Mast Cell Function da Silva, Elaine Zayas Marcelino; Jamur, Maria Célia; Oliver, Constance
Journal of Histochemistry & Cytochemistry,
10/2014, Letnik:
62, Številka:
10
Book Review, Journal Article
Recenzirano
Odprti dostop
Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their ...involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.
During the infectious process, pathogenic microorganisms must obtain nutrients from the host in order to survive and proliferate. These nutritional sources include the metallic nutrient copper. ...Despite its essentiality, copper in large amounts is toxic. Host defense mechanisms use high copper poisoning as a fungicidal strategy to control infection. Transcriptional analyses showed that yeast cultured in the presence of copper or inside macrophages (24 h) had elevated expression of CRP1, a copper efflux pump, suggesting that Histoplasma capsulatum could be exposed to a high copper environment in macrophages during the innate immune stage of infection. Accordingly, macrophages cultured in high copper are more efficient in controlling H. capsulatum growth. Also, silencing of ATP7a, a copper pump that promotes the copper influx in phagosomes, increases fungal survival in macrophages. The rich copper environment faced by the fungus is not dependent on IFN‐γ, since fungal CRP1 expression is induced in untreated macrophages. Appropriately, CRP1 knockdown fungal strains are more susceptible to macrophage control than wild‐type yeasts. Additionally, CRP1 silencing decreases fungal burden in mice during the phase of innate immune response (4‐day postinfection) and CRP1 is required for full virulence in a macrophage cell lines (J774 A.1 and RAW 264.7), as well as primary cells (BMDM). Thus, induction of fungal copper detoxifying genes during innate immunity and the attenuated virulence of CRP1‐knockdown yeasts suggest that H. capsulatum is exposed to a copper‐rich environment at early infection, but circumvents this condition to establish infection.
Histoplasma capsulatum elevates Crp1 expression in the presence of copper in vitro or in macrophage infection. Copper chelation hampered macrophage ability to control the fungus, while fungal burden decreases in copper‐treated immune cells. ATP7a silencing (phagosome copper pump) also caused increased fungal burden. H. capsulatum CRP1‐knockdown strains attenuated virulence. These data show that copper increase is a strategy for phagocytes to control H. capsulatum, and Crp1 is responsible for H. capsulatum virulence.
This study aimed to assess the microbiological quality of natural mineral waters commercialized in 20 L returnable packs in Brazil by investigating the presence of bacteria and viruses in packs with ...different manufacturing times (Tm). With this purpose, 99 water samples from 33 lots (n = 3/batch) of 15 brands, obtained from packs with three intervals of Tm, were analyzed. Total coliforms (16.2%), Pseudomonas aeruginosa (9.9%), sulphite-reducing Clostridium (5.0%) and Escherichia coli (2.0%) were detected but enterococci and norovirus GII not. Regarding brands, 11 (73.3%) presented unsatisfactory results for at least one of the lots analyzed. Pseudomonas aeruginosa analysis revealed six sequence types and strains were susceptible to all antibiotics tested and were able to produce biofilms. Human adenovirus (4) and norovirus GI (9) were also identified in nine samples randomly selected. Natural mineral waters commercialized in 20 L packs with Tm ≥ 2 years presented more microbiological contamination (P ≤ 0.012) than ones with a Tm of 0-1 year or a Tm of 1-2 years. These results suggest that the validity period of reusable 20 L packs should be reduced or that they can no longer be reused.
SARS-CoV-2 has spread worldwide and has become a global health problem. As a result, the demand for inputs for diagnostic tests rose dramatically, as did the cost. Countries with inadequate ...infrastructure experience difficulties in expanding their qPCR testing capacity. Therefore, the development of sensitive and specific alternative methods is essential. This study aimed to develop, standardize, optimize, and validate conventional RT-PCR targeting the N gene of SARS-CoV-2 in naso-oropharyngeal swab samples compared to qPCR. Using bioinformatics tools, specific primers were determined, with a product expected to be 519 bp. The reaction conditions were optimized using a commercial positive control, and the detection limit was determined to be 100 fragments. To validate conventional RT-PCR, we determined a representative sampling of 346 samples from patients with suspected infection whose diagnosis was made in parallel with qPCR. A sensitivity of 92.1% and specificity of 100% were verified, with an accuracy of 95.66% and correlation coefficient of 0.913. Under current Brazilian conditions, this method generates approximately 60% savings compared to qPCR costs. Conventional RT-PCR, validated herein, showed sufficient results for the detection of SARS-CoV-2 and can be used as an alternative for epidemiological studies and interspecies correlations.
This study evaluated the long-term effects of percutaneous intervention in children and adolescents with transplant renal artery stenosis (TRAS).
Twenty patients had significant stenosis (>50%) and ...underwent percutaneous transluminal angioplasty (PTA/stenting) (TRAS group-intervention); 14 TNS (non-significant group -control) patients did not have significant stenosis (≤50%) and were treated clinically. The combined primary endpoints were death from all causes and late graft failure. The secondary endpoints were serum creatinine (SCr), systolic blood pressure (SBP), and diastolic blood pressure (DBP).
No statistically significant difference was found between TRAS-Intervention(N = 20) and TNS groups-Control (N = 14) for these clinical parameters: deaths, 1 (5.0%) vs. 0 (0.0%) (p = 1.000) and graft loss, 4 (20.0%) vs. 2 (14.3%) (p = 1.000). For the secondary endpoints, after 1 month and 1 year the values of SCr, SBP, and DBP were similar between the two groups but not statistically significant.
In the TRAS group (intervention), the stent implantation was beneficial for treating refractory hypertension and reducing blood pressure (BP) in children and adolescents. Despite the outcomes being similar in the two groups, it can be inferred that the patients in the TRAS group (intervention) would have had a worse outcome without the percutaneous intervention.
TRAS treatment with stenting can be considered for children and adolescents. Because the sample in the present study comprised of only a specific population, further studies are needed for generalization.
The trial was registered at clinictrials.gov with trial registration number NCT04225338.
Iron is a micronutrient required by almost all living organisms, including fungi. Although this metal is abundant, its bioavailability is low either in aerobic environments or within mammalian hosts. ...As a consequence, pathogenic microorganisms evolved high affinity iron acquisition mechanisms which include the production and uptake of siderophores. Here we investigated the utilization of these molecules by species of the Paracoccidioides genus, the causative agents of a systemic mycosis. It was demonstrated that iron starvation induces the expression of Paracoccidioides ortholog genes for siderophore biosynthesis and transport. Reversed-phase HPLC analysis revealed that the fungus produces and secretes coprogen B, which generates dimerumic acid as a breakdown product. Ferricrocin and ferrichrome C were detected in Paracoccidioides as the intracellular produced siderophores. Moreover, the fungus is also able to grow in presence of siderophores as the only iron sources, demonstrating that beyond producing, Paracoccidioides is also able to utilize siderophores for growth, including the xenosiderophore ferrioxamine. Exposure to exogenous ferrioxamine and dimerumic acid increased fungus survival during co-cultivation with macrophages indicating that these molecules play a role during host-pathogen interaction. Furthermore, cross-feeding experiments revealed that Paracoccidioides siderophores promotes growth of Aspergillus nidulans strain unable to produce these iron chelators. Together, these data denote that synthesis and utilization of siderophores is a mechanism used by Paracoccidioides to surpass iron limitation. As iron paucity is found within the host, siderophore production may be related to fungus pathogenicity.
Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus
and mainly affects low-income rural workers after inhalation of fungal ...conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and
protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of
spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of
essential targets using validated genes from
; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.
Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown ...that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-2-(dimetilamino)etilamino-4-(hidroximetil)-7-(4-metilfenil)sulfoniloxi-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.
No presente artigo, problematizamos as apropriações para o ensino de geometria elaboradas por José Augusto Coelho, na passagem do século XIX para o XX, no Brasil e em Portugal. Mobilizamos manuais ...pedagógicos de Portugal, normativas e pesquisas sobre a formação de professores portugueses e brasileiros, para a análise, diálogo e cotejamento das fontes. Como conclusões, destacamos que as divergências e tensões entre as abordagens dos ‘saberes a ensinar e para ensinar’ contribuem para elucidar a apropriação de Coelho no processo formativo de professores nos dois países. O alargamento no processo analítico, de modo a incluir outras disciplinas que participaram da formação do professor primário, como a de Desenho, permite melhor compreender os saberes profissionais em questão, seja no contexto de Portugal, seja no do Brasil.
Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction ...(ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021–1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.
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