Combining Desferriferrioxamine B and 1-Hydroxy-2-Piperidone ((PIPO)H) to Chelate Zirconium. Solution Structure of a Model Complex of the [89Zr]Zr-DFOcyclo*-mAb Radioimmunoconjugate.

89Zr-immunoPET is a hot topic as 89Zr cumulates the advantages of 64Cu and 124I without their drawbacks. We report the synthesis of a model ligand of a chiral bioconjugable tetrahydroxamic chelator combining the desferriferrioxamine B siderophore and 1-hydroxy-2-piperidone ((PIPO)H), a chiral cyclic hydroxamic acid derivative, and the study by NMR spectroscopy of its zirconium complex. Nuclear Overhauser effect measurements (ROESY) indicated that the complex exists in the form of two diastereomers, in 77 : 23 ratio, resulting from the combination of the central chiralities at the 3-C of the (PIPO)H component and at the Zr4+ cation. The 44 lowest energy structures out of more than 1000 configurations/conformations returned by calculations based on density functional theory were examined. Comparison of the ROESY data and the calculated interatomic H⋅⋅⋅H distances allowed us to select the most probable configuration and conformations of the major complex.

Cyclotribenzylene alkynylgold(I) phosphine complexes: synthesis, chirality, and exchange of phosphine.

Two different alkynyl-substituted C3-symmetric cyclotribenzylenes (CTB) were synthesized in racemic and enantiomerically pure forms, and six gold(I) phosphine complexes differing by the nature of the CTB and the phosphine were prepared and characterized, in particular by NMR spectroscopy, DOSY, electronic circular dichroism (ECD), and electrospray ionization mass spectrometry (ESI-MS). Their ECD patterns depended on the substitution of the starting CTBs and were shifted bathochromically by comparison with the latter. ESI-MS in the presence of HCO2H allowed us to detect the complexes as proton adducts. The intensities of the signals were stronger when the phosphine was more electron-rich. This technique was also used to investigate the exchange of phosphine betweeen pairs of CTB complexes. The scrambling reaction was demonstrated by the higher intensity of the signals of the complexes subjected to the exchange of a single phosphine ligand by comparison with the intensity of the signals of the starting complexes.

The common denominators of Parkinson's disease pathogenesis and methamphetamine abuse.

The pervasiveness and mortality associated with methamphetamine abuse has doubled during the past decade suggesting a possible worldwide substance use crisis. Epitomizing the pathophysiology and toxicology of methamphetamine abuse proclaims severe signs and symptoms of neurotoxic and neurobehavioral manifestations in both humans and animals. Most importantly, chronic use of this drug enhances the probability of developing neurodegenerative diseases manifolds. Parkinson's disease is one such neurological disorder, which significantly and evidently not only shares a number of toxic pathogenic mechanisms induced by methamphetamine exposure but is also interlinked both structurally andgenetically. Methamphetamine-induced neurodegeneration involves altered dopamine homeostasis that promotes the aggregation of α-synuclein protofibrils in the dopaminergic neurons and drives these neurons to make them more vulnerable to degeneration as recognized in Parkinson's disease. Moreover, the pathologic mechanisms such as mitochondrial dysfunction, oxidative stress, neuroinflammation and decreased neurogenesis detected in methamphetamine abusers dramatically resemble to what is observed in Parkinson's disease cases. Therefore, the present review comprehensively cumulates a holistic illustration of various genetic and molecular mechanisms putting across the notion of how methamphetamine administration and intoxication might lead to Parkinson's disease-like pathology and Parkinsonism.

BACE1-dependent metabolism of neuregulin 1: Bridging the gap in explaining the occurrence of schizophrenia-like symptoms in Alzheimer's disease with psychosis?

Alzheimer's disease is a neurodegenerative disease mainly characterized by cortico-neuronal atrophy, impaired memory and other cognitive declines. On the other hand, schizophrenia is a neuro-developmental disorder with an overtly active central nervous system pruning system resulting into abrupt connections with common symptoms including disorganised thoughts, hallucination and delusion. Nevertheless, the fronto-temporal anomaly presents itself as a common denominator for the two pathologies. There is even a strong presumption of increased risk of developing co-morbid dementia for schizophrenic individuals and psychosis for Alzheimer's disease patients, overall leading to a further deteriorated quality of life. However, convincing proofs of how these two disorders, although very distant from each other when considering their aetiology, develop coexisting symptoms is yet to be resolved. At the molecular level, the two primarily neuronal proteins ß-amyloid precursor protein and neuregulin 1 have been considered in this relevant context, although the conclusions are for the moment only hypotheses. In order to propose a model for explaining the psychotic schizophrenia-like symptoms that sometimes accompany AD-associated dementia, this review projects out on the similar sensitivity shared by these two proteins regarding their metabolism by the ß-site APP cleaving enzyme 1.

Melatonin as a Harmonizing Factor of Circadian Rhythms, Neuronal Cell Cycle and Neurogenesis: Additional Arguments for Its Therapeutic Use in Alzheimer's Disease.

The synthesis and release of melatonin in the brain harmonize various physiological functions. The apparent decline in melatonin levels with advanced aging is an aperture to the neurodegenerative processes. It has been indicated that down regulation of melatonin leads to alterations of circadian rhythm components, which further causes a desynchronization of several genes and results in an increased susceptibility to develop neurodegenerative diseases. Additionally, as circadian rhythms and memory are intertwined, such rhythmic disturbances influence memory formation and recall. Besides, cell cycle events exhibit a remarkable oscillatory system, which is downstream of the circadian phenomena. The linkage between the molecular machinery of the cell cycle and complex fundamental regulatory proteins emphasizes the conjectural regulatory role of cell cycle components in neurodegenerative disorders such as Alzheimer's disease. Among the mechanisms intervening long before the signs of the disease appear, the disturbances of the circadian cycle, as well as the alteration of the machinery of the cell cycle and impaired neurogenesis, must hold our interest. Therefore, in the present review, we propose to discuss the underlying mechanisms of action of melatonin in regulating the circadian rhythm, cell cycle components and adult neurogenesis in the context of AD pathogenesis with the view that it might further assist to identify new therapeutic targets.

Cdk5-p25 as a key element linking amyloid and tau pathologies in Alzheimer's disease: Mechanisms and possible therapeutic interventions.

Despite the fact that the small atypical serine/threonine cyclin-dependent kinase 5 (Cdk5) is expressed in a number of tissues, its activity is restricted to the central nervous system due to the neuron-only localization of its activators p35 and p39. Although its importance for the proper development and function of the brain and its role as a switch between neuronal survival and death are unmistakable and unquestionable, Cdk5 is nevertheless increasingly emerging, as supported by a large number of publications on the subject, as a therapeutic target of choice in the fight against Alzheimer's disease. Thus, its aberrant over activation via the calpain-dependent conversion of p35 into p25 is observed during the pathogenesis of the disease where it leads to the hyperphosphorylation of the ß-amyloid precursor protein and tau. The present review highlights the pivotal roles of the hyperactive Cdk5-p25 complex activity in contributing to the development of Alzheimer's disease pathogenesis, with a particular emphasis on the linking function between Aß and tau that this kinase fulfils and on the fact that Cdk5-p25 is part of a deleterious feed forward loop giving rise to a molecular machinery runaway leading to AD pathogenesis. Additionally, we discuss the advances and challenges related to the possible strategies aimed at specifically inhibiting Cdk5-p25 activity and which could lead to promising anti-AD therapeutics.

A Single Bioinspired Hexameric Nickel Catechol-Alloxazine Catalyst Combines Metal and Radical Mechanisms for Alkene Hydrosilylation.

Mechanisms combining organic radicals and metallic intermediates hold strong potential in homogeneous catalysis. Such activation modes require careful optimization of two interconnected processes: one for the generation of radicals and one for their productive integration towards the final product. We report that a bioinspired polymetallic nickel complex can combine ligand- and metal-centered reactivities to perform fast hydrosilylation of alkenes under mild conditions through an unusual dual radical- and metal-based mechanism. This earth-abundant polymetallic complex incorporating a catechol-alloxazine motif as redox-active ligand operates at low catalyst loading (0.25 mol%) and generates silyl radicals and a nickel-hydride intermediate through a hydrogen atom transfer (HAT) step. Evidence of an isomerization sequence enabling terminal hydrosilylation of internal alkenes points towards the involvement of the nickel-hydride species in chain walking. This single catalyst promotes a hybrid pathway by combining synergistically ligand and metal participation in both inner- and outer- sphere processes.

Alkynylgold(I) C3 -Chiral Concave Complexes: Aggregation and Luminescence.

Chiral gold(I) acetylide trinuclear complexes 1-3 based on the cyclotribenzylene platform and terminal PR3 ligands (R=Ph, Et, and Cy, respectively), were characterized and their light emission studied. They exhibited long-lived blue phosphorescence in CHCl3 and a weak fluorescence in the UV. In MeOH/CHCl3 mixtures of >1:1 volume ratio, 1 and 2 exhibited a new emission band at ca. 540 nm that developed at the expense of the UV emission. DLS studies demonstrated the presence of molecular aggregates of Ø 30-80 nm. The green emission observed in MeOH-rich solvent mixtures was therefore induced by aggregation, and could originate from Au⋅⋅⋅Au interactions. The AIE spectrum of 3 was observed only in solutions containing 99 % of MeOH, and correlated with its solid state emission. The AIE profiles of the enantiomers of 1 differed from that of rac-1, suggesting that the latter is a true racemate.

Synthesis and Characterization of Andrographolide Derivatives as Regulators of ßAPP Processing in Human Cells.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aß) in the brain. Whereas ß-secretase supports Aß formation along the amyloidogenic processing of the ß-amyloid precursor protein (ßAPP), α-secretase counterbalances this pathway by both preventing Aß production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting ß-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5',7'-dichloro-8'-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2'-methyl-5',7'-dichloro-8'-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as ß-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting ß-secretase that could prove useful in our quest for the therapeutic treatment of AD.

Methamphetamine abuse disturbs the dopaminergic system to impair hippocampal-based learning and memory: An overview of animal and human investigations.

Diverse intellectual functions including memory are some important aspects of cognition. Dopamine is a neurotransmitter of the catecholamine family, which contributes to the experience of pleasure and/or emotional states but also plays crucial roles in learning and memory. Methamphetamine is an illegal drug, the abuse of which leads to long lasting pathological manifestations in the brain. Chronic methamphetamine-induced neurotoxicity results in an alteration of various parts of the memory systems by affecting learning processes, an effect attributed to the structural similarities of this drug with dopamine. An evolving field of research established how cognitive deficits in abusers arise and how they could possibly trigger neurodegenerative disorders. Thus, the drugs-induced tenacious neurophysiological changes of the dopamine system trigger cognitive deficits, thereby affirming the influence of this addictive drug on learning, memory and executive function in human abusers. Here we present an overview of the effects of methamphetamine abuse on cognitive functions, dopaminergic transmission and hippocampal integrity as they have been validated in animals and in humans during the past 20 years.

Phenanthroline impairs ßAPP processing and expression, increases p53 protein levels and induces cell cycle arrest in human neuroblastoma cells.

Mis-functional ßAPP processing is deemed to be the major phenomenon resulting in increased neuronal cell death, impaired neurogenesis and the loss of synapses, which eventually manifest as the complex symptoms of Alzheimer's disease. Despite of several milestones having been achieved in the field of drug development, the stigma of the disorder as an incurable disease still remains. Some ADAM proteases mediate the physiological non-amyloidogenic α-secretase processing of ßAPP that generates neuroprotective sAPPα production. Earlier studies have also pointed out the role of p53 in Alzheimer's disease neuropathology, although a direct link with metalloprotease activities remains to be established. In this study, we explored the consequences of α-secretase inhibition on p53 status in cultured human neuroblastoma SH-SY5Y cells by means of specific inhibitors of ADAM10 and ADAM17 and the metal chelator and general metalloprotease inhibitor phenanthroline. We establish that, beyond the ability of all inhibitors to affect sAPPα production to varying degrees, phenanthroline specifically and dose-dependently lessened ßAPP expression, a phenomenon that correlated with a strong increase in p53 protein levels and a concomitant decrease of the p53-degrading calpain protease. Furthermore, treatment of cells at concentrations of phenanthroline similar to those inducing increased levels of p53 induced cell cycle arrest leading to apoptosis. Altogether, our results identify new roles of phenanthroline in perturbing ßAPP, p53 and calpain biology, and suggest that the use of this compound and its derivatives as antimicrobial and anti-cancer therapies might trigger Alzheimer's disease pathogenesis.

N-Heterocyclic Carbene Platinum(IV) as Metallodrug Candidates: Synthesis and 195Pt NMR Chemical Shift Trend.

A series of octahedral platinum(IV) complexes functionalized with both N-heterocyclic carbene (NHC) ligands were synthesized according to a straightforward procedure and characterized. The coordination sphere around the metal was varied, investigating the influence of the substituted NHC and the amine ligand in trans position to the NHC. The influence of those structural variations on the chemical shift of the platinum center were evaluated by 195Pt NMR. This spectroscopy provided more insights on the impact of the structural changes on the electronic density at the platinum center. Investigation of the in vitro cytotoxicities of representative complexes were carried on three cancer cell lines and showed IC50 values down to the low micromolar range that compare favorably with the benchmark cisplatin or their platinum(II) counterparts bearing NHC ligands.

Cassia tora extract alleviates Aß1-42 aggregation processes in vitro and protects against aluminium-induced neurodegeneration in rats.

OBJECTIVES: To examine the ability of Cassia tora extract to produce, in vitro and in vivo, beneficial effects with respect to events occurring during Alzheimer's disease. METHODS: Previously characterised methanol extract of C. tora was tested for its ability to lessen Aß42 aggregation processes in vitro and to alleviate aluminium-induced impairments in vivo in rats. KEY FINDINGS: Cassia tora extract prevents the aggregation of monomeric, oligomeric and fibrillary Aß1-42 in vitro. Moreover, the daily ingestion of 100 and 400 milligrams of the extract per kilogram of body weight for 60 days ameliorates the neurobehavioral and cognitive abilities of aluminium-treated rats in vivo. Importantly, treatments with the extract trigger a significant recovery of antioxidant enzymes function, a diminution of lipid peroxidation and acetylcholinesterase activity, a decrease of pro-inflammatory cytokines expression and an increase of brain-derived neurotrophic factor levels in both the hippocampus and the frontal cortex. Finally, we evidence that the extract is able to ameliorate the aluminium-dependent loss of neuronal integrity in the CA1 and CA3 regions of the hippocampus. CONCLUSIONS: Altogether, our results reveal that methanol extract of C. tora is able to prevent typical AD-related events and therefore stands as a promising mild and natural anti-AD multitarget compound.

The multi-faceted impact of methamphetamine on Alzheimer's disease: From a triggering role to a possible therapeutic use.

Although it has been initially synthesized for therapeutic purposes and currently FDA-approved and prescribed for obesity, attention-deficit/hyperactivity disorder, narcolepsy and depression, methamphetamine became a recreational drug that is nowadays massively manufactured illegally. Because it is a powerful and extremely addictive psychotropic agent, its abuse has turned out to become a major health problem worldwide. Importantly, the numerous effects triggered by this drug induce neurotoxicity in the brain ultimately leading to serious neurological impairments, tissue damage and neuropsychological disturbances that are reminiscent to most of the symptoms observed in Alzheimer's disease and other pathological manifestations in aging brain. In this context, there is a growing number of compelling evidence linking methamphetamine abuse with a higher probability of developing premature Alzheimer's disease and consequent neurodegeneration. This review proposes to establish a broad assessment of the effects that this drug can generate at the cellular and molecular levels in connection with the development of the age-related Alzheimer's disease. Altogether, the objective is to warn against the long-term effects that methamphetamine abuse may convey on young consumers and the increased risk of developing this devastating brain disorder at later stages of their lives, but also to discuss a more recently emerging concept suggesting a possible use of methamphetamine for treating this pathology under proper and strictly controlled conditions.

Jouissance and death drive in Lacan's teaching / Gozo e pulsão de morte no ensino de Lacan

ABSTRACT: This article aims to analyze the Lacanian notion of jouissance and its connection to the notion of death drive. Our purpose is to highlight the evolution of the articulation between these two notions across Lacan's teaching. When Lacan first gives a theoretical basis to the notion of jouissance, he criticizes the validity of death drive as a concept. Ten years later, death drive is rehabilitated and partially assimilated to jouissance. Between these two moments, jouissance plays a central role in the French psychoanalyst's teaching.

Resumo: Este artigo tem como objetivo analisar a noção lacaniana de gozo e sua conexão com a noção de pulsão de morte. Nosso objetivo é destacar a evolução da articulação entre essas duas noções através do ensino de Lacan. Quando Lacan primeiro fornece uma base teórica à noção de gozo, ele critica a validade da pulsão de morte como um conceito. Dez anos depois, a pulsão de morte é reabilitada e parcialmente assimilada ao gozo. Entre esses dois momentos, o gozo desempenha um papel central no ensino do psicanalista francês.

Methylerythritol Phosphate Pathway: Enzymatic Evidence for a Rotation in the LytB/IspH-Catalyzed Reaction.

IspH/LytB, an oxygen-sensitive [4Fe-4S] enzyme, catalyzes the last step of the methylerythritol phosphate (MEP) pathway, a target for the development of new antimicrobial agents. This metalloenzyme converts (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Here, the synthesis of (S)-[4-2 H1 ]HMBPP and (R)-[4-2 H1 ]HMBPP is reported together with a detailed NMR analysis of the products formed after their respective incubation with E. coli IspH/LytB in the presence of the biological reduction system used by E. coli to reduce the [4Fe-4S] center. (S)-[4-2 H1 ]HMBPP was converted into [4-2 H1 ]DMAPP and (E)-[4-2 H1 ]IPP, whereas (R)-[4-2 H1 ]HMBPP yielded [4-2 H1 ]DMAPP and (Z)-[4-2 H1 ]IPP, hence providing the direct enzymatic evidence that the mechanism catalyzed by IspH/LytB involves a rotation of the CH2 OH group of the substrate to display it away from the [4Fe-4S].

A Promiscuous CYP706A3 Reduces Terpene Volatile Emission from Arabidopsis Flowers, Affecting Florivores and the Floral Microbiome.

Flowers are essential but vulnerable plant organs, exposed to pollinators and florivores; however, flower chemical defenses are rarely investigated. We show here that two clustered terpene synthase and cytochrome P450 encoding genes (TPS11 and CYP706A3) on chromosome 5 of Arabidopsis (Arabidopsis thaliana) are tightly coexpressed in floral tissues, upon anthesis and during floral bud development. TPS11 was previously reported to generate a blend of sesquiterpenes. By heterologous coexpression of TPS11 and CYP706A3 in yeast (Saccharomyces cerevisiae) and Nicotiana benthamiana, we demonstrate that CYP706A3 is active on TPS11 products and also further oxidizes its own primary oxidation products. Analysis of headspace and soluble metabolites in cyp706a3 and 35S:CYP706A3 mutants indicate that CYP706A3-mediated metabolism largely suppresses sesquiterpene and most monoterpene emissions from opening flowers, and generates terpene oxides that are retained in floral tissues. In flower buds, the combined expression of TPS11 and CYP706A3 also suppresses volatile emissions and generates soluble sesquiterpene oxides. Florivory assays with the Brassicaceae specialist Plutella xylostella demonstrate that insect larvae avoid feeding on buds expressing CYP706A3 and accumulating terpene oxides. Composition of the floral microbiome appears also to be modulated by CYP706A3 expression. TPS11 and CYP706A3 simultaneously evolved within Brassicaceae and form the most versatile functional gene cluster described in higher plants so far.plantcell;31/12/2947/FX1F1fx1.

Cassia tora prevents Aß1-42 aggregation, inhibits acetylcholinesterase activity and protects against Aß1-42-induced cell death and oxidative stress in human neuroblastoma cells.

BACKGROUND: Alzheimer's is a complex neurodegenerative disease and is characterized by extraneuronal accumulation of ß-amyloid peptide. Because of its complex nature, multi-target directed ligands (MTDLs) are increasingly being considered as promising anti-Alzheimer therapeutic agents. This study is aimed at determining the effects of Cassia tora ethyl acetate fraction on several Alzheimer-associated deleterious events in test tubes as well as in human neuroblastoma SK-N-SH and SH-SY5Y cell lines. METHOD: Ethyl acetate fraction of C. tora was purified by chromatography, characterized by 1H and 13C NMR, and tested for its ability to prevent Aß 1-42 aggregation by thioflavin-T fluorescence and transmission electron microscopy. We also analyzed the intracellular ROS level and cytotoxicity in SK-N-SH and SH-SY5Y cell lines. RESULTS: The extract inhibits the formation of Aß 1-42 aggregation from monomers and oligomers, as also acetylcholinesterase activity, Aß 1-42 -induced cell death, and Aß 1-42 -dependent intracellular ROS production in both SK-N-SH and SH-SY5Y cells. In-depth chromatographic and spectroscopic analysis of the extract revealed that the active molecules are most likely triglycerides of oleic acid (C18H34O2). CONCLUSION: We demonstrate for the first time that Cassia tora fraction prevents Aß 1-42 aggregation, inhibits acetylcholinesterase and alleviates Aß 1-42 -induced oxidative stress in human neuroblastoma cells. We further suggest the possible use of triglycerides of oleic acid as efficient anti-Alzheimer agents.

PFG-NMR as a Tool for Determining Self-Diffusivities of Various Probe Molecules through H-ZSM-5 Zeolites.

The understanding of major zeolite applications is partially based on diffusion of molecules inside or outside microporous networks. However, it is still a challenge to measure such phenomena. The diffusion ordered nuclear magnetic resonance spectroscopy (DOSY) technique has been reported to measure a probe molecule's diffusion inside porous solids. Pulsed-field gradient (PFG)-NMR has been used herein to measure the self-diffusivity of different probe molecules, such as neopentane, benzene, toluene and 1-dodecene with increasing dynamic diameter, respectively, on a series of H-ZSM-5 zeolites. The latter materials exhibit different crystal sizes, Si/Al ratios and the presence (or absence) of crystalline defects. In addition, shaped zeolite bodies representing industrial catalysts were compared with the afore-mentioned samples.