbered aldehydes (heptanal and nonanal) with no detectable unsaturated aldehydes. By comparison the crested auklet odorant is dominated by even-numbered aldehydes, both saturated and monounsaturated, ranging in size from 6 to 12 carbons. This is evidence of species-specific acquisition or biosynthetic pathways. We clarify the chemistry of the crested auklet odorant. We cite evidence that the C-12:1 aldehyde in crested auklets is actually two isomers, (Z)-4-dodecenal and (Z)-6-dodecenal. We also report on experimental evidence that aldehyde constituents kill and repel ectoparasites. Efficacy of the aldehydes may increase when they are combined in a mixture. The repellency of the mixture increases with chemical concentration. This suggests that individuals with higher chemical production are likely to repel ectoparasites more effectively.