1,720,967 research outputs found
Characterization of an in vivo model of neuroinflammation and evaluation of the anti-inflammatory and neuroprotective effects of curcumin as a potential lead compound for the development of new agents useful to treat neuroinflammatory disorders
Full text linkNeuroinflammation is a complex and multifactorial response of the central nervous system (CNS) to trauma, infection and neurodegenerative diseases orchestrated by specialized immune cells (microglial and astrocytes). In particular, microglia, the main resident immune cells of the CNS, undergo rapid “activation” in response to noxious stimuli, releasing a plethora of inflammatory and potentially neurotoxic soluble factors, such as cytokines [e.g., interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α], chemokines and reactive oxygen and nitrogen species (e.g., nitric oxide). Although an efficient microglial immune response is necessary and critical for proper resolution of pathological events, it is clear that an excessive activation of these cells contributes to neuronal cell damage in neurodegenerative and psychiatric disorders. However, the molecular mechanism(s) by which these cells exert their deleterious effects on neurons remain poorly understood. Recent evidence suggests that microglial cells can be “activated” in response to a systemic inflammatory stimulus. For example, a single peripheral administration of the bacterial endotoxin lipopolysaccharide (LPS), the main component of Gram-negative bacteria walls, in adult mice, can induce microglial activation and an inflammatory state in the CNS that persists long after peripheral stimulus has decline. Identification of molecules which prevent or down-regulate microglial inflammatory responses or direct microglia towards a protective anti-inflammatory phenotype could prove efficacious in neurodegenerative diseases in which inflammation is implicated. Recently, increasing interest has focused on identifying natural compounds with potential inhibitory effects on microglial activation and subsequent inflammatory processes. Among these compounds, curcumin (diferuloylmethane), the main bioactive component isolated from the rhizome of the turmeric plant (Curcuma longa) with multiple pharmacological effects, including anti-inflammatory activities, possesses neuroprotective properties against many neurodegenerative conditions. The principal focus of this doctoral project has been the study of the possible anti-inflammatory effect of curcumin in an in vivo model of neuroinflammation based on a single systemic LPS injection. Young adult mice were intraperitoneally injected with a single dose of LPS (0.5 or 5 mg/kg) or vehicle and then tested for “sickness behavior” (e.g., changes in body weight and food intake), mRNA (real-time RT-PCR) and protein (enzyme-linked immunosorbent assay, ELISA) expression of pro-inflammatory mediators and microglia morphological changes (immune-staining with the microglial marker ionized calcium binding adaptor molecule 1) in different brain areas. Both LPS doses induced a significant decrease in food intake and body weight within the first 4 days, followed by a gradual recovery to control values; however, only 5 mg/kg LPS significantly increased TNF-α, IL-1β, IL-6, COX-2 and iNOS gene expression 2 h post-injection. Pre-treatment with 50 mg/kg curcumin (orally administered by gavage for 2 consecutive days before LPS injection) facilitated the recovery from sickness behavior (anorexia and weight loss), suppressed LPS-induced microglial morphological changes and increased of mRNA levels of TNF-α, IL-1β and COX-2 in all brain areas, while limiting expression of IL-6 and iNOS to more selected brain regions. Possible neuroprotective properties of curcumin were also investigated. In particular, mRNA expression of brain-derived neurotrophic factor (BDNF), known to play a key role in the regulation of neuronal function, as well as in learning and memory processes. Its reduced expression, described in numerous neurodegenerative disorders, contributes to the onset of structural abnormalities and functional damage in the CNS. LPS treatment reduced mRNA levels of BDNF in all brain areas analyzed up to 7 days after treatment. Pre-treatment with 50 mg/kg curcumin restored BDNF gene expression 24 hours after LPS injection, while a higher dose of curcumin (100 mg/kg) completely restored the expression of BDNF 2 hours after the inflammatory stimulus. Finally, behavioral tests demonstrated that LPS induced motor and memory impairments, that persisted even when the inflammatory process had been solved. Moreover, curcumin reversed motor deficits induced by LPS. Taken together, these data show that curcumin can prevent neuroinflammation by modulating the expression of brain pro-inflammatory mediators in vivo and also suggest a potential role of curcumin as a neuroprotective molecule able to restore BDNF levels and behavioral impairments under inflammatory conditions. In conclusion, curcumin represents a promising lead compound to discover new drug candidates, with improved therapeutic efficacy in the treatment of neurodegenerative and age-related diseases with an inflammatory etiology.La neuroinfiammazione è una risposta complessa e multifattoriale a diversi tipi di stimoli nocivi come le infezioni virali, batteriche o traumi. é noto che in questo processo le cellule microgliali giochino in ruolo chiavenel bilancio tra la risoluzione del processo infiammatorio o la progressione di questo ferso un profilo neurodegenerativo. Nel nostro lavoro abbiamo valutato gli effetti antiinfiammatori e neuroprotettivi di curcumina in un modello in vivo di neuroinfiammazione creato mediante una singola iniezione di lipopolisaccaride (LPS) intraperitoneale ad una dose di 5 mg/Kg. L'effetto di curcumina è stato valutato sul profilo citochinico, su molecole proinfimmatorie come COX-2 e iNOS su molecole neuroprotettive come il BDNF mediante saggi di RT-PCR, immunoistochimica per evidenziare l'effetto di curcumina sull'attivazione microgliale e sulla sopravvivenza dei neuroni dopaminergici in substantia nigra, attraverso l'uso di test comportamentali ai fini di valutare l'effetto protettivo di curcumina sull'attività locomotoria e la memoria dichiarativa. In cocnlusione, la curcumina è risultata essere un valido composto con proprietà antiinfiammatorie e neuroprotettive e rappresenta una molecola chiave per lo sviuppo di nuovi composti con aumentata efficacia terapeutica nel trattamento e la prevenzione di patologie neurodegenerative su base infiammatoria
A model of systemic inflammation to study neuroinflammation
Full text linkIncreasing evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. This is a reactive response of the central nervous system against noxious elements that interfere with tissue homeostasis. Neuroinflammation is mediated by inflammatory molecules released by microglial cells. Understanding and controlling interactions between the immune system and microglial activation might represent the key to prevent or delay the onset of central nervous system diseases. This chapter details techniques to generate and characterize an in vivo model of neuroinflammation based on a single intraperitoneal injection of lipopolysaccharide, which can be used to understand the wide variety of cellular and molecular mechanisms of neuroinflammation, as well as to identify new therapies by testing the anti-inflammatory properties of synthetic and natural molecules
Molecular network-selected pharmacogenomics in a case of bipolar spectrum disorder
No full textPersonal genomic analysis was used for molecular diagnosis and pharmacogenomics in a 53-year-old female suffering from alternating depressive and dysphoric episodes. A total of 52 genes and 108 SNPs were analyzed in the whole genome. Results from the pharmacogenomic analysis were consistent with the pharmacological history and indicate mutations associated with low monoaminergic tone, but also a hyperactive 5HT2A receptor, a feature that associates to a high probability of developing a bipolar condition, especially under 5-hydroxytryptamine potentiating pharmacology. This aligns with the patient developing dysphoria with high clomipramine. The pharmacokinetic genomics pointed out to some absorption, distribution, metabolism, and excretion (ADME) alterations that can lower or nullify drug's activity. A personalized regimen was proposed, with a positive outcome after 1 year
Saffron the “Red Gold” and Its CNS Activity: A Challenge for Future Applications in Nutraceuticals
Full text linkSaffron, indicated as "the red gold,"is an extraordinary spice with a unique aroma and organoleptic properties that is largely diffused in food preparation as well as a traditional medicine in many countries of the world. In the last years, several studies have considered this spice for CNS-based disorders showing its potential usefulness. In this review, we considered the role of saffron as a nutraceutical for the management of the most diffused CNS diseases considering the important role of oxidative stress on the pathogenesis of such diseases. In fact, recent findings support a crucial role of oxidative stress in different CNS diseases suggesting an important role of antioxidants. Preclinical and clinical evidence of its efficacy in different physiopathological pathways involved in several CNS diseases were discussed showing evidence of pharmacological activities and beneficial effects in pathological models or in small trials. Due to low toxicity and significant activities on oxidative stress and inflammation as well as the ability to modulate mitochondrial function, the saffron extracts and their constituents appear to be promising nutraceutical active compounds in this area. Further investigations are in progress to assess the efficacy and safety of preventive agents as nutraceuticals or as adjuvant compounds to be used in combinations with other therapeutic approaches. Saffron nutraceuticals with significant antioxidant activity can be useful in improving the quality of life of patients suffering from several different pathological conditions related to CNS. In this review, we summarized the more recent studies showing that standardized saffron products can be a valuable instrument of well-being due to their effects on multiple targets that support the health of the brain and related tissues
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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