PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung ...inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses, and return to lung homeostasis. However, an exaggerated immune response, ...characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. We investigated the role of ACKR2 during IAV infection in mice. Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2
) mice were protected from IAV, presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B lymphocytes, formation of inducible bronchus-associated lymphoid tissue and production of IgA in the airways of ACKR2
mice post-IAV. CCL5 neutralization in ACKR2
mice prevented lymphocyte recruitment and increased bronchoalveolar lavage fluid protein levels and pulmonary dysfunction. Finally, CCR5
mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5
T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice.
Food allergy is a pathological condition that can lead to hives, swelling, gastrointestinal distress, cardiovascular and respiratory compromise, and even anaphylaxis. The lack of treatment resources ...emphasizes the necessity for new therapeutic strategies, and in this way, probiotics has been pointed out as an alternative, especially because of its immunomodulatory properties. The goal of this study was to evaluate the probiotic effect of
Bifidobacterium longum
subsp.
longum
5
1A
(BL5
1A
) in a murine model of ovalbumin (OVA) food allergy, as well as to investigate the effect of the dose and viability of the bacteria on the proposed model. For this purpose, the probiotic effect was assessed by clinical, immunological, and histological parameters in mice treated or not with the BL5
1A
and sensitized or not with OVA. Oral administration of BL5
1A
prevented weight loss and reduced serum levels of IgE anti-OVA and of sIgA in the intestinal fluid. Also, it reduced the intestinal permeability, proximal jejunum damage, recruitment of eosinophils and neutrophils, and levels of eotaxin-1, CXCL1/KC, IL4, IL5, IL6, IL13, and TNF. Furthermore, the treatment was able to increase the levels of IL10. Investigating different doses administered, the level of 10
8
CFU showed the best results in terms of protective effect. In addition, the administration of the inactivated bacteria did not present any beneficial effect. Results demonstrate that BL5
1A
promotes a systemic immunomodulatory protective effect in a murine model of food allergy that depends on the dose and viability of the bacteria, suggesting its use as probiotic in such disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The ST2 receptor plays an important role in the gut such as permeability regulation, epithelium regeneration, and promoting intestinal immune modulation. Here, we studied the role of ST2 receptor in ...a murine model of oral infection with
, its influence on gut homeostasis and control of bacterial replication. Balb/c (wild-type, WT) and ST2 deficient mice (ST2
) were infected by oral gavage and the results were obtained at 3 and 14 days post infection (dpi). Our results suggest that ST2
are more resistant to
infection, as a lower bacterial colony-forming unit (CFU) was detected in the livers and spleens of knockout mice, when compared to WT. Additionally, we observed an increase in intestinal permeability in WT-infected mice, compared to ST2
animals. Breakage of the intestinal epithelial barrier and bacterial dissemination might be associated with the presence of the ST2 receptor; since, in the knockout mice no change in intestinal permeability was observed after infection. Together with enhanced resistance to infection, ST2
produced greater levels of IFN-γ and TNF-α in the small intestine, compared to WT mice. Nevertheless, in the systemic model of infection ST2 plays no role in controlling
replication in vivo. Our results suggest that the ST2 receptor is involved in the invasion process of
by the mucosa in the oral infection model.
The Yersinia pestis capsular antigen F1 is widely used in plague laboratory diagnosis. Here, we describe the production of an F1 recombinant protein within reduced time and biosafety requirements. ...Its evaluation in hemagglutination tests indicated that the recombinant F1 can replace the conventional F1 protein for plague diagnosis.
•The F1-rec can be produced with lower cost and biosafety requirements than F1-conv.•The use of histidine tag and chromatography reduce the time to F1 purification.•The F1-rec could replace F1-conv in hemagglutination test for plague diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For the first time, compounds developed from the 1,2,3‐triazole scaffold were evaluated as novel drugs to treat triple‐negative breast cancer (TNBC). Four organic salts were idealized as nonclassical ...bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long‐circulating and pH‐sensitive liposome (SpHL‐dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL‐dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL‐dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL‐dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4‐trisubstituted‐1,2,3‐triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.
Compounds developed from the 1,2,3‐triazole scaffold were evaluated as novel drugs to treat triple‐negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human MDA‐MB‐231 and mouse 4T1 cell lines, which are representatives of TNBC. dhmtAc incorporated in a long‐circulating, pH‐sensitive liposome (SpHL‐dhmtAc) shows reduced toxicity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Morinda citrifolia, commonly known as noni, is a plant belonging to the Rubiaceae family. This plant has a high biological potential, which has different biological properties, including antioxidant, ...antibacterial, antiviral, antifungal, antitumor and anti-inflammatory. In this work, the immunomodulatory, antitumor and antimicrobial activities of lignin isolated from Morinda citrifolia leaves were investigated. The results showed that this lignin was not cytotoxic and that it was able to promote activation and differentiation of immune cells in addition to inducing the production of anti-inflammatory cytokines. Furthermore, it was able to inhibit the growth of different tumor and microbial cells in vitro. This pioneering study on these different activities shows that the lignin isolated in this study can be used as a raw material to obtain biomedical and pharmaceutical products.
Surface Tension Measured with Arduino Goncalves, Alem-Mar B.; Freitas, Welica P. S.; Reis, Diogo D. ...
The Physics teacher,
12/2019, Volume:
57, Issue:
9
Journal Article
Peer reviewed
The popularization of microcontrollers like Arduino bring new possibilities of experiments for physics laboratories. For instance, load cell sensors have been used in experiments on impulse and ...buoyancy. Here we propose an experimental apparatus using Arduino connected to a load cell to measure surface tension by the du Noüy method (or ring method). The load cell gives the instantaneous and the maximum force value achieved during the experiment. This apparatus is presented as a simple and low-cost option for physics laboratories.
PURPOSEPancreatic cancer is the fourth most common cause of cancer-related death in the USA. This is mainly because of the chemoresistance of this type of tumor; thus, the development of novel ...therapeutic modalities is needed.
METHODSLong-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) were administered systemically into pancreatic tumor-bearing mice for a period of 14 days. The antitumor efficacy and toxicity of this new treatment method on the basis of cisplatin-loaded liposomes was compared with the classical free-CDDP method. Tc-HYNIC-βAla-bombesin(7–14) tumor uptake and histopathologic findings were used to monitor and compare the two treatment modalities.
RESULTSThe antitumor activity of SpHL-CDDP treatment was shown by (a) decrease in tumor volume, (b) development of tumor necrotic areas, and (c) decrease in Tc-HYNIC-βAla-bombesin(7–14) tumor uptake. Toxicity was evaluated by the development of inflammation and necrotic areas in the kidneys, liver, spleen, and intestinetoxic effects were greater with free-CDDP than SpHL-CDDP.
CONCLUSIONSpHL-CDDP showed significant antitumor activity in pancreatic cancer-bearing mice, with lower toxicity in comparison with free-CDDP.
This study aimed to identify pruning intensity and frequency that can be applied to eucalypt without imposing growth reduction, in an agroforestry system in Brazil (17°36’ S and 46°42’ W). Pruning ...treatments included removal of 0, 1/4 and 1/3 of the live crown height (LCH) with or without the removal of some thick branches above this height (TBA), in three or four lifts, which started at 9 months. There was no effect of pruning on tree height. Diameter (
dbh
) and volume per tree decreased (
P
≤ 0.05) only with the removal of 1/3 of the LCH + TBA, of all trees of the stand, in three lifts, up to 36 months. The Weibull diameter distribution curves showed a higher proportion of trees in the greatest diameter classes with the removal of 1/4 or 1/3 of the LCH + TBA of selected trees, in four lifts, at the age of 36 months. The time required for applying pruning to a height of 6 m did not differ among treatments (
P
> 0.05). Pruning up to 1/3 of the LCH + TBA of selected trees, in 4 lifts (6-month intervals) is recommended because there was a higher proportion of trees in the greatest diameter classes and the
dbh
at the time of the last pruning was smaller than for the other treatments, which implies in reduced knotty core. The production of trees with larger diameter and reduced knotty core may increase farmers’ income and reduce the pressure on native forests.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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