Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease

Alzheimer diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Aβ deposits in senile plaque and neurofibrillary tangles (NFT), are strongly intertwined with reactive oxygen species (ROS)production and oxidative stress (OS),which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions

Traditional Uses of Cannabinoids and New Perspectives in the Treatment of Multiple Sclerosis

Recent findings highlight the emerging role of the endocannabinoid system in the control of symptoms and disease progression in multiple sclerosis (MS). MS is a chronic, immune-mediated, demyelinating disorder of the central nervous system with no cure so far. It is widely reported in the literature that cannabinoids might be used to control MS symptoms and that they also might exert neuroprotective effects and slow down disease progression. This review aims to give an overview of the principal cannabinoids (synthetic and endogenous) used for the symptomatic amelioration of MS and their beneficial outcomes, providing new potentially possible perspectives for the treatment of this disease

Synthesis and evaluation of multi-functional NO-donor/insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications

Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity

Synthesis and functional evaluation of novel aldose reductase inhibitors bearing a spirobenzopyran scaffold

Background: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. Objectives: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. Results: Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. Conclusion: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs

Composition of health-promoting phenolic compounds in two extra-virgin olive oils and diversity of associated yeasts

Extra virgin olive oil (EVOO), a basic component of the Mediterranean diet, is an important functional food, for its content in health-promoting compounds, showing antioxidant, antiinflammatory and antiproliferative activities. Here, two Tuscan EVOOs were analyzed for the occurrence and concentrations of health-promoting phenols, such as tyrosol and hydroxytyrosol and the secoiridoid derivatives, oleocanthal and oleacein. Independently of the milling period, the two EVOOs showed different contents of oleocanthal and oleacein. During storage, the contents of oleocanthal and oleacein decreased, while those of simple phenols increased. In all oil samples oleacein displayed a higher rate of reduction than oleocanthal. Multivariate analyses of the polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) profiles, revealed the occurrence and diversity of oil-borne yeast communities, which differed in the two EVOOs. Sequences of excised DGGE bands identified Candida adriatica, Eremothecium coryli and Lachancea fermentati as the main components of the oil-borne yeast community. Our work detected, for the first time, differences in the content of tyrosol, hydroxytyrosol, oleocanthal and oleacein between the two Tuscan EVOOs analyzed, consistent with the differences found in yeast community composition. Further studies could confirm whether oil-borne yeasts may affect the composition of health-promoting oil phenolic compounds

A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions

Bisphosphonates (BPs) are the first-line treatment of bone loss resulting from various pathological conditions. Due to their high affinity to bone they have been used to develop conjugates with pro-Anabolic or anti-catabolic drugs. We recently demontrated that hydrogen sulfide (H2S), promotes osteogenesis and inhibits osteoclast differentiation. Here we developed an innovative molecule, named DM-22, obtained from the combination of alendronate (AL) and the H2S-releasing moiety aryl-isothiocyanate. DM-22 and AL were assayed in vitro in the concentration range 1-33 μM for effects on viability and function of human osteoclasts (h-OCs) and mesenchymal stromal cells (h-MSCs) undergoing osteogenic differentiation. Amperometric measures revealed that DM-22 releases H2S at a slow rate with a thiol-dependent mechanism. DM-22 significantly inhibited h-OCs differentiation and function, maintaining a residual h-OCs viability even at the high dose of 33 μM. Contrary to AL, in h-MSCs DM-22 did not induce cytotoxicity as revealed by LDH assay, significantly stimulated mineralization as measured by Alizarin Red staining and increased mRNA expression of Collagen I as compared to control cultures. In conclusion, DM-22 is a new BP which inhibits h-OCs function and stimulate osteogenic differentiation of h-MSCs, without cytotoxicity. DM-22 is an ideal candidate for a novel family of osteoanabolic drugs

miRNA Modulation and Antitumor Activity by the Extra-Virgin Olive Oil Polyphenol Oleacein in Human Melanoma Cells

Extra-virgin olive oil (EVOO) polyphenols contribute to Mediterranean diet health- promoting properties. One of the most abundant secoiridoid present in EVOO, Oleacein (OA), demonstrated anticancer activity against several tumors. Nevertheless, its role against melanoma has not still investigated. This study aimed at determining in vitro the antimelanoma activity of OA and the relative mechanism of action. OA induced cell growth inhibition in 501Mel melanoma cells with an IC50 in the low micromolar range of concentrations. Moreover, an OA concentration approximating the IC50 induced G1/S phase arrest, DNA fragmentation, and downregulation of genes encoding antiapoptotic (BCL2 and MCL1) and proproliferative (c-KIT, K-RAS, PIK3R3, mTOR) proteins, while increased transcription levels of the proapoptotic protein BAX. Concordantly, OA increased the levels of miR-193a-3p (targeting MCL1, c-KIT and K-RAS), miR-193a-5p (targeting PIK3R3 and mTOR), miR-34a-5p (targeting BCL2 and c-KIT) and miR-16-5p (miR-16-5p targeting BCL2, K-RAS and mTOR), while decreased miR-214-3p (targeting BAX). These modulatory effects might contribute to the inhibition of 501Mel melanoma cell growth observed after treatment with an olive leaves-derived formulation rich in OA, with potential application against in situ cutaneous melanoma. Altogether, these results demonstrate the ability of OA to contrast the proliferation of cutaneous melanoma cells through the transcriptional modulation of relevant genes and microRNAs, confirming the anticancer potential of EVOO and suggesting OA as a chemopreventive agent for cancer disease therapy

Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer

Although the anticancer properties of extra virgin olive oil (EVOO) extracts have been recognized, the role of single compounds in non-melanoma skin cancer is still unknown. The in vitro chemopreventive and anticancer action of EVOO extracts and oil-derived compounds in non-melanoma skin cancer models were evaluated on cutaneous squamous cell carcinoma cells and on immortalized human keratinocytes stimulated with epidermal growth factor. Preparation of EVOO extracts and isolation of single compounds was carried out by chromatographic methods. Antitumor activity was assessed by cell-based assays (cell viability, migration, clonogenicity, and spheroid formation) and apoptosis documented by internucleosomal DNA fragmentation. Finally, inhibition of key oncogenic signaling nodes involved in the progression from actinic keratosis to cutaneous squamous cell carcinoma was studied by western blot. EVOO extracts reduced non-melanoma skin cancer cell viability and migration, prevented colony and spheroid formation, and inhibited proliferation of atypical keratinocytes stimulated with epidermal growth factor. Such a pharmacological activity was promoted by oleocanthal and oleacein through the inhibition of Erk and Akt phosphorylation and the suppression of B-Raf expression, whereas tyrosol and hydroxytyrosol did not have effect. The current study provides in vitro evidence for new potential clinical applications of EVOO extracts and/or single oil-derived compounds in the prevention and treatment of non-melanoma skin cancers

Cytotoxic Activity of Oleocanthal Isolated from Virgin Olive Oil on Human Melanoma Cells

Oleocanthal is one of the phenolic compounds of extra virgin olive oil with important anti-inflammatory properties. Although its potential anticancer activity has been reported, only limited evidence has been provided in cutaneous malignant melanoma. The present study is aimed at investigating the selective in vitro antiproliferative activity of oleocanthal against human malignant melanoma cells. Since oleocanthal is not commercially available, it was obtained as a pure standard by direct extraction and purification from extra virgin olive oil. Cell viability experiments carried out by WST-1 assay demonstrated that oleocanthal had a remarkable and selective activity for human melanoma cells versus normal dermal fibroblasts with IC50s in the low micromolar range of concentrations. Such an effect was paralleled by a significant inhibition of ERK1/2 and AKT phosphorylation and downregulation of Bcl-2 expression. These findings may suggest that extra virgin olive oil phenolic extract enriched in oleocanthal deserves further investigation in skin cancer

CFBM - A Framework for Data Driven Approach in Agent-Based Modeling and Simulation

Recently, there has been a shift from modeling driven approach to data driven approach in Agent Based Modeling and Simulation (ABMS). This trend towards the use of data-driven approaches in simulation aims at using more and more data available from the observation systems into simulation models [1, 2]. In a data driven approach, the empirical data collected from the target system are used not only for the design of the simulation models but also in initialization, evaluation of the output of the simulation platform. That raises the question how to manage empirical data, simulation data and compare those data in such agent-based simulation platform. In this paper, we first introduce a logical framework for data driven approach in agent-based modeling and simulation. The introduced framework is based on the combination of Business Intelligence solution and a multi-agent based platform called CFBM (Combination Framework of Business intelligence and Multi-agent based platform). Secondly, we demonstrate the application of CFBM for data driven approach via the development of a Brown Plant Hopper Surveillance Models (BSMs), where CFBM is used not only to manage and integrate the whole empirical data collected from the target system and the data produced by the simulation model, but also to initialize and validate the models. The successful development of the CFBM consists not only in remedying the limitation of agent-based modeling and simulation with regard to data management but also in dealing with the development of complex simulation systems with large amount of input and output data supporting a data driven approach