Development of TNBS-induced colitis: animal model to test new pharmacological approaches

IBD is a gastro-intestinal disorder marked with chronic inflammation of intestinal epithelium, dam- aging mucosal tissue and manifests into several intestinal and extra-intestinal symptoms. Currently used medical therapy is able to induce and maintain the patient in remission, however no modifies or reverses the underlying pathogenic mechanism. The research of other medical approaches is crucial to the treatment of IBD and, for this, it ́s important to use animal models to mimic the characteristics of disease in real life. The aim of the study is to develop an animal model of TNBS-induced colitis to test new pharmacological approaches. TNBS was instilled intracolonic single dose as described by Morris et al. It was administered 2,5% TNBS in 50% ethanol through a catheter carefully inserted into the colon. Mice were kept in a Tredelenburg position to avoid reflux. On day 4 and 7, the animals were sacrificed by cervical dislocation. The induction was confirmed based on clinical symptoms/signs, ALP determination and histopathological analysis. At day 4, TNBS group presented a decreased body weight and an alteration of intestinal motility characterized by diarrhea, severe edema of the anus and moderate morbidity, while in the two control groups weren’t identified any alteration on the clinical symptoms/signs with an increase of the body weight. TNBS group presented the highest concentrations of ALP comparing with control groups. The histopathology analysis revealed severe necrosis of the mucosa with widespread necrosis of the intestinal glands. Severe hemorrhagic and purulent exsudates were observed in the submucosa, muscular and serosa. TNBS group presented clinical symptoms/ signs and histopathological features compatible with a correct induction of UC. The peak of manifestations became maximal at day 4 after induction. This study allows concluding that it’s possible to develop a TNBS- induced colitis 4 days after instillation. DII é um distúrbio gastro-intestinal caracterizado por inflamação crónica do epitélio intestinal com dano associado da mucosa, manifestando-se a partir de sintomas intestinais e extra-intestinais. A terapia médica utilizada é capaz de induzir e manter o doente em remissão, mas não modifica ou inverte o mecanismo patogénico subjacente. A procura de outras abordagens terapêuticas é crucial para o tratamento de DII e, para tal, é importante o uso de modelos animais para mimetizar as características da doença. O objetivo do estudo é desenvolver um modelo animal de colite induzida por TNBS de modo a testar novas abordagens farmacológicas. O TNBS foi instilado por via intracolónica em dose única como descrito por Morris et al. Foi administrado 2,5% de TNBS em 50% de etanol através de um cateter inserido no cólon. Os animais foram mantidos em posição Tredelenburg para evitar o refluxo. Nos dias 4 e 7, os animais foram sacrificados por deslocamento cervical. A indução de colite foi caracterizada com base nos sintomas/sinais clínicos, determinação de ALP e análise histopatológica. No dia 4, o grupo TNBS apresentou uma diminuição do peso corporal e uma alteração da motilidade intestinal caracterizada por diarreia, edema severo do ânus e morbilidade moderada, enquanto nos dois grupos controlo não foram identificados quaisquer alterações nos sintomas/ sinais clínicos com um aumento do peso corporal. O grupo TNBS apresentou as maiores concentrações de ALP, comparando com os grupos controlo. A análise histopatológica demonstrou necrose grave da mucosa com necrose generalizada das glândulas intestinais. Foi observado exsudato hemorrágico e purulento ao nível da submucosa, muscular e serosa. O grupo TNBS apresentou sintomas / sinais clínicos e características histopatológicas compatíveis com uma correta indução de colite. O pico das manifestações tornou-se máximo ao 4º dia após a indução. Este estudo permite concluir que é possível desenvolver colite induzida por TNBS 4 dias após a instilação.

Non-radial null geodesics in spherical dust collapse

The issue of the local visibility of the shell-focussing singularity in marginally bound spherical dust collapse is considered from the point of view of the existence of future-directed null geodesics with angular momentum which emanate from the singularity. The initial data (i.e. the initial density profile) at the onset of collapse is taken to be of class $C^3$. Simple necessary and sufficient conditions for the existence of a naked singularity are derived in terms of the data. It is shown that there exist future-directed non-radial null geodesics emanating from the singularity if and only if there exist future-directed radial null geodesics emanating from the singularity. This result can be interpreted as indicating the robustness of previous results on radial geodesics, with respect to the presence of angular momentum.Comment: 26 pages, 1 figur

Higher-Derivative Corrected Black Holes: Perturbative Stability and Absorption Cross-Section in Heterotic String Theory

This work addresses spherically symmetric, static black holes in higher-derivative stringy gravity. We focus on the curvature-squared correction to the Einstein-Hilbert action, present in both heterotic and bosonic string theory. The string theory low-energy effective action necessarily describes both a graviton and a dilaton, and we concentrate on the Callan-Myers-Perry solution in d-dimensions, describing stringy corrections to the Schwarzschild geometry. We develop the perturbation theory for the higher-derivative corrected action, along the guidelines of the Ishibashi-Kodama framework, focusing on tensor type gravitational perturbations. The potential obtained allows us to address the perturbative stability of the black hole solution, where we prove stability in any dimension. The equation describing gravitational perturbations to the Callan-Myers-Perry geometry also allows for a study of greybody factors and quasinormal frequencies. We address gravitational scattering at low frequencies, computing corrections arising from the curvature-squared term in the stringy action. We find that the absorption cross-section receives \alpha' corrections, even though it is still proportional to the area of the black hole event-horizon. We also suggest an expression for the absorption cross-section which could be valid to all orders in \alpha'.Comment: JHEP3.cls, 29 pages; v2: added refs, minor corrections and additions; v3: added more refs, more minor corrections and addition

Pharmacological characterisation of arthritis induced by Bothrops jararaca venom in rabbits: a positive cross talk between bradykinin, nitric oxide and prostaglandin E2.

BACKGROUND: Our previous results showed that nitric oxide (NO) and bradykinin (BK) mediate the arthritis induced by Bothrops jararaca venom (BjV) in rabbits. In this study, we investigated the contribution of each receptor of BK as well as the inter-relationship between NO and eicosanoids in BjV-induced arthritis. METHODS: The arthritis was induced in rabbits with 16 microg of BjV injected intra-articularly. Prostaglandin E2 (PGE2), thromboxane B2 (TxB2), leukotriene B4 (LTB4) (radioimmunoassay) and nitrite/nitrate concentrations (NO2/NO3) (Griess reaction) were evaluated in the synovial fluid 4 h later. The animals were prior treated with NO synthase inhibitor (L-NAME; 20 mg/kg/day for 14 days), the B2 antagonist of BK (HOE-140) and the B1 antagonist of BK (des-Arg9[Leu8]-bradykinin), both at a dose of 0.3mg/kg, 30 min prior to the venom injection. RESULTS: Data show that L-NAME and HOE-140 treatment were equally able to reduce PGE2 and NO2/NO3 levels without interfering with TxB2 and LTB4 production. On the contrary, the B1 antagonist of BK inhibited TxB2 and LTB4 production, and did not alter PGE2 and NO metabolites levels in the inflamed joint. DISCUSSIONS: The results presented clarify the contribution of the kinin system, mainly through the B2 receptor, to the local inflammatory response induced by BjV, as well as its positive interaction with PGE2 and NO production

Evolution of the density contrast in inhomogeneous dust models

With the help of families of density contrast indicators, we study the tendency of gravitational systems to become increasingly lumpy with time. Depending upon their domain of definition, these indicators could be local or global. We make a comparative study of these indicators in the context of inhomogeneous cosmological models of Lemaitre--Tolman and Szekeres. In particular, we look at the temporal asymptotic behaviour of these indicators and ask under what conditions, and for which class of models, they evolve monotonically in time. We find that for the case of ever-expanding models, there is a larger class of indicators that grow monotonically with time, whereas the corresponding class for the recollapsing models is more restricted. Nevertheless, in the absence of decaying modes, indicators exist which grow monotonically with time for both ever-expanding and recollapsing models simultaneously. On the other hand, no such indicators may found which grow monotonically if the decaying modes are allowed to exist. We also find the conditions for these indicators to be non-divergent at the initial singularity in both models. Our results can be of potential relevance for understanding structure formation in inhomogeneous settings and in debates regarding gravitational entropy and arrow of time. In particular, the spatial dependence of turning points in inhomogeneous cosmologies may result in multiple density contrast arrows in recollapsing models over certain epochs. We also find that different notions of asymptotic homogenisation may be deduced, depending upon the density contrast indicators used.Comment: 22 pages, 1 figure. To be published in Classical and Quantum Gravit

Hermitian Yang-Mills instantons on resolutions of Calabi-Yau cones

We study the construction of Hermitian Yang-Mills instantons over resolutions of Calabi-Yau cones of arbitrary dimension. In particular, in d complex dimensions, we present an infinite family, parametrised by an integer k and a continuous modulus, of SU(d) instantons. A detailed study of their properties, including the computation of the instanton numbers is provided. We also explain how they can be used in the construction of heterotic non-Kahler compactifications.Comment: 20 pages, 1 figure; typos corrected, section 3.1 expande

Kraft lignin solubility and its chemical modification in deep eutectic solvents

Lignin stands as a promising raw material to produce commodities and specialty chemicals, yet its poor solubility remains a big challenge. Recently, deep eutectic solvents (DES) have been proposed as sustainable solvents with high potential to dissolve and valorize lignin. In the present study, the ability of DES based on cholinium chloride ([Ch]Cl) combined with alcohols and carboxylic acids as hydrogen bond donors (HBDs) to dissolve kraft lignin and to change its chemical structure was examined. The influence of the chemical nature of HBDs, water content, and HBD:hydrogen bond acceptor (HBA) molar ratio on the solubility of kraft lignin in DES was studied (313.15 K). The kraft lignin solubility was enhanced by increasing both the HBD’s carbon chain length and the molar ratio, with [Ch]Cl:HEXA (1,6-hexanediol) and [Ch]Cl:MaleA (maleic acid) being the best studied solvents for kraft lignin dissolution, while the addition of water was a negative factor. The thermal treatments (393.15 K) of kraft lignin show that carboxylic acid-based DES promote chemical modifications to kraft lignin, including the disruption of several C–O covalent type bonds (e.g., β-O-4, α-O-4 and α-O-α), while alcohol-based DES were found to be nonderivatizing solvents maintaining the lignin chemical structure. These results show the versatility of DES, which, depending on their chemical nature, may offer distinct strategies for lignin valorization.publishe

Fast and efficient method to evaluate the potential of eutectic solvents to dissolve lignocellulosic components

The application of eutectic solvents (ESs) in lignocellulosic biomass fractionation has been demonstrated as a promising approach to accomplish efficient and environmentally friendly biomass valorization. In general, ESs are a combination of two components, a hydrogen-bonding donor and a hydrogen-bonding acceptor, in which the melting point of the mixture is lower than that of the individual components. However, there are plenty of possible combinations to form ESs with the potential to apply in biomass processing. Therefore, the development of fast and effective screening methods to find combinations capable to dissolve the main biomass components—namely cellulose, hemicelluloses, and lignin—is highly required. An accurate and simple technique based on optical microscopy with or without polarized lenses was used in this study to quickly screen and monitor the dissolution of cellulose, xylose (a monomer of hemicelluloses), and lignin in several ESs. The dissolution of these solutes were investigated in different choline-chloride-based ESs (ChCl:UREA, ChCl:PROP, ChCl:EtGLY, ChCl:OXA, ChCl:GLY, ChCl:LAC). Small amounts of solute and solvent with temperature control were applied and the dissolution process was monitored in real time. The results obtained in this study showed that cellulose was insoluble in these ESs, while lignin and xylose were progressively dissolved.publishe