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Nanotechnological approaches using curcumin and Withania somnifera: neuroprotection and antimicrobial activities
Get PDFTese de Doutoramento em Biologia de PlantasNeurological disorders contribute to 6.3% of the global burden of the diseases and this number is increasing every
year due to aging population. Despite enormous efforts in brain and central nervous system related research,
neurodegenerative diseases such as Alzheimer or Parkinson disease remain the world's leading cause of
disability. Moreover, neurodegenerative diseases are multifactorial pathogenesis with a complex combination of
genetic components and environmental factors. Although, several treatment methods are available to treat these
conditions, they are associated with the risk of infection, high neurosurgical cost and limited drug availability due
to the presence of blood–brain barrier (BBB).
Herbal medicine for neurological problems has gained much attention in the recent years, because of the
disadvantages of conventional therapies and increased patient compliance. Generally, the drugs obtained from
natural sources are considered to be safe alternatives. Since ancient times, plant extracts have been used in the
treatment of pathologic conditions of the central nervous system. As the methods to isolate active constituents
from plant extracts have greatly improved, the scientific understanding of psychoactive plants has also advanced
significantly. Curcuma species and Withania somnifera have been used as traditional therapeutic agents in Asian
medicine to treat various common ailments and recently reported to possess antioxidant, antidepressant and
neuroprotective effects.
Although a number of herbal-based medicines have been screened and identified, still the treatment for the
neurological disorders is not up to the required level. This is mainly because most of the herbal medicines exhibit
poor bioavailability due to low absorption, fast metabolism, and rapid systemic elimination in the body. Although
several approaches have been employed to overcome these problems, modification in the delivery method is a
promising approach. In particular, employing herbal medicine based nanocarrier system to treat neurological
disorder has gained specific interest because of its several advantages namely, the ability of nanoparticles to
deliver the drug in a pre-determined rate at a particular site of action, providing high bioavailability and low toxicity.
Compared to the conventional delivery methods, nanoparticle-mediated administration of drugs has been proven
to be the ideal way to deliver drugs for neurological disorders. Due to these advantages, pharmaceutical scientists
have started designing nanoparticle mediated drug delivery systems for herbal medicines with neurotherapeutic potential. Nanoencapsulation of bioactive compounds and extracts into the polymer matrix gives several
advantages, including protection against degradation, enhancing the solubility and bioavailability.
In this PhD thesis we have selected two important medicinal plants with proven antioxidant, antidepressant and
neuroprotective effects namely W. somnifera and Curcuma sps for nanoencapsulation and subsequent cellular
uptake with U251 glioma cells and biodistribution analysis in Zebrafish model.
First we developed HPLC methods to identify withanolides and quantify curcumin respectively from W. somnifera
extracts and Curcuma species . Extracts derived from different parts (leaves, roots and fruits) of W. somnifera were
tested. W. somnifera extract with maximum amount of withanolides and curcumin (active principle of Curcuma
sps) were selected for nanoencapsulation. We found that Purospher RP-18 e 5 µm column is ideal for efficient
separation and simultaneous quantification of withanolides whereas, Purospher C-18 column was optimum for
curcumin quantification from Curcuma sps extracts. HPLC quantification of different extracts of W. somnifera
revealed that the methanolic extract obtained from leaf tissues contain the highest amount of withanolides
compared to roots and fruits. Compared to C. aromatica, C. longa possess higher amount of curcumin.
W. somnifera extract/curcumin loaded polycaprolactone (PCL) and methoxy polyethylene glycol- polycaprolactone
(MPEG-PCL) nanoparticles were prepared by solvent displacement method. Prepared nanoparticles were
characterized for their physico-chemical properties such as size, shape, in vitro drug release and encapsulation
efficiency. After the physico-chemical characterization, we analyzed the in vitro cytotoxicity and cellular uptake of
nanoparticles by U251 glioma cells. In addition, we evaluated the protective effect of W. somnifera extract and
curcumin loaded nanoparticles against tBHP-induced insult in U251 glioblastoma cells, as a measure of
neuroprotection. Biodistribution of W. somnifera /curcumin loaded PCL and MPEG-PCL nanoparticles in animal
system were evaluated using zebrafish larvae as model organism.
Physical characterization of the prepared nanoparticles revealed that MPEG-PCL nanoparticles were smaller in
size compared to PCL nanoparticles irrespective of W. somnifera extract or curcumin encapsulation. Transmission
scanning electron microscopy (TEM) images of nanoparticles revealed a round shape in general, although the
surface of PCL nanoparticles appeared to be rough and porous. The entrapment efficacy of W. somnifera extract
and curcumin was higher in MPEG-PCL compared to PCL. We observed an initial burst release followed by a slow extended release profile for both W. somnifera extract and curcumin irrespective of the polymer used for
encapsulation.
Treatment of U251 glioma cells with PCL and MPEG-PCL nanoparticles loaded with W. somnifera extract/
curcumin evidenced the efficient cellular uptake of nanoparticles. However, MPEG-PCL nanoparticles showed
better internalization compared to PCL nanoparticles, irrespective of their W. somnifera extract/ curcumin load.
Neuroprotection assay showed that both W. somnifera/ curcumin loaded nanoparticles protect the cells from
oxidative damage. While the neuroprotective effect of W. somnifera extract increased in a dose dependent
manner, curcumin was much effective in lower concentrations. Together, our results show that W. somnifera/
curcumin loaded MPEG-PCL nanoparticles possess significantly higher neuroprotective effect in U251 human
glioma cells compared to the free drugs and their PCL counterparts.
The in vivo localization of nanoparticles in Zebrafish model suggested that the MPEG-PCL nanoencapsulation had
efficient and quicker delivery into the larvae compared with the free drug or PCL nanoparticles. Fluorescence
imaging of nanoparticles revealed that the nanoparticles were distributed throughout the animal. However, in
terms of fluorescence, the head region of animals treated with MPEG-PCL nanoparticles was more intense than
that of PCL nanoparticles, indicating that the former might be accumulating in the brain region. Together our
results suggest that delivery of W. somnifera extract/ curcumin as MPEG-PCL nanoparticles could enhance the
neuroprotective activity.
We have also tested the possibility of green synthesis of silver nanoparticles using W. somnifera extract and
evaluated the biosynthesized silver nanoparticles for their antibacterial activity in a cream formulation. We
developed a simple, fast and cost effective green synthesis technique for silver nanoparticles with potent
antimicrobial activity using W. somnifera extract. We also found that catechin, p-couparic acid, luteolin-7-glucoside
and a non-identified withanolide are the various compounds present in W. somnifera aqueous leaf extract
responsible for green synthesis. The cream incorporated with silver nanoparticles showed antimicrobial activity
against a wide variety of clinical isolates.As doenças neurodegenerativas representam 6,3% do gasto geral na saúde e este número tem vindo a aumentar
continuamente, anualmente, devido ao envelhecimento da população. Apesar do imenso esforço feito na
investigação de doenças foro neurológico, as doenças neurodegenerativas, tais como Alzheimer ou Parkinson,
permanecem uma das maiores causas de incapacidade em humanos. Além disso, as doenças
neurodegenerativas paresentam patogénese multifactorial, com uma complexa combinação de componentes
genéticos e factores ambientais. Apesar de existirem alguns métodos usados no tratamente destas patologias,
elas estão associadas a risco de infecção, custos elevados e biodisponibilidade reduzida devido à presença da
barreira hematoencefálica (BEE).
O uso de plantas medicinais em patologias do foro neurológico tem sido bastante estudado nos anos recentes,
em virtude das desvantagens da terapia convencional e indo ao encontro da vontade dos pacientes. De um modo
geral, os produtos farmacológicos derivados de plantas são considerados alternativas seguras. Desde tempos
remotos que o uso de extractos de plantas tem sido utilizado no tratamento de patologias do foro neurológico.
Assim como os dos métodos de extracção dos compostos de plantas têm evoluído significativamente, também o
conhecimento científico da acção destes compostos a nível neurológico tem aumentado de forma substancial. A
curcuma e Withania somnifera são utilizadas na medicina tradicional asiática no tratamento de várias patologias e
recentemente foram evidenciadas as suas actividades antioxidante, antidepressiva e neuroprotectora.
Apesar de algumas formulações, compostos e fitofármacos baseados em plantas terem sido identificados como
potenciais no tratamento de várias neuropatologias o seu desenvolvimento ainda não está no nível requerido para
a sua utilização. Uma das razões principais deve-se ao facto deste exibirem baixa biodisponibilidade devido à sua
baixa absorção, metabolismo e eliminação rápida pelo corpo humano. Comparado com os métodos
convencionais, a administração de fármacos via nanoparticulas tem provado ser uma alternativa eficaz para o uso
em neuropatologias. Devido a estas vantagens, os pesquisadores têm vindo a desenvolver sistemas baseados em
nanopartículas como veículos de extractos e compostos de plantas com actividade neurológica reconhecida, para
o uso em neuropatologias. A nanoencapsulação de compostos e extractos bioactivos numa matriz polimérica
apresenta várias vantagens, nomeadamente protecção contra a degradação, aumento da solubilidade e
biodisponibilidade. Neste trabalho foram seleccionadas duas plantas medicinais importantes, com actividade antioxidante,
antidepressivo e efeitos neuroprotetores comprovados, designadamente W. somnifera e Curcuma sp., para
nanoencapsulação e posteriores estudos em células U251 (de glioma) e análise de biodistribuição no modelo do
peixe zebra.
Metodologias de HPLC foram desenvolvidas para identificar a curcumina (princípio activo de Curcuma sp.) e
whitanólidos presentes em extractos de Curcuma sp e W. somnifera, respectivamente. Extractos obtidos de
diferentes partes (folhas, raízes e frutos) de W. somnifera foram testados. Os extractos contendo a máxima
quantidade de withanólidos e curcumina foram seleccionados para nanoencapsulação. Identificou-se que a
coluna Purospher RP18 (5Xm) é a ideal para uma separação eficiente e a quantificação simultânea dos
withanólidos e para uma eficiente quantificação de curcumina em extractos de Curcuma sp.. A quantificação por
HPLC de diferentes extratos de W. somnifera revelou que o extrato metanólico obtido a partir de tecidos foliares
contêm a maior quantidade de withanólidos, por comparação com raízes e frutos. Em comparação com C.
aromatica, a C. longa possui maior quantidade de curcumina.
Extractos de W. somnifera / curcumina foram incorporados em nanopartículas de policaprolactona (PCL) e
polietilenoglicol metoxi-policaprolactona (MPEG-PCL) usando o método de deslocamento de solvente. As
nanopartículas preparadas foram caracterizado pelas suas propriedades físico-químicas, tais como tamanho,
forma, libertação do fármaco e a eficiência de encapsulação. Após a caracterização físico-química, analisou-se a
citotoxicidade in vitro e a absorção celular das nanopartículas usando células de glioma U251. Além disso,
avaliou-se o efeito protector das nanopartículas contendo extracto de W. somnifera ou curcumina contra o insulto
oxidativo induzida por t-BHP, como uma medida de neuroproteção. A biodisponibilidade destas nanopartículas
contendo o extracto de de W. somnifera ou curcumina foi avaliada ainda num modelo animal, usando alevins de
peixe zebra.
A caracterização física das nanopartículas revelou que as nanopartículas de MPEG - PCL foram menores em
dimensão em comparação com as nanopartículas de PCL, independentemente do encapsulamento ter utilizado
extracto de W. somnifera ou curcumina. A microscopia de varrimento electrónico de transmissão (TEM) das
nanopartículas revelou uma forma redonda, em geral , embora a superfície das nanopartículas de PCL parece ser
áspero e poroso. A eficácia de aprisionamento do extracto de W. somnifera e curcumina foi maior em MPEG-PCL, quando
comparado com o PCL. Observou-se uma libertação rápida. inicial, seguida de um perfil de libertação lenta e
prolongada para ambos extractos, W. somnifera e curcumina, independentemente do polímero utilizado para a
encapsulação.
O tratamento de células U251 (giloma) com nanopartículas de PCL e MPEG-PCL carregadas com extracto de W.
somnifera ou curcumina evidenciou uma absorção celular eficiente de nanopartículas. No entanto, as
nanopartículas de MPE-PCL mostraram uma melhor internalização em comparação com as nanopartículas de
PCL, independentemente da sua carga com extracto de W. somnifera ou curcumina. Ensaios de neuroproteção
mostraram que nanopartículas contendo extracto de W. somnifera ou curcumina protegem as células dos danos
oxidativos. Enquanto o efeito neuroprotector do extracto W. somnifera aumentou de uma forma dependente da
dose, a curcumina foi muito eficaz em concentrações mais baixas. Em conjunto, os nossos resultados mostraram
que em células de glioma humano U251 as nanopartículas de MPEG-PCL carregadas com extracto de W.
somnifera ou curcumina possuem, significativamente. um maior efeito neuroprotector em comparação com os
fármacos livres ou seus homólogos encapsulados em PCL .
A localização in vivo das nanopartículas no modelo de peixe zebra sugeriu que a nanoencapsulação em MPEGPCL
teve uma biodisponibilidade mais eficiente e rápida quando comparado com o fármaco livre ou em
nanopartículas de PCL. Imagiologia de fluorescência das nanopartículas revelou que as mesmas encontram-se
distribuídas por todo o animal. No entanto, a região da cabeça dos animais tratados com nanopartículas de
MPEG-PCL era mais intensa do que com nanoparticulas de PCL. Os resultados sugerem que a entrega de
extracto de W. somnifera / curcumina por nanopartículas de MPEG-PCL poderá aumentar a atividade
neuroprotetora.
Também foi testada a possibilidade de biossíntese de nanopartículas de prata usando o extrato de W. somnifera e
avaliou-se a sua atividade antibacteriana numa formulação de creme. Foi desenvolvido um método rápido, de
baixo custo e eficaz para a síntese verde de nanopartículas de prata com potente atividade antimicrobiana
utilizando o extrato de W. somnifera. Também foi evidenciado que entre os vários compostos presentes no
extracto de W. somnifera, a catequina, ácido p-couparico, luteolina -7- glicosídeo e um withanolido (não identificada) são os responsáveis pela biossíntese das nanopartículas. O creme incorporando nanopartículas de
prata mostrou actividade antimicrobiana contra uma ampla variedade de isolados clínicos (bactérias e leveduras).A tese de doutoramento aqui apresentada foi desenvolvida no âmbito de financiamento pela Fundação para a Ciência e Tecnologia (FCT) através de uma bolsa individual de doutoramento, com a referência SFRH/BD/72809/2010 (no âmbito do QREN - POPH - Tipologia 4.1 - Formação Avançada, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES)
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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