Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier

Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15â 20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0(3) was found to be a selective COX-1 inhibitor (COX-1 IC50= 0.27 μM and COX-2 IC50= 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0(3) powerfully inhibits PGE2release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site

Ligand-guided investigation of a series of formamidine-based thiuram disulfides as potential dual-inhibitors of COX-1and COX-2

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available in the supplementary material of this article.A series of thiuram disulfides 1–6 which had been previously synthesized and characterized, were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.The College of Agriculture, Science, and Engineering, the University of Kwazulu-Natal, Olabisi Onabanjo University and the National Research Foundation (NRF), South Africa.http://www.cb.wiley.comam2024BiochemistryGeneticsMicrobiology and Plant PathologySDG-03:Good heatlh and well-bein

Synthesis and biological studies of N,N'-diarylformamidine dithiocarbamate metal complexes.

Doctoral Degree. University of KwaZulu-Natal, Durban.Abstract available in PDF

Chemical probes for studying cyclooxygenase-2 and nitric oxide in living systems

Molecular imaging enables the direct detection of analytes and biomolecular species within their native biological environment. Although the field derives from diagnostic biomedical imaging, there has been a significant shift over the past couple decades towards using imaging to evaluate and discover biology. In general, molecular imaging relies on the development of chemical or biochemical tools that accumulate at the site of interest or under undergo a selective, observable change following target engagement. Activity-based sensing is a powerful expansion of molecular imaging because it measures chemical reactivity rather than concentration. Chapter 1 serves as an introduction to molecular imaging with a historical tone. It also defines and highlights key examples of binding-based and activity-based sensing probes to contextualize the following chapters. Chapter 2 discusses the design and validation of a fluorescent probe for detecting cyclooxygenase-2 activity with live cells, as well as the discovery of oxygen-dependent regulation that is not observed on the protein expression level. Chapter 3 summarizes our progress towards the development of photoacoustic probes for imaging nitric oxide within live animals. Topics include the preparation of a photoacoustic probe for imaging nitric oxide in a small animal model of inflammation, the optimization of the aza-BODIPY dye platform to detect cancer-derived nitric oxide, and progress towards a multimodal dye platform for photoacoustic and fluorescence imaging

1913-2013

One hundred have passed, and the journey continues. This work was created by a group of professors of the (former) Faculty of Agriculture of the University of Florence, and has the sole purpose of telling, through a few significant subjects, about the first one hundred years (1913-2013) of an institution which, thanks to its researchers, technicians and administrative department, has contributed as one to the advancement of knowledge in the Agricultural Sciences and, in the local area, to the success of the agri-food sector in Tuscany. However, the real protagonists of this work are not only the Teachers of the School of Agricultural and Forestry Sciences of the University of Florence, but also the thousands of students who, over a century, have attended the National Forestry Institute first, and then the Faculty, and who have brought the fruits of the teachings they received in Florence to Italy and to the whole world

Role of Natural Compounds in Inflammation and Inflammatory-Related Diseases

The papers reported here will contribute to proposing new insights into the mechanisms of several conditions, as well as suggesting new diagnostic alternatives and therapeutic targets in widespread pathologies such inflammation and inflammatory-based diseases. The discovery of the new is, as always, anchored in recourse to the old

Modelo de interacción molecular de metabolitos presentes en la especie Cannabis satival con la enzima ciclooxigebasa-1 (COX1) y la enzima ciclooxigensa-2 (COX2) de homo sapines

265 páginas : ilustraciones, gráficasEn el represente estudio se determinó la interacción molecular de los metabolitos conocidos en la especie Cannabis sativa L. con las dos isoformas de la enzima ciclooxigenasa (COX1 y COX2) de Homo sapiens, a partir del uso de técnicas computacionales de modelamiento por homología y acoplamiento (docking). Se modelaron por medio de homología de proteínas las dos isoformas enzimáticas COX1 y COX2 de Homo sapiens, obteniéndose modelos teóricos moleculares validos según el grafico de Ramachandran. Además, se sometieron los modelos obtenidos a un acoplamiento molecular con dos compuestos endógenos: ácido araquidónico y PGG2, y dos fármacos de actividad conocida: Flurbiprofeno y Celecoxib. Dichos acoplamientos fueron establecidos en los sitios catalíticos peroxidasa, para la enzima COX1 y ciclooxigenasa, para la enzima COX2, demostrando la idoneidad de los modelos para el posterior cribado virtual. Por otro lado, los 113 compuestos seleccionados, provenientes de la especie Cannabis sativa L. fueron evaluados a partir de los criterios establecidos por Lipinski, en donde 93 de los compuestos cumplieron con todos los criterios. El metabolito de biotransformación mayoritario de cada uno de los 93 compuestos fue determinado, por medio de revisión bibliográfica, siendo la adición de grupos hidroxilos la reacción más frecuente en todos los compuestos. Los 93 compuestos seleccionados y sus metabolitos de biotransformación fueron sometidos a un proceso de cribado virtual, en donde se establecieron cuatro categorías de estudio y se seleccionaron los primeros cuatro compuestos o metabolitos de biotransformación con el valor de energía libre de unión (ΔG) y constante de inhibición (ki) más bajo en cada una de las categorías. El primer cribado virtual fue realizado para los 93 compuestos producto de biosíntesis en la especie Cannabis sativa L y la enzima COX1 (CATEGORIA I), el segundo relacionó los mismos compuestos y la enzima COX2 (CATEGORIA II); en la tercera categoría se efectuó el cribado virtual entre los productos de biotransformación y la COX1 (CATEGORIA III), y la cuarta categoría dichos productos de biotransformación fueron evaluados frente a la COX2 (CATEGORIA IV). Para la primera categoría se seleccionaron los siguientes compuestos: Friedelin, Delta-7-cis-isotetrahidrocannabivarina, Cannabinol-C2 y Epifriedelanol. En la Categoría II fueron seleccionados los siguientes compuestos: Delta-9-tetrahidrocannabinol, Cannabiorcol, Delta-9-tetrahidrocannabivarina y 10-oxo-delta-6a-tetrahidrocannabinol. En la Categoría III los metabolitos de biotransformación que siguen fueron seleccionados: Luteolin, Friedelin, Ácido delta-9-tetrahidrocannabinolico A y 3,3’-dihydroxy-5,4’-dimethoxy bibenzyl. Finalmente, en la Categoría IV fueron seleccionados los siguientes metabolitos de biotransformación: Luteolin, Delta-9-tetrahidrocannabivarina, Delta-7- cis-iso-tetrahidrocannabivarina y Cannabinol-C2. Los cuatro compuestos y los cuatro metabolitos de biotransformación seleccionados en el cribado virtual con el modelo teórico molecular de la enzima COX1 y COX2, respectivamente fueron sometidos a un proceso de acoplamiento molecular con las enzimas correspondientes. Todos los compuestos y metabolitos de biotransformación acoplados con la enzima COX1, presentaron interacciones de tipo hidrofóbico, pi-pi y catión-pi con aminoácidos importantes en el sitio catalítico peroxidasa (GLN203, HIS207 y PHE409). En contraste, siete de los compuestos acoplados con la enzima COX2 se unieron al sitio activo ciclooxigenasa y presentaron interacciones con aminoácidos involucrados en la reacción catalítica ciclooxigenasa (TYR248, VAL349, TYR355, TYR385 y SER530) excepto el metabolito de biotransformación Luteolin-7- glucósido, quien se unió al sitio activo catalítico peroxidasa, debido a su bajo valor de coeficiente de partición octanol:agua. Además, este metabolito fue el único compuesto evaluado que mostró una interacción tipo puente de hidrógeno. El tamaño de los compuestos y su hidrofobicidad puede estar implicado en la selectividad frente a los dos sitios activos catalíticos de las isoformas estudiadas. Así, los compuestos posible candidatos a fármacos inhibidores de la enzima COX1 se ven representados en los compuestos pertenecientes a la clase terpénica (Friedelin, Epifriedelanol y el metabolito de biotransformación del Friedelin), debido a su potencia. La alta selectividad del terpeno Friedelin frente al modelo teórico de la enzima COX1 de Homo sapiens, permite que dicho compuesto sea una alternativa viable al desarrollo de un posible fármaco. La subclase cannabinoide delta-9-tetrahidrocannabinol, por otro lado, presenta una inhibición selectiva frente al modelo teórico de la enzima COX2 de Homo sapiens, con una alta afinidad de unión. Los compuestos cannabinoides han sido ampliamente estudiados frente a su acción terapéutica, sin embargo, nuestros resultados demuestran que en otras clases fitoquímicas de compuestos pueden encontrarse una alternativa al tratamiento del dolor y la inflamaciónIn the present study, the molecular interaction of the metabolites known in the Cannabis sativa L. species with the two isoforms of the enzyme cyclooxygenase (COX1 and COX2) of Homo sapiens was determined, from the use of computational techniques of modeling by homology and coupling (docking). The two COX1 and COX2 enzymatic isoforms of Homo sapiens were modeled by means of protein homology, obtaining valid molecular theoretical models according to the Ramachandran graph. In addition, the obtained models were subjected to a molecular coupling with two endogenous compounds: arachidonic acid and PGG2, and two drugs of known activity: Flurbiprofen and Celecoxib. These couplings were established in peroxidase catalytic sites, for the enzyme COX1 and cyclooxygenase, for the COX2 enzyme, demonstrating the suitability of the models for subsequent virtual screening. On the other hand, the 113 selected compounds, from the Cannabis sativa L. species were evaluated based on the criteria established by Lipinski, where 93 of the compounds met all the criteria. The major biotransformation metabolite of each of the 93 compounds was determined by means of a literature review, the addition of hydroxyl groups being the most frequent reaction in all the compounds. The 93 selected compounds and their biotransformation metabolites were subjected to a virtual screening process, where four study categories were established and the first four biotransformation compounds or metabolites were selected with the value of binding-free energy (ΔG) and constant of inhibition (ki) lower in each of the categories. The first virtual screening was performed for the 93 compounds produced by biosynthesis in the species Cannabis sativa L and the enzyme COX1 (CATEGORY I), the second related the same compounds and the enzyme COX2 (CATEGORY II); in the third category, virtual screening was carried out between the biotransformation products and the COX1 (CATEGORY III), and the fourth category said biotransformation products were evaluated against the COX2 (CATEGORY IV). For the first category, the following compounds were selected: Friedelin, Delta-7-cis-isotetrahydrocannabivarin, Cannabinol-C2 and Epifriedelanol. In Category II the following compounds were selected: Delta-9- tetrahydrocannabinol, Cannabiorcol, Delta-9-tetrahydrocannabivarin and 10-oxo-delta-6a-tetrahydrocannabinol. In Category III the following biotransformation metabolites were selected: Luteolin, Friedelin, Delta-9-tetrahydrocannabinol A and 3,3'-dihydroxy-5,4'-dimethoxy bibenzyl. Finally, in Category IV the following biotransformation metabolites were selected: Luteolin, Delta-9-tetrahydrocannabivarin, Delta-7- cis-iso-tetrahydrocannabivarin and Cannabinol-C2. The four compounds and the four metabolites of biotransformation selected in the virtual screening with the theoretical molecular model of the enzyme COX1 and COX2, respectively, were subjected to a process of molecular coupling with the corresponding enzymes. All the biotransformation compounds and metabolites coupled with the COX1 enzyme showed interactions of hydrophobic type, pi-pi and cation-pi with important amino acids in the catalytic peroxidase site (GLN203, HIS207 and PHE409). In contrast, seven of the compounds coupled with the COX2 enzyme were linked to the active site cyclooxygenase and presented interactions with amino acids involved in the cyclooxygenase catalytic reaction (TYR248, VAL349, TYR355, TYR385 and SER530) except the biotransformation metabolite Luteolin-7- glucoside, who joined the peroxidase catalytic active site, due to its low partition coefficient octanol: water. In addition, this metabolite was the only compound evaluated that showed a hydrogen-bond type interaction. The size of the compounds and their hydrophobicity may be involved in the selectivity towards the two catalytic active sites of the isoforms studied. Thus, the possible candidate compounds for drugs that inhibit the COX1 enzyme are represented in the compounds belonging to the terpenic class (Friedelin, Epifriedelanol and the biotransformation metabolite of Friedelin), due to their potency. The high selectivity of the Friedelin terpene compared to the theoretical model of the COX1 enzyme of Homo sapiens, allows this compound to be a viable alternative to the development of a possible drug. The cannabinoid subclass delta-9-tetrahydrocannabinol, on the other hand, exhibits a selective inhibition against the theoretical model of the COX2 enzyme of Homo sapiens, with a high binding affinity. The cannabinoid compounds have been widely studied against their therapeutic action, however, our results show that in other phytochemical classes of compounds an alternative to the treatment of pain and inflammation can be found.Incluye bibliografíaPregradoQuímico(a) Farmacéutic

Regulation of HPGD and SLCO2A1 in Colorectal Cancer Development

A wide range of lipid mediators are synthesised from Polyunsaturated Fatty Acids. These mediators regulate inflammation and many other processes in the human body, and perturbation of their signalling can contribute to the survival and proliferation of cancer cells. Prostaglandin E2 has the most diverse range of functions amongst the prostaglandins and other lipid mediators, and increased PGE2 signalling has been associated with promoting tumour growth and survival by a number of mechanisms. NSAIDs target the synthesis side of the prostaglandin pathway through PTGS2, but only recently has the importance of the degradation component, involving the enzyme HPGD and prostaglandin transporter SLCO2A1 been discovered. Although a number of publications have shown that HPGD is downregulated in colorectal cancer, in addition to other malignancies, the mechanisms by which this takes place remain unclear. Only a few studies have indicated a comparable role for SLCO2A1, and the potential for these two genes to be co-regulated. Therefore, understanding how these two genes are regulated could reveal the mechanisms by which their expression is lost, and potentially how they could be upregulated to complement the action of NSAIDs when used prophylactically, or as an adjunct to chemotherapy. HPGD and SLCO2A1 expression was characterised, and the genes’ transcriptional start sites identified using two colorectal cancer cell lines. This information was used to design and carry out a promoter deletion series, which revealed the importance of the proximal 364 bp SLCO2A1 promoter region in driving transcription. Further analysis of this region revealed a possible role for the intestinal and colonic epithelium-specific transcription factor CDX2 for driving SLCO2A1 expression. Further experiments provided evidence to suggest that the TGF-β pathway, which is known to drive HPGD expression, may also co-regulate SLCO2A1

Delli Aspetti de Paesi. Vecchi e nuovi Media per l’Immagine del Paesaggio: Costruzione, descrizione, identità storica - Tomo I

[English]:Starting from one of the most significant chapters of Leonardo's Libro di Pittura, we hwant to focus on the media - namely on the narrative, descriptive and graphics methodologies together with the techniques adopting during the modern and contemporary age as 'diffusers' of the landscape image - and on the deriving potential models for the enhancement of the historical landscape heritage.Partendo dalla nozione di paesaggio nella storia moderna e contemporanea, nel testo si affrontano le problematiche concernenti l‟evoluzione del suo significato fino al dibattito sulle diverse accezioni recentemente acquisite, con particolare riferimento ai contesti storici urbani. La lezione che si trae dai primi studi di Leonardo sulla percezione del paesaggio naturale e antropizzato, dalle guide e taccuini di viaggio del Cinque e Seicento, fino alla produzione di artisti e viaggiatori tra Sette e Ottocento e al più recente repertorio fotografico o cinematografico, mostra l‟importante ruolo da attribuirsi oggi all‟immagine storica del paesaggio quale strumento per l‟individuazione dell‟identità di un territorio, ormai in buona parte scevra da meri contenuti percettivi e oleografici, e sempre più legata ai fattori umani, storici e sociali, in una parola „culturali‟, che nell‟immagine vanno letti e tradotti. / [Italiano]: Si tratta in effetti di riconoscere nei caratteri „percettibili‟ di un paesaggio, attraverso gli strumenti della storia della città e dell‟iconografia storica, i valori culturali condivisi di un sito o di un insediamento: in tal senso l‟esperienza del Convegno CIRICE 2016 potrà segnare un nuovo passo non solo ai fini di un più consapevole riconoscimento di tali valori attraverso lo studio dei media adottati nella descrizione del paesaggio storico, ma verso un‟azione di tutela volta alla trasmissione e valorizzazione della memoria di quei luoghi