Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 model.

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments.

UNC-49 is a redox-sensitive GABA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

The γ-aminobutyric acid-mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction, and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in and enhances vulnerability to proteostasis disease in the absence of oxidative stress.

Impact of rapeseed pomace extract on markers of oxidative stress and DNA damage in human SH-SY5Y cells.

With increased longevity and subsequent rise in people with age-related neurodegenerative diseases, protection of neurons from oxidative stress damage has become an important field of study. For the first time, we highlight the neuroprotective properties of rapeseed pomace (RSP) extract in SH-SY5Y human neuroblastoma cells. We used resazurin to determine cell metabolism, 2,7'-dichlorofluorescin diacetate (H DCFDA) to assess the potential of RSP extracts to shield cells from reactive oxygen species (ROS) induced by H O using flow cytometry, HPLC to analyze for malondialdehyde (MDA) as a lipid peroxidation marker and the COMET assay to assess DNA strand breakage.

Synthesis and in vitro evaluation of vanillin derivatives as multi-target therapeutics for the treatment of Alzheimer's disease.

A number of novel naphthalimido and phthalimido vanillin derivatives were synthesised, and evaluated as antioxidants and cholinesterase inhibitors in vitro. Antioxidant activity was assessed using DPPH, FRAP, and ORAC assays. All compounds demonstrated enhanced activity compared to the parent compound, vanillin.

Current and emerging therapeutic targets of alzheimer's disease for the design of multi-target directed ligands.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying.

Interaction between Amorphous Zirconia Nanoparticles and Graphite: Electrochemical Applications for Gallic Acid Sensing Using Carbon Paste Electrodes in Wine.

Amorphous zirconium oxide nanoparticles (ZrO) have been used for the first time, to modify carbon paste electrode (CPE) and used as a sensor for the electrochemical determination of gallic acid (GA). The voltammetric results of the ZrO nanoparticles-modified CPE showed efficient electrochemical oxidation of gallic acid, with a significantly enhanced peak current from 261 µA ± 3 to about 451 µA ± 1. The modified surface of the electrode and the synthesised zirconia nanoparticles were characterised by scanning electrode microscopy (SEM), Energy-dispersive x-ray spectroscopy (EDXA), X-ray powdered diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR).

GST-4-Dependent Suppression of Neurodegeneration in Models of Parkinson's and Machado-Joseph Disease by Rapeseed Pomace Extract Supplementation.

Genetic mutations and aging-associated oxidative damage underlie the onset and progression of neurodegenerative diseases, like Parkinson's disease (PD) and Machado-Joseph disease (MJD). Natural products derived from plants have been regarded as important sources of novel bioactive compounds to counteract neurodegeneration. Here, we tested the neuroprotective effect of an ethanolic extract of rapeseed pomace (RSP), a rapeseed (canola) oil production by-product, in models of MJD and PD.

Synthesis of novel vanillin derivatives: novel multi-targeted scaffold ligands against Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a "multi-target-directed ligands" (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including β-amyloid peptide aggregating and acetylcholinesterase inhibiting properties.

The Potential Use of Plant Natural Products and Plant Extracts with Antioxidant Properties for the Prevention/Treatment of Neurodegenerative Diseases: In Vitro, In Vivo and Clinical Trials.

Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Huntington's disease, present a major health issue and financial burden for health care systems around the world. The impact of these diseases will further increase over the next decades due to increasing life expectancies. No cure is currently available for the treatment of these conditions; only drugs, which merely alleviate the symptoms.

Determination of sinapine in rapeseed pomace extract: Its antioxidant and acetylcholinesterase inhibition properties.

Sinapine is the main secondary metabolite present in rapeseed pomace (RSP) with its concentration being dependent on rapeseed processing, growing conditions, extraction parameters and the country of origin. Here we report, the concentration of sinapine from an extract of defatted RSP harvested in the North East of Scotland. Using liquid chromatography tandem mass spectrometry, the most abundant phenolic compound in the RSP extract was, as expected, sinapine (109.

A Novel PAA Derivative with Enhanced Drug Efficacy in Pancreatic Cancer Cell Lines.

Nanoparticles have been shown to be effective drug carriers in cancer therapy. Pancreatic cancer forms dense tumours which are often resistant to drug molecules. In order to overcome such multidrug resistance, new drug entities, novel delivery systems and combination therapy strategies are being explored.

Caspase-independence and characterization of bisnaphthalimidopropyl spermidine induced cytotoxicity in HL60 cells.

Bisnaphthalimides are DNA intercalators of potential use as chemotherapeutics but for which the range of mechanism of action is only gradually being elucidated. Using human promyelocytic HL-60 cells, we extend characterization of the cytotoxicity of bisnaphthalimidopropylspermidine (BNIPSpd) and examine the relationship with caspase-activity. Within 4 h exposure, BNIPSpd (1-10 μM) induced significant DNA strand breakage.

Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease.

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease.

Novel vanillin derivatives: Synthesis, anti-oxidant, DNA and cellular protection properties.

Antioxidants have been the subject of intense research interest mainly due to their beneficial properties associated with human health and wellbeing. Phenolic molecules, such as naturally occurring Resveratrol and Vanillin, are well known for their anti-oxidant properties, providing a starting point for the development of new antioxidants. Here we report, for the first time, the synthesis of a number of new vanillin through the reductive amination reaction between vanillin and a selection of amines.

Revalorisation of rapeseed pomace extracts: An in vitro study into its anti-oxidant and DNA protective properties.

Rapeseed pomace (RSP) is a waste product obtained after edible oil production from Brassica napus. Analysis of ubiquitous secondary metabolites in RSP samples (two breeds, harvested in 2012/2014 respectively from North East of Scotland) and their ethanol/water (95:5) Soxhlet extracts were carried out. Soxhlet extraction of the RSP (petroleum ether followed by 95% ethanol) gave a solid extract.

Thermally triggered theranostics for pancreatic cancer therapy.

Hybrid iron oxide-gold nanoparticles (HNPs) show the ability to bind drugs onto their surface with a triggered release at elevated temperatures. The iron oxide core allows for diagnostic imaging whilst heating of the gold shell upon laser irradiation reverses drug binding. This study exploits the reversible binding of novel polyamine based drugs in order to provide a specific and effective method for pancreatic cancer treatment.

Dual-Laboratory Validation of a Method for the Determination of Fructans in Infant Formula and Adult Nutritionals: First Action 2016.14.

Until recently, only two AOAC Official MethodsSM have been available for the analysis of fructans: Method 997.08 and Method 999.03.

Novel bisnaphthalimidopropyl (BNIPs) derivatives as anticancer compounds targeting DNA in human breast cancer cells.

Bisnaphthalimidopropyl (BNIP) derivatives are a family of compounds that exert anti-cancer activities in vitro and, according to previous studies, variations in the linker sequence have increased their DNA binding and cytotoxic activities. By modifying the linker sequence of bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM), a previously synthesised BNIP derivative with anti-cancer properties, three novel BNIP derivatives were designed. Bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), a structural isomer of BNIPDaCHM, bisnaphthalimidopropyl ethylenedipiperidine dihydrobromide (BNIPPiEth), an isoform of BNIPDaCHM with a shorter linker chain, and (trans(trans))-bisnaphthalimidopropyl diaminodicyclohexylmethane (trans,trans-BNIPDaCHM), a stereoisomer of BNIPDaCHM, were successfully synthesised (72.

Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei.

Current treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives againstTrypanosoma brucei BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showedin vitroinhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed.

Development and validation of HPLC method with fluorometric detection for quantification of bisnaphthalimidopropyldiaminooctane in animal tissues following administration in polymeric nanoparticles.

A simple, sensitive and specific high-performance liquid chromatography method for the quantification of bisnaphthalimidopropyldiaminooctane (BNIPDaoct), a potent anti-Leishmania compound, incorporated into poly(d,l-lactide-co-glycolic acid) (PLGA) nanoparticles was developed and validated toward bioanalysis application. Biological tissue extracts were injected into a reversed-phase monolithic column coupled to a fluorimetric detector (λexc=234nm, λem=394nm), using isocratic elution with aqueous buffer (acetic acid/acetate 0.10M, pH 4.

Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression.

Bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM) bisintercalates to DNA and is a potential anti-cancer therapeutic. In an attempt to elucidate the mechanism(s) underlying the potential of BNIPDaCHM; earlier work was extended to investigate its effect on DNA damage and repair as well as cell cycle modulation, in a triple negative breast cancer (TNBC) cell line in vitro. BNIPDaCHM significantly decreased cell viability in a concentration (≥ 5 μM) and time (≥ 24 h) dependent manner.

Synthesis, cytotoxicity and DNA binding of oxoazabenzo[de]anthracenes derivatives in colon cancer Caco-2 cells.

New oxoazabenzo[de]anthracenes derivatives were synthesised and characterised. Their interactions with calf thymus DNA were studied by UV spectrophotometric analysis and a competitive ethidium bromide displacement assay. Cytotoxicity was determined by MTT assay, against colon adenocarcinoma (Caco-2 cells).

A review on comb-shaped amphiphilic polymers for hydrophobic drug solubilization.

Comb-shaped amphiphilic polymers are rapidly emerging as an alternative approach to amphiphilic block copolymers for hydrophobic drug solubilization. These polymers consist of a homopolymer or copolymer backbone to which hydrophobic and hydrophilic pendant groups can be grafted resulting in a comb-like architecture. The hydrophobic pendants may consist of homopolymers, copolymers and other low-molecular weight hydrophobic structures.

Characterization and evaluation of BNIPDaoct-loaded PLGA nanoparticles for visceral leishmaniasis: in vitro and in vivo studies.

Objective: To overcome the limitation of bisnaphthalimidopropyldiaaminooctane (BNIPDaoct) low physiological solubility and potentially increase its efficiency against visceral leishmaniasis (VL), a delivery system based on poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles was developed.

Materials & Methods: BNIPDaoct-PLGA nanoparticles were prepared by nanoprecipitation and characterized. Anti-Leishmania activity was evaluated using in vitro and in vivo VL infection models.