Potent induction of trained immunity by Saccharomyces cerevisiae ß-glucans.

Candida albicans cell wall component ß-glucan has been extensively studied for its ability to induce epigenetic and functional reprogramming of innate immune cells, a process termed trained immunity. We show that a high-complexity blend of two individual ß-glucans from Saccharomyces cerevisiae possesses strong bioactivity, resulting in an enhanced trained innate immune response by human primary monocytes. The training required the Dectin-1/CR3, TLR4, and MMR receptors, as well as the Raf-1, Syk, and PI3K downstream signaling molecules. By activating multiple receptors and downstream signaling pathways, the components of this ß-glucan preparation are able to act synergistically, causing a robust secondary response upon an unrelated challenge. In in-vivo murine models of melanoma and bladder cell carcinoma, pre-treatment of mice with the ß-glucan preparation led to a significant reduction in tumor growth. These insights may aid in the development of future therapies based on ß-glucan structures that induce an effective trained immunity response.

Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker.

INTRODUCTION: Untreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout flares are self-limited inflammatory reactions involving multiple mediators. This study aimed to characterise the inflammatory profiles of gout at different phases. METHODS: Using the Olink targeted proteomics, levels of 92 inflammation-related proteins were measured in plasma samples of a prospective gout population (GOUTROS), collected at gout flare (T1), the intercritical phase (T2) and after reaching the target serum urate level under urate-lowering therapy (T3). Results were validated in an independent cohort (OLT1177-05) with plasmas collected at T1 and T2. Ex vivo and in vitro experiments were performed to assess the inflammatory properties of new biomarkers. RESULTS: In total, 21 inflammatory new biomarkers were differentially expressed during the three time-points of gout disease. The levels of four of these proteins (interleukin 6 (IL-6), colony-stimulating factor 1, vascular endothelial growth factor A and tumour necrosis factor superfamily 14 (TNFSF14)) were increased during gout flare in an independent cohort. IL-6 and TNFSF14 had the highest fold change in expression during T1 versus T2 or T3. TNFSF14 was produced at the inflamed joint and enhanced the inflammatory response induced by lipopolysaccharide and MSU crystal stimulation. Conversely, TNFSF14 blockade reduced the inflammatory response. Additionally, single nucleotide polymorphisms of TNFSF14 affected the ability of myeloid cells to produce inflammatory cytokines. CONCLUSION: Gout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

Skin innate immune response against fungal infections and the potential role of trained immunity.

Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory-like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non-immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL-36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections.

Antibody- Based Immunotherapy Combined With Antimycotic Drug TMP- SMX to Treat Infection With Paracoccidioides brasiliensis.

Monoclonal antibodies (mAbs) are promising alternatives to treat infectious diseases, especially given their potential for applications in combination therapies with antimicrobial drugs to enhance the antifungal efficacy. Protection mediated by mAbs used to treat experimental paracoccidioidomycosis (PCM) has been demonstrated previously. Our aim in the present work was to characterize a monoclonal antibody (mAbF1.4) raised against a cell wall glycoconjugate fraction of Paracoccidioides spp. and to analyze its efficacy combined with trimethoprim-sulfamethoxazole (TMP/SMX) as treatment for experimental PCM. We demonstrated that the epitope recognized by mAbF1.4 is consistent with branched glucose residues present on a cell wall ß-glucan polymer. In vitro, mAbF1.4 increased the phagocytic capacity and nitric oxide concentration induced by the macrophage cell line J774.1A, and this resulted in a significant reduction in the viability of the opsonophagocytized yeasts. In vivo, we detected a significant reduction in pulmonary fungal burdens of mice treated with mAbF1.4 in association with TMP/SMX, which correlated with increased pulmonary concentrations (determined by ELISA) of IFN- Î³, TNF-α, IL-10 and IL-17. In parallel, we observed a decrease in IL-4, suggesting that the treatment was associated with a mixed Th1-Th17 type immune response. Histopathology of lung segments from mice receiving the combination therapy showed a significant reduction in granulomas, which were well-defined, and improved maintenance of lung architecture. These findings demonstrate that mAbF1.4 + TMP/SMX therapy is a promising approach to combat PCM as well as decrease disease sequelae and highlights the potential benefits of immune mediators in PCM combined immunotherapy.

Antiproliferative activity and energy calculations of a new triterpene isolated from the palm tree Acrocomia totai.

Acrocomia totai Mart (Arecaceae) is a palm tree native to South America, widely studied for biodiesel production. The aim of this work was to perform the first phytochemical study of A. totai leaves, as well as to do biological assays against human cancer cell lines. A new triterpene of the hopane class named totaiol (1), three known triterpenes (2-4), and two phytosteroids (5-6) were identified. The new natural product was characterized using 1 D and 2 D NMR, single crystal X-ray diffraction analises, and high resolution mass spectrometry. The intercontacts in the crystal packing were also analised. Complete stereochemical characterization of compound 1 revealed an unusual positioning pattern for methyl and isopropenyl groups in the polycyclic skeleton. Compounds 1-5 were evaluated for the first time in antiproliferative assays against Ca Ski, MCF-7 and MCF-10 cells. The new natural product was active against Ca Ski cells with IC50 ≤ 6.25 µg mL-1.

Nanopartículas de prata biossintetizadas por mikania glomerata sprengel inibem o crescimento de candida albicans e staphylococcus aureus / Biosynthesized silver nanoparticles by mikania glomerata sprengel inhibit the growth of candida albicans and staphylococcus aureus

Introdução: Nos últimos anos ocorreu o aumento de casos relacionados com a infecção por Candida spp. e Staphylococcus spp., bem como o aparecimento de cepas resistentes a antibióticos convencionais. A biossíntese de nanopartículas consiste na redução de um íon metálico por compostos de origem natural como metabólitos secundários de plantas e organismos, sendo a forma mais indicada por apresentar menor toxicidade quando comparada à síntese química. Desta forma, a síntese biológica constitui uma alternativa para a obtenção de novos agentes ativos para o tratamento de infecções microbianas. Objetivos: Sintetizar nanopartículas de prata a partir do extrato aquoso de Mikania glomerata Sprengel e avaliar possível atividade microbicida e citotóxica. Material e Métodos: Para a síntese das nanopartículas de prata (AgNPs) foi utilizado um extrato aquoso das folhas de M. glomerata e uma solução de nitrato de prata. As AgNPs sintetizadas foram avaliadas por espectrofotômetro UV-vis e espectrometria de absorção atômica com chama. Além disso, a atividade antimicrobiana foi avaliada contra cepas de Candida albicans e Staphylococcus aureus e atividade citotóxica contra linhagens celulares HeLa e Vero. Resultados: As AgNPs são mais eficientes no combate à linhagem de Candida albicans e Staphylococcus aureus quando comparadas ao extrato puro administrado. Até a concentração de 100 mg/mL do extrato puro não foi observado efeito inibitório em ambos os micro-organismos. Entretanto quando em contato com as AgNPs, a concentração inibitória foi de 0,006 mg/mL e 0,1 mg/mL para S. aureus e C. albicans, respectivamente. O efeito citotóxico nas células se comportou de maneira dose-dependente, apresentando maior potencial citotóxico contra a linhagem celular cancerosa HeLa. Conclusão: As AgNPs sintetizadas apresentaram potencial antimicrobiano contra C. albicans e S. aureus, além de baixa atividade contra células normais, indicando sua confiabilidade para aplicação das AgNPs como forma alternativa de tratamento. Estes resultados são promissores e contribuem para pesquisa relacionada à produção de medicamentos utilizando extrato de plantas e metais.

Introduction: In recent years there has been an increase in cases related to infection by Candidaspp. and Staphylococcus spp., as well as the appearance of strains resistant to conventional antibiotics. Nanoparticle biosynthesis consists of the reduction of a metal ion by compounds of natural origin as secondary metabolites of plants and organisms, being the most indicated form because it presents less toxicity when compared to the chemical synthesis. In this way, the biological synthesis is an alternative to obtain new active agents for the treatment of microbial infections. Objective: Synthesize silver nanoparticles from the aqueous extract of Mikania glomerata Sprengel and evaluate possible microbicidal and cytotoxic activity. Material and Methods: For the synthesis of the silver nanoparticles (AgNPs) an aqueous extract of the leaves of Mikania glomerata plus a solution of silver nitrate was used. AgNPs synthesized was evaluated by UV-vis spectrophotometer and FAAS. Furthermore, antimicrobial activity was evaluated against strains of Candida albicans and Staphylococcus aureus and cytotoxicity activity against HeLa and Vero cell lines. Results: AgNPs are shown to be more efficient in combating Candida albicans and Staphylococcus aureusstrains when compared to the pure administered extract. Up to the concentration of 100 mg/mL of the pure aqueous extract no inhibitory effect was observed on both microorganisms. However when the strains were in contact with AgNPs, the inhibitory concentration was 0.006 mg/mL and 0.1 mg/mL for S. aureus and C. albicans, respectively. The cytotoxic effect on the cells behaves in a dose-dependent manner, presenting greater cytotoxic potential against the HeLa cancer cell line. Conclusion: Thus, these results are promising and contribute to research related to the production of drugs using plant extract and metals. The AgNPs synthesized presented the antimicrobial potential against C. albicans and S. aureus, in addition to low activity against normal cells, indicating their reliability for application of AgNPs as an alternative form of treatment.

γ-irradiation from radiotherapy improves the virulence potential of Candida tropicalis.

AIM: To evaluate if radiation used in radiotherapy can cause changes in the virulence potential of Candida tropicalis ATCC 750. MATERIALS & METHODS: C. tropicalis was exposed in vitro to identical dose and scheme of irradiation would be used in patients with head and neck cancer. Some virulence parameters were analyzed before and after irradiation. RESULTS: Colony morphologies were irreversibly affected by irradiation. Increase in growth rate, filamentation, adhesion on cell lines and phagocytosis process were also observed. Overall the irradiated C. tropicalis cells became more efficient at causing systemic infection in mice. CONCLUSION: γ-radiation induced important changes in C. tropicalis increasing its virulence profile, which could directly affect the relationship between yeasts and hosts.