Adipose tissue (AT) has been highlighted as a promising reservoir of infection for viruses, bacteria and parasites. Among them is
, which causes Chagas disease. The recommended treatment for the ...disease in Brazil is Benznidazole (BZ). However, its efficacy may vary according to the stage of the disease, geographical origin, age, immune background of the host and sensitivity of the strains to the drug. In this context, AT may act as an ally for the parasite survival and persistence in the host and a barrier for BZ action. Therefore, we investigated the immunomodulation of T. cruzi-infected human AT in the presence of peripheral blood mononuclear cells (PBMC) where BZ treatment was added.
We performed indirect cultivation between T. cruzi-infected adipocytes, PBMC and the addition of BZ. After 72h of treatment, the supernatant was collected for cytokine, chemokine and adipokine assay. Infected adipocytes were removed to quantify T. cruzi DNA, and PBMC were removed for immunophenotyping.
Our findings showed elevated secretion of interleukin (IL)-6, IL-2 and monocyte chemoattractant protein-1 (MCP-1/CCL2) in the AT+PBMC condition compared to the other controls. In contrast, there was a decrease in tumor necrosis factor (TNF) and IL-8/CXCL-8 in the groups with AT. We also found high adipsin secretion in PBMC+AT+T compared to the treated condition (PBMC+AT+T+BZ). Likewise, the expression of CD80+ and HLA-DR+ in CD14+ cells decreased in the presence of T. cruzi.
Thus, our findings indicate that AT promotes up-regulation of inflammatory products such as IL-6, IL-2, and MCP-1/CCL2. However, adipogenic inducers may have triggered the downregulation of TNF and IL-8/CXCL8 through the peroxisome proliferator agonist gamma (PPAR-g) or receptor expression. On the other hand, the administration of BZ only managed to reduce inflammation in the microenvironment by decreasing adipsin in the infected culture conditions. Therefore, given the findings, we can see that AT is an ally of the parasite in evading the host's immune response and the pharmacological action of BZ.
Dengue virus (DENV) is an arbovirus that belongs to the Flaviviridae family. Studies reveal that peptides secreted by amphibians have many functions, such as antiviral and antimicrobial activities. ...As there is no antiviral drug effective against the DENV, the antiviral activity of a synthetic peptide called HS-1, derived from the secretion of the anuran Hypsiboas semilineatus, has been evaluated. The assays of neutralization in the Vero cells show a complete inhibition of infection of the serotypes 2 and 3. Furthermore, the direct action of peptides on the viral particle can be observed through atomic force microscopy. In vivo tests display 80% protection against the dengue-2 virus due to the presence of HS-1, which reveals its potential as an antiviral against the DENV.
•The use of antimicrobial peptides (AMPs) as antivirals has increased in recent times and has shown promise.•Many molecules have been described as being able to inhibit viral replication, such as, analogs of defensins, dermaseptins, and latarcins.•On account of the lack of a vaccine and treatment against the dengue virus, it has been considered necessary to test antivirals against the dengue virus.•The results are promising against dengue-2 and dengue-3 and the antivirals tested have shown efficiency in both in vitro and in vivo experiments, in which the antiviral appears to act directly on the viral particle, disrupting the lipoprotein envelope.
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In recent times, studies have demonstrated that carbon nanotubes are good candidates for use as vehicles for transfection of exogenous material into the cells. However, there are few studies ...evaluating the behavior of carbon nanotubes as DNA vectors and few of these studies have used multi-walled carbon nanotubes (MWCNTs) or carboxylated MWCNTs. Thus, this study aims to assess the MWCNTs' (carboxylated or not) efficiency in the increase in expression of the tetravalent vaccine candidate (TVC) plasmid vector for dengue virus in vitro using Vero cells, and in vivo, through the intramuscular route, to evaluate the immunological response profile.
Multi-walled carbon nanotubes internalized by Vero cells, have been found in the cytoplasm and nucleus associated with the plasmid. However, it was not efficient to increase the messenger ribonucleic acid (mRNA) compared to the pure vaccine candidate associated with Lipofectamine(®) 2000. The in vivo experiments showed that the use of intramuscular injection of the TVC in combination with MWCNTs reduced the immune response compared to pure TVC, in a general way, although an increase was observed in the population of the antibody-producing B cells, as compared to pure TVC.
The results confirm the data found by other authors, which demonstrate the ability of nanotubes to penetrate target cells and reach both the cytoplasm and the cell nucleus. The cytotoxicity values are also in accordance with the literature, which range from 5 to 20 µg/mL. This has been found to be 10 µg/mL in this study. Although the expression levels are higher in cells that receive the pure TVC transfected using Lipofectamine(®) 2000, the nanotubes show an increase in B-cells producing antibodies.
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Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
Dengue is a major international public health concern. There is no drug to treat dengue virus infections and a vaccine is yet to be licensed. The laboratory diagnosis of dengue virus infection has ...been greatly improved during the last decade; therefore, the main limiting factor is the production of recombinant viral antigens on a large scale. Domain III of dengue virus envelope protein contains multiplex conformation-dependent neutralizing epitopes, making it an attractive diagnostic candidate. In this work, we have demonstrated the expression of dengue virus type 1 envelope domain III protein (EDIII-D1) in methylotrophic yeast, Pichia pastoris GS115. The recombinant secreted protein (sEDIII-D1) was purified by affinity chromatography and characterized by SDS–PAGE. Purified protein was recognized in immunoblot analysis and enzyme-linked immunosorbent assay (ELISA) with dengue-infected human serum samples. In conclusion, secreted expressions of domain III protein can be obtained in P. pastoris by methanol induction. This product has the potential to be used for the diagnosis of dengue infections.
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3147 Background: OPC exhibits distinct epidemiological, genetic, and clinical characteristics, significantly influenced by the presence of HPV. Despite multidisciplinary therapy, approximately 40% of ...OPC patients (pts) experience recurrence, and those who achieve cure often endure late and morbid sequelae of treatment. In this study, we comprehensively explored the composition and functional status of the tumor immune microenvironment (TIME) in a cohort of OPC pts treated with curative intent and investigated TIME differences based on HPV infection, smoking status, and clinical outcomes. Methods: Two tissue microarrays with baseline OPC tissues were stained with a previously validated panel containing 33 metal-tagged markers. Imaging mass cytometry was performed with the Fluidigm Helios CyTOF instrument, and analysis performed with Visiopharm software. HPV status was determined by p16 IHC and/or DNA testing. Comparison of cell types and markers densities among subgroups (HPV positive vs negative) were analyzed with Wilcoxon signed-rank test and its association with clinical outcomes (recurrence vs no-recurrence) with log-rank and Cox Proportional Hazards. Multiple comparisons were corrected by Benjamini Hochberg procedure. Results: A total of 99 samples from 61 pts from a single institution were included in this study. The majority of pts were male (N=47, 77%) and heavy smokers (N=55, 90%); 72% were HPV-negative. The median age was 61 years (range, 39 – 87 years), and 52% of cases were diagnosed with stages III-IVB (AJCC 8th edition). Most pts (57%) was treated with surgery (±RT). Thirty-three pts (54%) experienced recurrent disease. Smoking, stage III-IVB, and HPV-negative tumors were associated with higher recurrence rates (p <0.01). Regarding the OPC TIME, the most prevalent cell populations in the stroma were fibroblasts (22%), followed by T-cells (17%) and endothelial cells (10%). The stroma of HPV+ tumors exhibited higher densities of memory T cells (FDR < 0.01), B cells (FDR = 0.02), and T cells (FDR = 0.02) compared to HPV negative counterparts, which displayed an increased density of neutrophils (FDR = 0.04). The density of cancer stem cells was directly associated with smoking history (FDR<0.001), and an increased density of intra-tumoral B-cells was found in non-smokers (FDR=0.01). Higher intra-tumoral neutrophil density was linked to recurrent disease (FDR < 0.001). Conversely, higher densities of memory CD8+ T cells and non-M2 macrophages in the TIME were associated with a lower chance of recurrence (FDR < 0.1). Conclusions: The intricate analysis of the OPC TIME revealed significant differences according to HPV and smoking status and highlighted the prognostic role of neutrophils, memory CD8+ T cells, and non-M2 macrophages. These findings may guide the development of personalized therapeutic strategies for OPC.
The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was ...updated 5 years ago. It is based on the type of therapy needed to correct the complication. The principle of the classification was to be simple, reproducible, flexible, and applicable irrespective of the cultural background. The aim of the current study was to critically evaluate this classification from the perspective of its use in the literature, by assessing interobserver variability in grading complex complication scenarios and to correlate the classification grades with patients', nurses', and doctors' perception.
Reports from the literature using the classification system were systematically analyzed. Next, 11 scenarios illustrating difficult cases were prepared to develop a consensus on how to rank the various complications. Third, 7 centers from different continents, having routinely used the classification, independently assessed the 11 scenarios. An agreement analysis was performed to test the accuracy and reliability of the classification. Finally, the perception of the severity was tested in patients, nurses, and physicians by presenting 30 scenarios, each illustrating a specific grade of complication.
We noted a dramatic increase in the use of the classification in many fields of surgery. About half of the studies used the contracted form, whereas the rest used the full range of grading. Two-thirds of the publications avoided subjective terms such as minor or major complications. The study of 11 difficult cases among various centers revealed a high degree of agreement in identifying and ranking complications (89% agreement), and enabled a better definition of unclear situations. Each grade of complications significantly correlated with the perception by patients, nurses, and physicians (P < 0.05, Kruskal-Wallis test).
This 5-year evaluation provides strong evidence that the classification is valid and applicable worldwide in many fields of surgery. No modification in the general principle of classification is warranted in view of the use in ongoing publications and trials. Subjective, inaccurate, or confusing terms such as "minor or major" should be removed from the surgical literature.
Written medicine information (WMI) is a collection of facts for a specific medication, and it helps facilitate patient understanding of medication therapy. The primary objective of this study was to ...assess consumer satisfaction with National Alliance on Mental Illness (NAMI) WMI. A secondary objective was to assess health care professional satisfaction.
National Alliance on Mental Illness WMI and surveys were offered to consumers, health care professionals, and trainees at 3 treatment centers with psychiatric services. All adults who received medication counseling were eligible for inclusion. Survey responses were evaluated using descriptive statistics.
Most consumers (82.4%) and providers (74.5%) reported overall satisfaction with NAMI WMI. Consumers were least satisfied with information on how to manage unwanted effects, drug-drug interactions, and readability (9.5%, 14.9%, 41.9% dissatisfaction).
Evaluation and feedback from consumers and health care professionals may influence decisions to refine NAMI WMI to meet consumer needs.
Bacteriocins are ribosomally synthesized antimicrobial peptides produced by Bacteria and some Archaea. The assessment of the toxic potential of antimicrobial peptides is important in order to apply ...these peptides on an industrial scale. The aim of the present study was to investigate the in vitro cytotoxic and haemolytic potential of bovicin HC5, as well as to determine whether cholesterol influences bacteriocin activity on model membranes. Nisin, for which the mechanism of action is well described, was used as a reference peptide in our assays. The viability of three distinct eukaryotic cell lines treated with bovicin HC5 or nisin was analysed by using the MTT assay and cellular morphological changes were determined by light microscopy. The haemolytic potential was evaluated by using the haemoglobin liberation assay and the role of cholesterol on bacteriocin activity was examined by using model membranes composed of DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DPoPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The IC(50) of bovicin HC5 and nisin against Vero cells was 65.42 and 13.48 µM, respectively. When the MTT assay was performed with MCF-7 and HepG2 cells, the IC(50) obtained for bovicin HC5 was 279.39 and 289.30 µM, respectively, while for nisin these values were 105.46 and 112.25 µM. The haemolytic activity of bovicin HC5 against eukaryotic cells was always lower than that determined for nisin. The presence of cholesterol did not influence the activity of either bacteriocin on DOPC model membranes, but nisin showed reduced carboxyfluorescein leakage in DPoPC membranes containing cholesterol. In conclusion, bovicin HC5 only exerted cytotoxic effects at concentrations that were greater than the concentration needed for its biological activity, and the presence of cholesterol did not affect its interaction with model membranes.
The Dengue virus is the main arbovirus that affects man in terms of morbidity and mortality. The detection of the virus is very important for epidemiological surveillance, so here we propose to ...standardize and compare the immunodot blot (IDB) and multiplex reverse transcriptase-polymerase chain reaction (M-RT-PCR) techniques to detect and characterize the dengue virus (DENV) serotypes in samples of Aedes aegypti larvae. Thus, the IDB and M-RT-PCR techniques were standardized using macerated samples of larvae collected in nature. The use of monoclonal antibodies in IDB has not shown great results, but DENV detection through this method was possible using polyclonal antibodies. The distinction of serotypes 1, 2 and 3 was carried out by M-RT-PCR.
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