A Curcumin há muito tempo é utilizada como condimento, colorífico e na medicina tradicional asiática. Conhecida como açafrão-da-índia, recentemente tem chamado a atenção devido ao grande potencial medicinal. Surgiram trabalhos principalmente sobre seus supostos efeitos benignos no tratamento de câncer e Alzheimer porém não limitados a estas enfermidades. Na tentativa de otimizar as propriedades medicinais surgiu a Dimethoxy Curcumin, um composto sintético que apresenta maior citotoxicidade e estabilidade biológica que a Curcumin. A maioria das reações químicas e biológicas ocorrem em soluções e os efeitos dos solventes são de extrema importância e complexidade. Neste trabalho nós estudamos os efeitos dos solventes ciclohexano e acetonitrila nos espectros de absorção e emissão da Dimethoxy Curcumin. Consideramos a contribuição de diferentes isômeros e estados excitados usando a Teoria do Funcional Densidade Dependente do Tempo (TD-DFT) utilizando a aproximação Modelo Contínuo Polarizável para o solvente. Nós observamos que as energias de emissão dos estados singletos sofrem um deslocamento para o vermelho enquanto que os estados tripletos sofrem um deslocamento para o azul. Respondemos estas questões analisando a variação do momento de dipolo durante a transição. Neste trabalho encontramos boa concordância com os valores experimentais dos espectros de absorção, emissão, deslocamento espectral e deslocamento Stokes. / The Curcumin has long been used as a condiment, pigment and in the traditional Asian medicine. Known as turmeric, recently has attracted attention because of the large medical potential. Several studies were made mainly about the supposed benign effects in the treatment of cancer and Alzheimer but not limited to these diseases. Attempt to optimize their medicinal properties there appeared the Dimethoxy Curcumin, a synthetic compound that has a higher cytotoxicity and biological stability than Curcumin. Most of the chemical and biological reactions occur in solutions and the solvent effects are of great importance and complexity. In the present work, we study the effects of the solvents cyclohexane and acetonitrile in the absorption and emission spectra of Dimethoxy Curcumin. We consider the contribution of various isomers and excited states using the Time Dependent Density Functional Theory (TD-DFT) with the Polarizable Continuum Model (PCM) approximation for the solvent. We observe that the emission energy of the singlet states are red shifted while the triplet states are blue shifted. We address this by analyzing the dipole moment variation after the transition. We find good agreement with the experimental values for the absorption, emission, spectral shift and Stokes shift

Les nerfs périphériques sont sujets à de nombreuses pathologies et l’étiologie des neuropathies périphériques (NP) est vaste (troubles métaboliques, infections, toxines, blessures physiques et mutations génétiques, ect.). Par exemple, les NP d’origine traumatique sont courantes et sont caractérisées par une dégénérescence dite Wallérienne des fibres nerveuses. Autre exemple, la maladie de Charcot-Marie-Tooth 1A (CMT1A) qui est la NP génétique héréditaire la plus fréquente. Elle est caractérisée par une surexpression de la protéine PMP22 impliquée dans le maintien de la gaine de myéline. Actuellement, il n’existe pas de traitement pharmacologique de ces deux affections des nerfs. Récemment, l’intérêt pour le rôle des antioxydants alimentaires, tels que la curcumine, a suscité de nombreuses recherches. Cette molécule est depuis longtemps utilisée en médecine asiatique pour ces propriétés thérapeutiques. Cependant, elle possède une très faible biodisponibilité et nécessite donc l’emploi de doses très élevées pour obtenir des effets bénéfiques. Dans une première étude, nos résultats ont montré que des faibles doses de curcumine administrées localement et en continu, améliorent la récupération fonctionnelle, les paramètres électrophysiologiques et histologiques, et l’expression des principales protéines de la myéline dans un modèle d’écrasement du nerf sciatique chez le rat. Ces effets bénéfiques ont été attribués aux propriétés antioxydantes de la curcumine. Dans une seconde étude, nos résultats ont montré qu’une faible dose de nanocristaux de curcumine (Nano-Cur), injectée en IP, améliorent le phénotype, les paramètres électrophysiologiques et histologiques dans un modèle transgénique de rat CMT1A. Dans cette étude, les effets positifs ont été attribués aux propriétés antioxydantes des Nano-Cur, couplés à l’activation de la voie de dégradation associée au réticulum endoplasmique, permettant la réduction de la surexpression nocive de PMP22 chez les rats CMT1A. L'ensemble de ces résultats démontrent que, l’administration de faibles doses de curcumine constitue un traitement prometteur dans la réparation des nerfs périphériques. / Peripheral nerves are subject to many pathologies and the etiology of peripheral neuropathies (PN) is vast (metabolic disorders, infections, toxins, physical injuries and genetic mutations, etc.). For example, PN of traumatic origin are common and are characterized by a called Wallerian degeneration of nerve fibres. Another example is Charcot-Marie-Tooth disease 1A (CMT1A), which is the most common hereditary genetic PN. It is characterized by an overexpression of the PMP22 protein involved in maintaining the myelin sheath. Currently, there is no pharmacological treatment for these two nerve disorders. Recently, interest in the role of dietary antioxidants, such as curcumin, has led to much research. This molecule has long been used in Asian medicine for its therapeutic properties. However, it has a very low bioavailability and therefore requires the use of very high doses to obtain beneficial effects. In a first study, our results showed that low doses of curcumin administered locally and continuously improve functional recovery, electrophysiological and histological parameters, and expression of major myelin proteins in a rat sciatic nerve crush model. These beneficial effects have been attributed to the antioxidant properties of curcumin. In a second study, our results showed that a low dose of curcumin nanocrystals (Nano-Cur), injected in IP, improves phenotype, electrophysiological and histological parameters in a transgenic model of CMT1A rats. In this study, the positive effects were attributed to the antioxidant properties of the Nano-cur, coupled with the activation of the endoplasmic reticulum associated degradation pathway, allowing the reduction of harmful overexpression of PMP22 in CMT1A rats. All these results show that the administration of low doses of curcumin is a promising treatment for peripheral nerve repair

Orientador: Morgana Rodrigues Guimarães Stabili / Resumo: Curcumin é um composto ativo derivado da planta Curcuma longa que exibe uma variedade de atividades biológicas. Inúmeros estudos têm documentado seu potencial anti-inflamatório e imunomodulatório, que pode ser associado ao tratamento de uma série de condições, como doenças inflamatórias intestinais, artrite reumatoide, câncer, diabetes, periodontite, bem como no tratamento de lesões de líquen plano oral (LPO). LPO é uma doença autoimune, mediada por células T e caracterizada pelo aparecimento de lesões nos tecidos orais, geralmente associada a sintomatologia dolorosa e com potencial de malignidade de 0,4% a 5%. Inúmeras pesquisas têm sido conduzidas com objetivo de determinar um tratamento eficaz e seguro para a doença, mas até o momento não há um protocolo padrão. O uso de corticosteroides tem sido a modalidade de tratamento mais indicada, entretanto, a necessidade de utilização destes fármacos por longos períodos e em altas doses podem provocar imunossupressão da cavidade oral. A literatura tem mostrado benefícios do curcumin sobre a redução dos sinais e sintomas da doença, além da ausência de toxicidade, mas a baixa biodisponibilidade do composto parece limitar sua efetividade clínica. Sua veiculação em nanopartículas tem sido uma das estratégias utilizadas para melhorar as características farmacológicas do composto e potencializar seus efeitos biológicos. Nesse estudo, propomos avaliar o potencial da aplicação tópica do curcumin nanoparticulado sobre a redução de sinais e... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Curcumin is an active compound derived from the Curcuma longa plant that exhibits a variety of biological activities. Numerous studies have documented its anti-inflammatory and immunomodulatory potential, which can be associated with the treatment of a number of conditions, such as inflammatory bowel diseases, rheumatoid arthritis, cancer, diabetes, periodontitis, as well as in the treatment of oral lichen planus lesions (OLP). OLP is an autoimmune disease, mediated by T cells and characterized by the appearance of lesions in the oral tissues, usually associated with painful symptoms and with a malignant potential of 0.4% to 5%. Countless research have been conducted with the objective of determining an effective and safe treatment for the disease, but so far there is no standard protocol. The use of corticosteroids has been the most indicated treatment modality, however, the need to use these drugs for long periods and in high doses can cause immunosuppression of the oral cavity. The literature has shown benefits of curcumin on reducing signs and symptoms of the disease, in addition to the absence of toxicity, but the low bioavailability of the compound seems to limit its clinical effectiveness. Its delivery in nanoparticles has been one of the strategies used to improve the pharmacological characteristics of the compound and enhance its biological effects. In this study, we propose to evaluate the potential of topical application of curcumin -loaded nanoparticle on the redu... (Complete abstract click electronic access below) / Mestre

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<p>Neuroinflammation associated with lumbar radiculopathy and peripheral nerve injury is characterized by locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF&alpha;). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in local delivery of anti-inflammatory drugs to treat this pathology, as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNF&alpha; in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. </p><p>ELPs are biopolymers capable of thermally-triggered in situ depot formation and have been successfully employed as drug carriers and biomaterials in several applications. A library of ELP-curcumin conjugates were synthesized and characterized. One lead conjugate was shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNF&alpha; and NF-&kappa;B with near-equivalent potency compared to free curcumin. When injected into the perineural space via intramuscular (i.m.) injection proximal to the sciatic nerve in mice, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4 days post-injection and decreased systemic exposure of curcumin 3-fold. </p><p>The results of this dissertation support the use of ELP as a drug carrier for local perineural drug delivery, and the strategy presented here for drug conjugate development and use of depot-forming ELP-curcumin conjugates represents a novel means of providing sustained treatment of neuroinflammation and pain associated with radiculopathy and peripheral nerve injury.</p> / Dissertation

Alzheimer’s disease is a devastating neurodegenerative disorder and the leading cause of dementia. The disease manifests via several pathologies including neuroinflammation, oxidative stress, metal ion dyshomeostasis, and cell death. To address the multifaceted nature of this disorder, the design of several diverse compounds, targeting many pathological effects, was generated. First, a series of compounds based on curcumin and diosgenin were synthesized following the bivalent design strategy. Two compounds were discovered to have neuroprotective ability, anti-oxidative function, and anti-Aß oligomerization (AßO) properties. A second set of molecules was also designed, wherein a hybrid compound strategy was utilized. Three hybrids were to shown to protect MC65 cells from Aß-induced toxicity and to have significant anti-oxidative activity. Mechanistic studies propose that protection is through disruption of interactions between AßOs and partner proteins. Furthermore, one hybrid was also shown to be able to pass the BBB. Lastly, studies of glyburide, an anti-diabetic medication, have shown an off-target anti-inflammatory effect specific for the NLRP3 inflammasome, which has been implicated in AD development. Therefore, a series of glyburide analogs were synthesized and characterized. One analog was able to successfully inhibit the NLRP3 inflammasome and reduce IL-1ß expression without affecting blood glucose. In vivo studies demonstrated an ability to prevent or ameliorate adverse inflammation-related outcomes in murine inflammatory models. Altogether, these investigations have yielded three novel series of compounds, all capable of modifying Alzheimer’s disease pathology. These results warrant future investigations into the development, optimization, and characterization of these analogs as potential treatments for Alzheimer’s disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab has developed hybrid molecules of curcumin and melatonin that exhibited potent neuroprotective ability in various AD models. Further modifications identified a lead compound with potent neuroprotective and antioxidative activity in MC65 cells, while also establishing the hybrid strategy as a viable approach in providing unique chemotypes with novel pharmacology. Further preliminary biological studies suggest that the lead is orally available and exhibits multifunctional properties both in vitro and in vivo on AD pathologies, thus strongly encouraging further structural examination. Herein, we report the structural exploration of this chemical template through structure-activity relationship studies at three domains: the phenyl domain, α,β-unsaturated β-ketone amide domain, and the indole domain. Collectively, the results show that the chemical space around the curcumin portion doesn’t favor electronic or steric/hydrophobic interactions, but might favor pi-pi (π-π) and hydrogen-bond interactions. Additionally, the α,β-unsaturated β-ketone amide domain is not as important as the linearity of the β-ketone acetamide. Moreover, the results indicate that a free rotatable β-OH might be the actual moiety that is important for the observed biological activity through favorable hydrogen bonds. Finally, steric interactions are not favored in the chemical space surrounding the indole nitrogen, suggesting that hydrogen bond interactions are required for the observed neuroprotective activity. Conversely, a hydrogen bond acceptor is necessary at the 5-position of the indole ring and bulky substitutions can be accommodated, with restrictions, suggesting steric tolerance and hydrophobic interactions at this position. These modifications have yielded a series of novel compounds that are capable of modifying AD pathology while shedding further light onto the chemical scaffold thus warranting future investigations into the development, optimization, and characterization of these curcumin/melatonin hybrids as potential treatments for AD.

Orientador: Alessandra Nara de Souza Rastelli / Resumo: A inativação fotodinâmica é descrita como terapêutica promissora na inativação de micro-organismos bucais. A curcumina é um fotossensibilizador com característica hidrofóbica, e que pode comprometer a sua eficiência. Dessa forma, torna-se relevante o desenvolvimento de estudos que verifiquem o seu efeito quando conjugada a micelas poliméricas. O objetivo deste estudo foi avaliar a efetividade da inativação fotodinâmica em biofilme de Streptococcus mutans utilizando-se curcumina, conjugada ou não, a micelas como fotossensibilizador, irradiado por luz LED. Realizou-se a caracterização das micelas poliméricas nas concentrações de 0.1 e 0.5% de curcumina, por meio do Potencial Zeta, determinação do espalhamento de luz dinâmico, microscopia eletrônica de transmissão e a investigação dos mecanismos envolvidos na reação fotodinâmica. Após, foi selecionada a melhor concentração a ser utilizada na inativação fotodinâmica sobre biofilme de Streptococcus mutans. As concentrações inibitória mínima (CIM) e bactericida mínima (CBM) foram determinadas. Foram induzidos em placa de 96 poços biofilmes single espécie. Os biofilmes foram irradiados uniformemente com sistema de iluminação a LED (Biotable, MMO) em comprimento de onda de 460 nm com dose/densidade de energia de 15 J/cm2 . Unidades formadoras de colônia (UFC/mL), a partir da CIM e CBM foram obtidas. Por meio de microscopia confocal utilizando-se corante BacLight® LIVE/DEAD foi avaliado a viabilidade celular nos biofilmes. Diferente... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Photodynamic inactivation is described as promising therapy in the inactivation of oral microorganisms. Curcumin is a hydrophobic photosensitizer, which can compromise its efficiency. Thus, the development of studies that verify its effect when conjugated to polymeric micelles becomes relevant. The objective of this study was to evaluate the effectiveness of photodynamic inactivation in Streptococcus mutans biofilm using curcumin, conjugated or not, to micelles as photosensitizer, irradiated by LED light. The characterization of the polymeric micelles in the 0.1% and 0.5% concentrations of curcumin was carried out by Zeta Potential, determination of dynamic light scattering, transmission electron microscopy and investigation of the mechanisms involved in the photodynamic reaction. After that, the best concentration to be used in photodynamic inactivation on Streptococcus mutans biofilm was selected. Minimum inhibitory concentrations (MIC), minimal bactericidal (MBC) were determined. Single-species biofilms were induced in 96-well plate. The biofilms were uniformly irradiated with a LED illumination system (Biotable, MMO) at wavelength of 460 nm with dose or energy density of 15 J/cm2. Colony forming units (CFU / mL) from CIM and CBM were obtained. By means of confocal microscopy using BacLight® LIVE/DEAD dye, cell viability in biofilms was evaluated. Different groups were analyzed: FSM+L+ (Photosensitizer conjugate micelles Pluronic + Light), FSD+L+ (Photosensitizer in 10% DM... (Complete abstract click electronic access below) / Mestre

Orientador: Celso Valentim Santilli / Resumo: A incidência de infecções cutâneas causadas por agentes bacterianos resistentes ao tratamento convencional com antibióticos tornou-se um grande problema de saúde pública. Algumas abordagens terapêuticas alternativas têm sido propostas, dentre elas a terapia fotodinâmica antimicrobiana (aPDT) e hipertermia magnética (HM). A aPDT envolve a geração de espécies reativas de oxigênio (EROs) por meio da combinação de luz, oxigênio molecular e um agente fotossensibilizador (FS), e a HM promove o aumento da temperatura de uma região anatômica submetendo nanopartículas superparamagnéticas de óxido de ferro (SPIONPs) a um campo magnético alternado (CMA). O FS de escolha para este estudo foi a curcumina (CUR), muito usado em aPDT, porém tem a fotoavidade fortemente afetada em meios aquosos devido à tendência a agregação. Visando evitar isto, além de promover a melhoria da administração da CUR e a combinação de aPDT e HM num único material foi proposto neste trabalho a síntese de conjugados SPIONP-curcumina (Magh-CUR), assim como a sua avaliação em aPDT e HM contra Staphylococcus aureus em fase planctônica. Este material magnético foi preparado por uma metodologia de coprecipitação alcalina seguida por uma etapa de conjugação com a CUR. Os conjugados foram caracterizados por difração de raios X, microscopia eletrônica de transmissão, potencial zeta, espectroscopia no infravermelho com transformada de Fourier, termogravimetria, magnetometria e ensaios de HM. Os resultados evidenciaram que ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The incidence of cutaneous infections caused by bacteria resistant to conventional antibiotic treatment has become a major public health problem. Some alternative therapeutic approaches have been proposed, among them antimicrobial photodynamic therapy (aPDT) and magnetic hyperthermia (MH). The aPDT involves the generation of reactive oxygen species (ROS) by using the combination of light, molecular oxygen and a photosensitizing agent (PS), and MH promotes temperature increase of an anatomic region by subjecting superparamagnetic iron oxide nanoparticles (SPIONPs) to an alternating magnetic field (AMF). The PS of choice for this study was curcumin (CUR), widely used in aPDT, but still has its photoactivity strongly affected in aqueous media due to the tendency of aggregation. In order to solve this problem and to promote the improvement of the administration of CUR, we propose the combination of CUR and SPIONPs of maghemite in a single material. Therefore, the objective of this work was to synthesize a SPIONPs-curcumin conjugate (Magh-CUR) and, mediated by the aPDT, to evaluate it against Staphylococcus aureus in the planktonic phase. This magnetic material was prepared by an alkaline coprecipitation method followed by a conjugation step with CUR. The conjugates were characterized by X-ray diffraction, electron transmission microscopy, zeta potential, infrared spectroscopy with Fourier transform, thermogravimetry, magnetometry, MH assays. The characterizations showed that the ... (Complete abstract click electronic access below) / Mestre