João C.V.P. Moura

The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing

Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some of the most important complications include macrovascular abnormalities, e.g., heart disease and atherosclerosis, and microvascular abnormalities, e.g., retinopathy, nephropathy and neuropathy, in particular diabetic foot ulceration. The highly conserved endogenous small non-coding RNA molecules, the micro RNAs (miRNAs) have in recent years been found to be involved in a number of biological processes, including the pathogenesis of disease. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation, suppression of translation or even gene activation. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for disease. This review aims to describe the most recent findings regarding the important roles of miRNAs in diabetes and its complications, with special attention given to the different phases of diabetic wound healing.

The effect of additives on the photostability of dyed polymers

Two principal types of photodegradation can take place when solar radiation falls on a dyed polymer: (i) change in shade and/or depth of shade of the colorant and/or (ii) chemical degradation of the substrate. Many factors influence the lightfastness of dyes on polymers, and these principally include the chemical structure of the dye, the physical state of the dye within the fibre, the chemical structure of the substrate, additives within the substrate, atmospheric composition (oxygen, water and/or contaminants), ambient temperature and the spectral distribution of the incident light. Similar parameters influence the concomitant photochemical degradation of the polymer host. The chemical changes that molecules undergo following absorption of solar radiation is a field of great interest to organic chemists and over the last 40 years significant progress has been made in our understanding of the photochemistry of dyes and polymers and the mechanisms of their photodegradation. To reduce the undesirable degradation effects of solar radiation on dyed polymeric materials, several approaches have been considered ranging from deliberate structural modification of dyes to the use of protective agents

Synthesis of naphtho[2,3-a]phenoxazinium chlorides: Structure–activity relationships of these heterocycles and benzo[a]phenoxazinium chlorides as new antimicrobials

Synthesised functionalised naphtho[2,3-a]phenoxazinium chlorides revealed great fluorescence with maximum emission wavelengths between 630 and 676 nm, in ethanol and water at physiological pH. Naphtho[2,3-a]phenoxazines, as well as a series of benzo[a]phenoxazines, were evaluated against Saccharomyces cerevisiae, in a broth microdilution assay. This family of compounds exhibited antifungal activity depending both on the substituents of the heterocycle nucleus as well as on its size. The best activities were obtained for four-ring systems, and particularly for 5,9-diaminobenzo[a]phenoxazines with R=Me, R(1)=H and R(2)=Et. As for R(3) substitution, the greatest efficiency was obtained for R(3)=(CH(2))(3)Cl, with a MIC of 3.75 microM. The linkage of different amino acids to the functional group of the 5-amino position of diaminobenzo[a]phenoxazinium moiety resulted in compounds with diverse antimicrobial efficiencies, depending on the polar character of the amino acid, on its linkage position and on the size of the alkyl chain linker.

A novel carboxy-dye reactive system of potential applicability to wool and nylon fibres. Part 1. Studies with model amines

Abstract Dyes containing carboxylic acid groups have the potential to be reacted with the amino groups of wool and nylon fibres by prior activation with ethyl chloroformate (forming a mixed anhydride). The scope of this reaction has been examined in solution using a range of carboxy dyes with cyclohexyl-amine or lysine as model amine substrates. The expected amides are formed in good yields, and have been isolated and characterised. A preliminary study of the reactive dyeing of wool andnylon-6.6 indicates that dyeings with high wet fastness can he achieved with this system.

Chemokine Receptor Expression on Normal Blood CD56+ NK-Cells Elucidates Cell Partners That Comigrate during the Innate and Adaptive Immune Responses and Identifies a Transitional NK-Cell Population

Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal blood CD56+low CD16+ and CD56+high  CD16−/+low NK-cells. Conventional CD56+low and CD56+high NK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patterns CD56+low NK-cells are mainly CXCR1/CXCR2+ and CXCR3/CCR5−/+, whereas mostly CD56+high NK-cells are CXCR1/CXCR2− and CXCR3/CCR5+. Both NK-cell subsets have variable CXCR4 expression and are CCR4− and CCR6−. The CKR repertoire of the CD56+low NK-cells approaches to that of neutrophils, whereas the CKR repertoire of the CD56+high NK-cells mimics that of Th1+ T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we named CD56+int NK-cells. These NK-cells are CXCR3/CCR5+, they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57− and CD158a−. In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-known CD56+high and CD56+low NK-cells populations.

Chemokine receptor repertoire reflects mature T-cell lymphoproliferative disorder clinical presentation

The World Health Organization classification of mature T-cell lymphoproliferative disorders, combines clinical, morphological and immunophenotypic data. The latter is a major contributor to the classification, as well as to the understanding of the malignant T-cell behavior. The fact that T-cell migration is regulated by chemokines should, in theory, enable us to identify tissue tropism and organ involvement by neoplastic T-cells by monitoring chemokine receptor surface expression. To address this issue we compared the expression of several early and late inflammatory, homeostatic, and organ specific chemokine receptors on blood T-cells from normal individuals and patients with T-cell large granular lymphocytic leukemia and peripheral T-cell lymphoma. T-cell large granular lymphocytic leukemia cells mainly express late inflammatory chemokine receptors (CXCR1 and CXCR2), whereas peripheral T-cell lymphoma cells usually express one or more organ homing receptors (CCR4, CCR6 and CCR7). Nevertheless, no clear correlation was found between CCR4 and CCR7 expression and skin and lymph node involvement, respectively. Compared to their normal counterparts, lymphoma T-cells displayed an exaggerated CCR4 expression, whereas leukemic T-cells had abnormally high CXCR1 and CXCR2 expression. Further analysis revealed that, in leukemia patients, the percentage of neoplastic cells expressing CCR5 correlates directly with lymphocytosis. In addition, in the case of CD8 T-cell leukemia patients, an inverse correlation with neutropenia was found. In lymphoma patients, higher CCR4 and CCR7 expression is accompanied by lower to absent CCR5 expression.

5-Arylazo-2,2´-Bithiophenes: A Novel Promising Series of NLO Chromophores

The synthesis of 5-arylazo- substituted bithiophenes and their UV-visible, solvatochromic and nonlinear optical properties (NLO) are described. In agreement with the solvatochromic data and also with the second-order molecular NLO characterization, the new donor-acceptor systems could find application as suitable solvatochromic probes and also as new NLO materials.

Reaction of carboxylic dyes with wool and polyamide : part. III : effect of the activating agent

Dyes containing a carboxylic acid group had been shown to react with wool and polyamide fibres when activated with ethyl chloroformate (Parts I and II). One of the dyes, 3-aminobenzoic acid →N,N-dimethylaniline, was, in this work, activated with other chlorofirmates, so as to improve the dyeing conditions. Benzyl chloroformate was found to be a good substitute since it is not as volatile as ethyl chloroformate, which suggests that it will be easier to apply in practical dyeing conditions. The yield of the reaction with cyclohexylamine is similar to the one obtained with ethyl chloroformate, suggesting that the fixation of the dye on wool or polyamide will be much the same. The fastness results are also equivalent.

Microbiota of Chronic Diabetic Wounds: Ecology, Impact, and Potential for Innovative Treatment Strategies

World Health Organization considered diabetes as one of the 20th century epidemics, estimating that over 10% of the world population is diabetic or at high risk. Self-assessment studies indicate that diabetic patients consider chronic wounds to affect their quality of life more dramatically than vision loss or renal failure. In addition to being the main reason for diabetic patients’ hospitalization, the economic burden of diabetic chronic wounds is close to 1% of United Kingdom and United States health systems budgets, which exceeds the funds allocated to the treatment of some types of cancer in both countries. Among the factors preceding the emergence of chronic diabetic wounds, also designated diabetic foot ulcers (DFUs), hygiene and pressure in specific areas are under patient control, while others are still far from being understood. A triple impairment in the innervation, immune responses, and vascularization associated to DFU has been extensively studied by the scientific community. However, the skin natural microbiota has only recently emerged as having a tremendous impact on DFU emergence and evolution to chronicity. Despite the great inter- and intra-variability of microbial colonizers, ongoing efforts are now focused on deciphering the impact of commensal and pathogenic microbiota on DFU etiology, as well as the mechanisms of interkingdom microbial–host communication. This review summarizes recent work in this context and offers new microbiological perspectives that may hold potential in the prevention and treatment of chronic diabetic wounds.

Impaired T-cell differentiation in diabetic foot ulceration

Foot ulceration is one of the most debilitating complications associated with diabetes, but its cause remains poorly understood. Several studies have been undertaken to understand healing kinetics or find possible therapies to enhance healing. However, few studies have been directed at understanding the immunological alterations that could influence wound healing in diabetes. In this study, we analysed the T-cell receptor (TCR) repertoire diversity in TCR-αβ+ T cells. We also analysed the distribution and phenotype of T cells obtained from the peripheral blood of healthy controls and diabetic individuals with or without foot ulcers. Our results showed that diabetic individuals, especially those with foot ulcers, have a significantly lower naive T-cell number and a poorer TCR-Vβ repertoire diversity. We also showed that the reduced TCR-Vβ repertoire diversity in diabetic individuals was mainly owing to the accumulation of effector T cells, the major source of tumour necrosis factor-α production, which was even more pronounced in patients with acute foot ulceration. Moreover, the expression of several inflammatory chemokine receptors was significantly reduced in diabetic patients. In conclusion, effector T-cell accumulation and TCR repertoire diversity reduction appear to precede the development of foot ulcers. This finding may open new immunological therapeutic possibilities and provide a new prognostic tool in diabetic wound care.