Publications by authors named "Milena Botelho Soares"

129 Publications

The protective effect of solidagenone from Solidago chilensis Meyen in a mouse model of airway inflammation.

Basic Clin Pharmacol Toxicol 2021 Oct 11. Epub 2021 Oct 11.

Instituto Gonçalo Moniz, Oswaldo Cruz Foundation, FIOCRUZ, Salvador, BA, Brazil.

Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 mg/kg or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF, and IL-1β, as well as gene expression of pro-inflammatory mediators in macrophages cultures were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity.
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http://dx.doi.org/10.1111/bcpt.13672DOI Listing
October 2021

A Novel High-Content Screening-Based Method for Anti- Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Stem Cells Int 2021 11;2021:2642807. Epub 2021 Aug 11.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.

Chagas disease is caused by infection and remains a relevant cause of chronic heart failure in Latin America. The pharmacological arsenal for Chagas disease is limited, and the available anti- drugs are not effective when administered during the chronic phase. Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to accelerate the process of drug discovery for Chagas disease, through predictive preclinical assays in target human cells. Here, we aimed to establish a novel high-content screening- (HCS-) based method using hiPSC-CMs to simultaneously evaluate anti- activity and cardiotoxicity of chemical compounds. To provide proof-of-concept data, the reference drug benznidazole and three compounds with known anti- activity (a betulinic acid derivative named BA5 and two thiazolidinone compounds named GT5A and GT5B) were evaluated in the assay. hiPSC-CMs were infected with and incubated for 48 h with serial dilutions of the compounds for determination of EC50 and CC50 values. Automated multiparametric analyses were performed using an automated high-content imaging system. Sublethal toxicity measurements were evaluated through morphological measurements related to the integrity of the cytoskeleton by phalloidin staining, nuclear score by Hoechst 33342 staining, mitochondria score following MitoTracker staining, and quantification of NT-pro-BNP, a peptide released upon mechanical myocardial stress. The compounds showed EC values for anti- activity similar to those previously described for other cell types, and GT5B showed a pronounced trypanocidal activity in hiPSC-CMs. Sublethal changes in cytoskeletal and nucleus scores correlated with NT-pro-BNP levels in the culture supernatant. Mitochondrial score changes were associated with increased cytotoxicity. The assay was feasible and allowed rapid assessment of anti- action of the compounds, in addition to cardiotoxicity parameters. The utilization of hiPSC-CMs in the drug development workflow for Chagas disease may help in the identification of novel compounds.
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http://dx.doi.org/10.1155/2021/2642807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380504PMC
August 2021

Potential application of novel technology developed for instant decontamination of personal protective equipment before the doffing step.

PLoS One 2021 4;16(6):e0250854. Epub 2021 Jun 4.

SENAI CIMATEC, SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil.

The use of personal protective equipment (PPE) has been considered the most effective way to avoid the contamination of healthcare workers by different microorganisms, including SARS-CoV-2. A spray disinfection technology (chamber) was developed, and its efficacy in instant decontamination of previously contaminated surfaces was evaluated in two exposure times. Seven test microorganisms were prepared and inoculated on the surface of seven types of PPE (respirator mask, face shield, shoe, glove, cap, safety glasses and lab coat). The tests were performed on previously contaminated PPE using a manikin with a motion device for exposure to the chamber with biocidal agent (sodium hypochlorite) for 10 and 30s. In 96.93% of the experimental conditions analyzed, the percentage reduction was >99% (the number of viable cells found on the surface ranged from 4.3x106 to <10 CFU/mL). The samples of E. faecalis collected from the glove showed the lowest percentages reduction, with 86.000 and 86.500% for exposure times of 10 and 30 s, respectively. The log10 reduction values varied between 0.85 log10 (E. faecalis at 30 s in glove surface) and 9.69 log10 (E. coli at 10 and 30 s in lab coat surface). In general, E. coli, S. aureus, C. freundii, P. mirabilis, C. albicans and C. parapsilosis showed susceptibility to the biocidal agent under the tested conditions, with >99% reduction after 10 and 30s, while E. faecalis and P. aeruginosa showed a lower susceptibility. The 30s exposure time was more effective for the inactivation of the tested microorganisms. The results show that the spray disinfection technology has the potential for instant decontamination of PPE, which can contribute to an additional barrier for infection control of healthcare workers in the hospital environment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177472PMC
June 2021

The Neurobiology of Zika Virus: New Models, New Challenges.

Front Neurosci 2021 29;15:654078. Epub 2021 Mar 29.

Hospital Israelita Albert Einstein, São Paulo, Brazil.

The Zika virus (ZIKV) attracted attention due to one striking characteristic: the ability to cross the placental barrier and infect the fetus, possibly causing severe neurodevelopmental disruptions included in the Congenital Zika Syndrome (CZS). Few years after the epidemic, the CZS incidence has begun to decline. However, how ZIKV causes a diversity of outcomes is far from being understood. This is probably driven by a chain of complex events that relies on the interaction between ZIKV and environmental and physiological variables. In this review, we address open questions that might lead to an ill-defined diagnosis of CZS. This inaccuracy underestimates a large spectrum of apparent normocephalic cases that remain underdiagnosed, comprising several subtle brain abnormalities frequently masked by a normal head circumference. Therefore, new models using neuroimaging and artificial intelligence are needed to improve our understanding of the neurobiology of ZIKV and its true impact in neurodevelopment.
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http://dx.doi.org/10.3389/fnins.2021.654078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059436PMC
March 2021

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease.

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296-710, Brazil.

Chagas disease, caused by the parasite (), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of -infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.
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http://dx.doi.org/10.3390/ijms22073307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036348PMC
March 2021

Physalis angulata reduces the progression of chronic experimental periodontitis by immunomodulatory mechanisms.

J Ethnopharmacol 2021 Jun 3;273:113986. Epub 2021 Mar 3.

College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, Bahia, Brazil. Electronic address:

Ethnopharmacological Relevance: Physalis angulata is an herb found in tropical and subtropical regions of the world; it is widely applied in popular medicine due to the therapeutic properties of the whole plant and its parts. Extracts and infusions of this plant have been extensively applied in folk medicine worldwide to treat inflammatory and immune-mediated diseases, including oral inflammatory conditions such as sore throat and gingivitis.

Aim Of The Study: The present study was designed to investigate the protective effects of the ethanolic extract of P. angulata (EEPA) in a murine model of chronic periodontitis, aiming to corroborate its traditional use as an anti-inflammatory and immunomodulatory agent, and to point out possible mechanisms involved in these effects.

Materials And Methods: EEPA was obtained from the stems of P. angulata collected in Belém (PA, Brazil). Chronic periodontitis was induced in male C57BL/6 mice by 12 administrations of lipopolysaccharide (LPS; 20 μg/1μL) into the gingival papilla in the course of 28 days. Starting from the 15 day after the first LPS injection, mice were daily treated with EEPA (50 or 100 mg/kg), nimesulide (25 mg/kg, reference drug), or vehicle by oral route for 14 days. At the end of the experimental period, alveolar bone loss was evaluated along with the gingival expression of biomarkers of periodontitis and cytokines by RT-q-PCR and ELISA. Hematological and biochemical parameters suggestive of systemic toxicity were also evaluated. The transcriptional activity of NF-κB was investigated using the luciferase assay in macrophages.

Results: Mice with chronic experimental periodontitis suffered alveolar bone loss that was prevented by the treatment with EEPA (50 or 100 mg/kg) or nimesulide (25 mg/kg). EEPA (50 and 100 mg/kg) and nimesulide (25 mg/kg) reduced mRNA levels of MMP-9 mRNA, but not of TIMP-1 in gingival tissue of periodontitis-induced mice. Both treatments also reduced the production of the pro-inflammatory cytokines IL-1β and IL-6. The treatment with EEPA (100 mg/kg) increased the production of the anti-inflammatory cytokine TGF-β. No hematological or biochemical alterations were caused by the daily treatment with EEPA. In vitro luciferase assay suggested that a putative mechanism of EEPA is reducing the transcriptional activity of NF-κB.

Conclusions: EEPA exhibited a disease-modifying effect in the chronic experimental periodontitis, along with unidentifiable systemic toxicity. This work corroborates the traditional use of P. angulata in oral inflammatory conditions and provides mechanistic hypotheses to explain its therapeutic effects.
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http://dx.doi.org/10.1016/j.jep.2021.113986DOI Listing
June 2021

In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an -Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against .

Front Pharmacol 2020 16;11:590544. Epub 2020 Dec 16.

Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.

Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an -acylhydrazone derivative. Here we investigated the and activity of LASSBio-1386 against . LASSBio-1386 inhibited the proliferation of promastigotes of (EC = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC = 74.1 ± 2.9 µM). incubation with LASSBio-1386 reduced the percentage of -infected macrophages and the number of intracellular parasites (EC = 9.42 ± 0.64 µM). Also, treatment of BALB/c mice infected with resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated control. Moreover, LASSBio-1386 caused ultrastructural changes, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of . Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against through the modulation of leishmanial PDE activity. In conclusion, our results indicate that LASSBio-1386 is a promising candidate for the development of new leishmaniasis treatment.
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http://dx.doi.org/10.3389/fphar.2020.590544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772393PMC
December 2020

The Main Molecular and Serological Methods for Diagnosing COVID-19: An Overview Based on the Literature.

Viruses 2020 12 29;13(1). Epub 2020 Dec 29.

SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Bahia, Brazil.

Diagnostic tests have been considered as the main alternative for the control of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a correct diagnosis allows for decision making when facing the disease, particularly as there is a lack of effective therapeutic protocols and vaccines. Thus, in this review, we summarized the main diagnostic approaches currently available for the diagnosis of SARS-CoV-2 infection in humans based on studies available in article databases. The tests can be organized into two main categories: nucleic acid-based tests, recommended for the initial detection of the virus, and serological tests, recommended for assessing the disease progression. The studies have shown that the performance of diagnostic methods depends on different factors, such as the type of samples and the characteristics of each assay. It was identified that the positivity of the tests is mainly related to the onset of symptoms. We also observed that point-of-care diagnoses are considered as one of the main trends in this area, due to the low-cost and simplicity of the assay; however, the analytical performance must be critically analyzed. Thus, the COVID-19 pandemic has highlighted the critical role of diagnostic technologies in the control of infectious diseases.
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http://dx.doi.org/10.3390/v13010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823618PMC
December 2020

Inhibition of CAL27 Oral Squamous Carcinoma Cell by Targeting Hedgehog Pathway With Vismodegib or Itraconazole.

Front Oncol 2020 10;10:563838. Epub 2020 Nov 10.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.

Oral Squamous Cell Carcinoma (OSCC) presents an important challenge for the health systems worldwide. Thus, unraveling the biological mechanisms involved in OSCC pathogenesis is essential to the discovery of new drugs with anticancer potential. The Hedgehog (HH) pathway has shown promising results as a therapeutic target both and This study aimed to investigate the effects of vismodegib and itraconazole on the expression of Hedgehog (HH) genes (PTCH1, SMO, and GLI1), cell cycle and cell death in OSCC cells. Alamar Blue assay was used to assess the cytotoxicity of vismodegib and itraconazole in a panel of oral cancer cell lines, including CAL27. The expression of HH signaling components after treatment with vismodegib and itraconazole, at concentrations of 25 or 50 μg/ml was evaluated by qPCR. Cell cycle and apoptosis were evaluated by flow cytometry after 72 h treatment with 50 μg/ml of vismodegib or itraconazole. HH signaling was activated in OSCC cell lines CAL27, SCC4, SCC9, and HSC3. Vismodegib and itraconazole significantly reduced CAL27 cell viability after 48 h of treatment. Gene expression of PTCH1, SMO, and GLI1 decreased in response to 24 h of treatment with vismodegib or itraconazole. Furthermore, CAL27 cells exhibited alterations in morphology, cell size, and cellular granularity. An increase in the DNA fragmentation was observed after treatment and both inhibitors induced apoptosis after 72 h. In conclusion, SMO inhibitors vismodegib and itraconazole demonstrably reduced the expression of HH genes in CAL27 OSCC cell line. In addition, treatment with vismodegib and itraconazole reduced cellular viability and altered the morphology of CAL27 cells, and also induced apoptosis.
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http://dx.doi.org/10.3389/fonc.2020.563838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703359PMC
November 2020

Mesenchymal stem cells reduce the oxaliplatin-induced sensory neuropathy through the reestablishment of redox homeostasis in the spinal cord.

Life Sci 2021 Jan 12;265:118755. Epub 2020 Nov 12.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation-FIOCRUZ, 40296-710 Salvador, BA, Brazil; College of Pharmacy, Federal University of Bahia, 40170-115 Salvador, BA, Brazil. Electronic address:

Aims: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties.

Main Methods: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 10), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively.

Key Findings: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1β and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-β, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment.

Significance: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.
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http://dx.doi.org/10.1016/j.lfs.2020.118755DOI Listing
January 2021

Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come?

Front Pharmacol 2020 29;11:529921. Epub 2020 Sep 29.

Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.

Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loading of MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.
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http://dx.doi.org/10.3389/fphar.2020.529921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553050PMC
September 2020

Genetic Engineering as a Strategy to Improve the Therapeutic Efficacy of Mesenchymal Stem/Stromal Cells in Regenerative Medicine.

Front Cell Dev Biol 2020 21;8:737. Epub 2020 Aug 21.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.

Mesenchymal stem/stromal cells (MSCs) have been widely studied in the field of regenerative medicine for applications in the treatment of several disease settings. The therapeutic potential of MSCs has been evaluated in studies and , especially based on their anti-inflammatory and pro-regenerative action, through the secretion of soluble mediators. In many cases, however, insufficient engraftment and limited beneficial effects of MSCs indicate the need of approaches to enhance their survival, migration and therapeutic potential. Genetic engineering emerges as a means to induce the expression of different proteins and soluble factors with a wide range of applications, such as growth factors, cytokines, chemokines, transcription factors, enzymes and microRNAs. Distinct strategies have been applied to induce genetic modifications with the goal to enhance the potential of MCSs. This review aims to contribute to the update of the different genetically engineered tools employed for MSCs modification, as well as the factors investigated in different fields in which genetically engineered MSCs have been tested.
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http://dx.doi.org/10.3389/fcell.2020.00737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471932PMC
August 2020

Characterization of Crystalline Phase of TiO Nanocrystals, Cytotoxicity and Cell Internalization Analysis on Human Adipose Tissue-Derived Mesenchymal Stem Cells.

Materials (Basel) 2020 Sep 14;13(18). Epub 2020 Sep 14.

Laboratory of Nanobiotechnology, Institute of Biotechnology (IBTEC), Federal University of Uberlandia, Uberlandia 38.400-000, Brazil.

Titanium dioxide (TiO) is manufactured worldwide as crystalline and amorphous forms for multiple applications, including tissue engineering, but our study proposes analyzing the impact of crystalline phases of TiO on Mesenchymal Stem Cells (MSCs). Several studies have already described the regenerative potential of MSCs and TiO has been used for bone regeneration. In this study, polydispersity index and sizes of TiO nanocrystals (NCs) were determined. Adipose tissue-derived Mesenchymal Stem Cells (AT-MSCs) were isolated and characterized in order to evaluate cellular viability and the internalization of nanocrystals (NCs). All of the assays were performed using the TiO NCs with 100% anatase (A), 91.6% anatase/9.4% rutile (AR), 64.6% rutile/35.4% anatase (RA), and 84.0% rutile/16% brookite (RB), submitted to several concentrations in 24-h treatments. Cellular localization of TiO NCs in the AT-MSCs was resolved by europium-doped NCs. Viability was significantly improved under the predominance of the rutile phase in NCs with localization restricted at the cytoplasm, suggesting that AR and RA NCs are not genotoxic and can be associated with most cellular activities and metabolic pathways, including glycolysis and cell division.
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http://dx.doi.org/10.3390/ma13184071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560242PMC
September 2020

In vitro and In Vivo Immunomodulatory Activity of Physalis angulata Concentrated Ethanolic Extract.

Planta Med 2021 Feb 16;87(1-02):160-168. Epub 2020 Sep 16.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.

The need for new immunomodulatory drugs is due to the side effects associated with the prolonged use of the currently used immunomodulatory drugs. In this context, the present work aimed to investigate the immunomodulatory effect of an ethanolic concentrated extract from The cytotoxicity of samples was determined using peritoneal macrophages though the Alamar Blue assay. The immunomodulatory activity of the ethanolic extract from on activated macrophages was determined by measurement of nitrite and cytokine production. The immunosuppressive effects of the ethanolic extract from was evaluated on lymphocyte proliferation and cytokine production. The effects of the extract on cell cycle progression and cell death on lymphocytes were evaluated by flow cytometry. Lastly, the ethanolic extract from was tested in toxicological tests and in models of peritonitis and delayed-type hypersensitivity response. The ethanolic extract from decreased nitrite, interleukin-6, interleukin-12, and TNF- production by activated macrophages without affecting the cell viability. In addition, the ethanolic extract from inhibited lymphoproliferation and the secretion of interleukin-2, interleukin-6, and IFN-, and increased interleukin-4 secretion by activated splenocytes. Flow cytometry analysis in lymphocyte cultures showed that treatment with the ethanolic extract from induces cell cycle arrest in the G1 phase followed by cell death by apoptosis. Moreover, mice treated with the extract from at 100 or 200 mg/kg did not show signs of toxicity or alterations in serum components. Finally, the ethanolic extract from significantly reduced neutrophil migration and reduced paw edema in bovine serum albumin-induced the delayed-type hypersensitivity response model. Our results demonstrate the potential of the ethanolic extract of as an alternative for the treatment of immune-inflammatory diseases.
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http://dx.doi.org/10.1055/a-1237-4268DOI Listing
February 2021

Leukemia Inhibitory Factor (LIF) Overexpression Increases the Angiogenic Potential of Bone Marrow Mesenchymal Stem/Stromal Cells.

Front Cell Dev Biol 2020 14;8:778. Epub 2020 Aug 14.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.

Mesenchymal stem/stromal cells (MSCs) have the ability to secrete bioactive molecules, exerting multiple biological effects, such as tissue regeneration, reduction of inflammation, and neovascularization. The therapeutic potential of MSCs can be increased by genetic modification to overexpress cytokines and growth factors. Here we produced mouse MSCs overexpressing human leukemia inhibitory factor (LIF) to assess their proangiogenic potential and . Mouse bone marrow-derived MSCs were transduced by using a second-generation lentiviral system to express human LIF. Leukemia inhibitory factor expression was confirmed by RT-qPCR and by ELISA, allowing the quantification of the transcript and secreted protein, respectively. Flow cytometry analysis and trilineage differentiation assay showed that the MSC_LIF cell line maintained the immunophenotype and a multipotency characteristic of MSCs. The immunosuppressive activity of MSC_LIF was confirmed using a lymphoproliferation assay. Moreover, gene expression analysis demonstrated upregulation of genes coding for strategic factors in the neovascularization process, such as angiogenin, IL-8, MCP-1, and VEGF, and for the perivascular cell markers αSMA, Col4a1, SM22, and NG2. To evaluate the pro-angiogenic potential of MSC_LIF, we first tested its effects on endothelial cells obtained from umbilical vein in a scratch wound healing assay. Conditioned medium (CM) from MSC_LIF promoted a significant increase in cell migration compared to CM from control MSC. Additionally, tube formation of endothelial cells was increased by the presence of MSC_LIF, as shown in microvessel sprouting in aortic ring cultures. Finally, an Matrigel plug assay was performed, showing that MSC_LIF were more potent in promoting angiogenesis and tissue vascularization than control MSCs. In conclusion, LIF overexpression is a promising strategy to increase the proangiogenic potential of MSCs and sets precedents for future investigations of their potential applications for the treatment of ischemic diseases and tissue repair.
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http://dx.doi.org/10.3389/fcell.2020.00778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456813PMC
August 2020

Mesenchymal Stem Cells and Atopic Dermatitis: A Review.

Front Cell Dev Biol 2020 14;8:326. Epub 2020 May 14.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.

Mesenchymal stem/stromal cells (MSCs) are stromal-derived non-hematopoietic progenitor cells that reside in and can be expanded from various tissues sources of adult and neonatal origin, such as the bone marrow, umbilical cord, umbilical cord blood, adipose tissue, amniotic fluid, placenta, dental pulp and skin. The discovery of the immunosuppressing action of MSCs on T cells has opened new perspectives for their use as a therapeutic agent for immune-mediated disorders, including allergies. Atopic dermatitis (AD), a chronic and relapsing skin disorder that affects up to 20% of children and up to 3% of adults worldwide, is characterized by pruritic eczematous lesions, impaired cutaneous barrier function, Th2 type immune hyperactivation and, frequently, elevation of serum immunoglobulin E levels. Although, in the dermatology field, the application of MSCs as a therapeutic agent was initiated using the concept of cell replacement for skin defects and wound healing, accumulating evidence have shown that MSC-mediated immunomodulation can be applicable to the treatment of inflammatory/allergic skin disorders. Here we reviewed the pre-clinical and clinical studies and possible biological mechanisms of MSCs as a therapeutic tool for the treatment of atopic dermatitis.
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http://dx.doi.org/10.3389/fcell.2020.00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240073PMC
May 2020

Phenylpropanoids from Croton velutinus with cytotoxic, trypanocidal and anti-inflammatory activities.

Fitoterapia 2020 Sep 22;145:104632. Epub 2020 May 22.

Instituto de Pesquisa em Fármacos e Medicamentos, Universidade Federal da Paraíba, João Pessoa 58051-900, PB, Brazil. Electronic address:

This current study presents the phytochemical analysis of Croton velutinus, describing phenylpropanoids obtained from this species. The fractionation of the roots hexane extract led to the isolation of four new phenylpropanoids derivatives, velutines A-D (1-4) and three known (5-7). Their structures were established based on spectroscopic (1D-2D NMR; HRMS and IR) analysis. Cytotoxic, trypanocidal and anti-inflammatory activities of compounds 1-7 were evaluated. Only compounds 2 and 5 showed cytotoxic activity against cancer cell lines (B16F10, HL-60, HCT116, MCF-7 and HepG2), with IC values ranging from 6.8 to 18.3 μM and 11.1 to 18.3 μM, respectively. Compounds 2 and 5 also showed trypanocidal activity against bloodstream trypomastigotes with EC values of 9.0 and 9.58 μM, respectively. Finally, the anti-inflammatory potential of these compounds was evaluated on cultures of activated macrophages. All compounds exhibited concentration-dependent suppressive activity on the production of nitrite and IL-1β by macrophages stimulated with LPS and IFN-γ. These results indicate phenylpropanoids esters (2 and 5) from C. velutinus as promising cytotoxic, trypanocidal and anti-inflammatory candidates that warrants further studies.
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http://dx.doi.org/10.1016/j.fitote.2020.104632DOI Listing
September 2020

Tolerogenic Dendritic Cells Reduce Cardiac Inflammation and Fibrosis in Chronic Chagas Disease.

Front Immunol 2020 7;11:488. Epub 2020 Apr 7.

Gonçalo Moniz Institute, FIOCRUZ, Salvador, Brazil.

Chronic Chagas disease cardiomyopathy (CCC) is the most frequent and severe form of this parasitic disease. CCC is caused by a progressive inflammation in the heart, resulting in alterations that can culminate in heart failure and death. The use of dendritic cells (DCs) appears as an option for the development of treatments due to their important role in regulating immune responses. Here, we investigated whether tolerogenic cells (tDCs) could interfere with the progression of CCC in an experimental model of Chagas disease. The tDCs were generated and characterized as CD11b CD11c cells, low expression of MHC-II, CD86, CD80, and CD40, and increased expression of PD-L. These cells produced low levels of IL-6 and IL-12p70 and higher levels of IL-10, compared to mature DCs (mDCs). Interestingly, tDCs inhibited lymphoproliferation and markedly increased the population of FoxP3 Treg cells , compared to mature DCs. In a mouse model of CCC, treatment with tDCs reduced heart inflammation and fibrosis. Furthermore, tDCs treatment reduced the gene expression of pro-inflammatory cytokines ( and ) and of genes related to cardiac remodeling ( and ), while increasing the gene expression of IL-10. Finally, administration of tDCs, increased the percentage of Treg cells in the hearts and spleens of chagasic mice. Ours results show that tolerogenic dendritic cells have therapeutic potential on CCC, inhibiting disease progression.
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http://dx.doi.org/10.3389/fimmu.2020.00488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154094PMC
March 2021

Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells.

Stem Cell Res Ther 2020 04 10;11(1):154. Epub 2020 Apr 10.

Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil.

Background: Hepatocyte-like cells (iHEPs) generated by transcription factor-mediated direct reprogramming of somatic cells have been studied as potential cell sources for the development of novel therapies targeting liver diseases. The mechanisms involved in direct reprogramming, stability after long-term in vitro expansion, and safety profile of reprogrammed cells in different experimental models, however, still require further investigation.

Methods: iHEPs were generated by forced expression of Foxa2/Hnf4a in mouse mesenchymal stromal cells and characterized their phenotype stability by in vitro and in vivo analyses.

Results: The iHEPs expressed mixed hepatocyte and liver progenitor cell markers, were highly proliferative, and presented metabolic activities in functional assays. A progressive loss of hepatic phenotype, however, was observed after several passages, leading to an increase in alpha-SMA fibroblast-like cells, which could be distinguished and sorted from iHEPs by differential mitochondrial content. The resulting purified iHEPs proliferated, maintained liver progenitor cell markers, and, upon stimulation with lineage maturation media, increased expression of either biliary or hepatocyte markers. In vivo functionality was assessed in independent pre-clinical mouse models. Minimal engraftment was observed following transplantation in mice with acute acetaminophen-induced liver injury. In contrast, upon transplantation in a transgenic mouse model presenting host hepatocyte senescence, widespread engraftment and uncontrolled proliferation of iHEPs was observed, forming islands of epithelial-like cells, adipocyte-like cells, or cells presenting both morphologies.

Conclusion: The results have significant implications for cell reprogramming, suggesting that iHEPs generated by Foxa2/Hnf4a expression have an unstable phenotype and depend on transgene expression for maintenance of hepatocyte-like characteristics, showing a tendency to return to the mesenchymal phenotype of origin and a compromised safety profile.
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http://dx.doi.org/10.1186/s13287-020-01665-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323614PMC
April 2020

Synthesis, crystal structure and leishmanicidal activity of new trimethoprim Ru(III), Cu(II) and Pt(II) metal complexes.

J Inorg Biochem 2020 04 23;205:111002. Epub 2020 Jan 23.

Instituto de Química, Universidade Federal de Alfenas, CEP: 37130-001 Alfenas, MG, Brazil. Electronic address:

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania, which has very limited treatment options and affects poor and underdeveloped populations. The current treatment is plagued by many complications, such as high toxicity, high cost and resistance to parasites; therefore, novel therapeutic agents are urgently needed. Herein, the synthesis, characterization and in vitro leishmanicidal potential of new complexes with the general formula [RuCl(TMP)(dppb)] (1), [PtCl(TMP)(PPh)]PF (2) and [Cu(CHCOO)(TMP)]·DMF (3) (dppb = 1,4-bis(diphenylphosphino)butane, PPH = triphenylphosphine and TMP = trimethoprim) were evaluated. The complexes were characterized by infrared, UV-vis, cyclic voltammetry, molar conductance measurements, elemental analysis and NMR experiments. Also, the geometry of (2) and (3) were determined by single crystal X-ray diffraction. Despite being less potent against promastigote L. amazonensis proliferation than amphotericin B reference drug (IC = 0.09 ± 0.02 μM), complex (2) (IC = 3.6 ± 1.5 μM) was several times less cytotoxic (CC = 17.8 μM, SI = 4.9) in comparison with amphotericin B (CC = 3.3 μM, SI = 36.6) and gentian violet control (CC = 0.8 μM). Additionally, complex (2) inhibited J774 macrophage infection and amastigote number by macrophages (IC = 6.6 and SI = 2.7). Outstandingly, complex (2) was shown to be a promising candidate for a new leishmanicidal therapeutic agent, considering its biological power combined with low toxicity.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111002DOI Listing
April 2020

Leishmania dual-specificity tyrosine-regulated kinase 1 (DYRK1) is required for sustaining Leishmania stationary phase phenotype.

Mol Microbiol 2020 05 11;113(5):983-1002. Epub 2020 Feb 11.

Molecular Parasitology Laboratory, Microbiology Department, Hellenic Pasteur Institute, Athens, Greece.

Although the multiplicative and growth-arrested states play key roles in Leishmania development, the regulators of these transitions are largely unknown. In an attempt to gain a better understanding of these processes, we characterised one member of a family of protein kinases with dual specificity, LinDYRK1, which acts as a stasis regulator in other organisms. LinDYRK1 overexpressing parasites displayed a decrease in proliferation and in cell cycle re-entry of arrested cells. Parasites lacking LinDYRK1 displayed distinct fitness phenotypes in logarithmic and stationary growth phases. In logarithmic growth phase, LinDYRK1 parasites proliferated better than control lines, supporting a role of this kinase in stasis, while in stationary growth phase, LinDYRK1 parasites had important defects as they rounded up, accumulated vacuoles and lipid bodies and displayed subtle but consistent differences in lipid composition. Moreover, they expressed less metacyclic-enriched transcripts, displayed increased sensitivity to complement lysis and a significant reduction in survival within peritoneal macrophages. The distinct LinDYRK1 growth phase phenotypes were mirrored by the distinct LinDYRK1 localisations in logarithmic (mainly in flagellar pocket area and endosomes) and late stationary phase (mitochondrion). Overall, this work provides first evidence for the role of a DYRK family member in sustaining promastigote stationary phase phenotype and infectivity.
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http://dx.doi.org/10.1111/mmi.14464DOI Listing
May 2020

Development and in vitro characterization of polymeric nanoparticles containing recombinant adrenomedullin-2 intended for therapeutic angiogenesis.

Int J Pharm 2020 Feb 29;576:118997. Epub 2019 Dec 29.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada, Universidade de Pernambuco (UPE), Rua Arnóbio Marques, 310, Santo Amaro, 50100-130 Recife/PE, Brazil. Electronic address:

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Growth factor therapy has emerged as novel therapeutic strategy under investigation for CVD. In this sense, adrenomedullin-2 (ADM-2) has been recently identified as a new angiogenic factor able to regulate the regional blood flow and cardiovascular function. However, the therapeutic value of ADM-2 is limited by its short biological half-life and low plasma stability. Poly (lactic-co-glycolic acid) (PLGA) micro- and nanoparticles have been investigated as growth factor delivery systems for cardiac repair. In this study, we aimed to develop PLGA nanoparticles containing ADM-2 intended for therapeutic angiogenesis. PLGA nanoparticles containing ADM-2 were prepared by a double emulsion modified method, resulting in 300 nm-sized stable particles with zeta potential around - 30 mV. Electron microscopy analysis by SEM and TEM revealed spherical particles with a smooth surface. High encapsulation efficiency was reached (ca.70%), as quantified by ELISA. ADM-2 associated to polymer nanoparticles was also determined by EDS elemental composition analysis, SDS-PAGE and LC-MS/MS for peptide identification. In vitro release assays showed the sustained release of ADM-2 from polymer nanoparticles for 21 days. Cell viability experiments were performed in J774 macrophages and H9c2 cardiomyocyte cells, about which PLGA nanoparticles loaded with ADM-2 did not cause toxicity in the range 0.01-1 mg/ml. Of note, encapsulated ADM-2 significantly induced cell proliferation in EA.hy926 endothelial cells, indicating the ADM-2 bioactivity was preserved after the encapsulation process. Collectively, these results demonstrate the feasibility of using PLGA nanoparticles as delivery systems for the angiogenic peptide ADM-2, which could represent a novel approach for therapeutic angiogenesis in CVD using growth factor therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118997DOI Listing
February 2020

concentrated ethanolic extract suppresses nociception and inflammation by modulating cytokines and prostanoids pathways.

Nat Prod Res 2019 Dec 24:1-5. Epub 2019 Dec 24.

Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Brazil.

Physalins are -steroids with a variety of pharmacological activities already described. In this study the pharmacological properties of a standardized concentrated ethanolic extract from (CEEPA), rich in physalins B, D, F and G, were studied in models of pain and inflammation in mice. Inflammatory mediators were measured by radioimmunoassay and Real-Time PCR in mice paws after the CFA stimuli. Systemic administration of CEEPA produced antinociceptive effect on the writhing test and formalin test. In the writhing test, physalins B, D, F and G showed that the antinociceptive effect of CEEPA is more potent than that of these purified compounds. In addition, CEEPA reduced the levels of TNF-α, IL-1β, COX-2 and iNOS mRNA in the CFA-induced paw inflammation. Likewise, CEEPA decreased the TNF-α, IL-1β and PGE paw levels. In conclusion, CEEPA induces antinociceptive and anti-inflammatory effects, with improved pharmacological potency relative to pure physalins, associated to modulation of cytokine and cyclooxygenase pathways.
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http://dx.doi.org/10.1080/14786419.2019.1705812DOI Listing
December 2019

Generation of human iPS cell line CBTCi001-A from dermal fibroblasts obtained from a healthy donor.

Stem Cell Res 2019 12 21;41:101630. Epub 2019 Oct 21.

Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, BA, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil; D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, RJ, Brazil. Electronic address:

Human-induced pluripotent stem cell (hiPSC) CBTCi001-A line was generated from a healthy 30-year old male dermal fibroblasts using non-integrative reprogramming method using episomal-based plasmids expressing OCT4, SOX2, KLF4, and MYCL. Characterization of CBTCi001-A was confirmed by the expression of typical markers of pluripotency and differentiation potential in vitro.
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http://dx.doi.org/10.1016/j.scr.2019.101630DOI Listing
December 2019

Circulating miRNAs as Potential Biomarkers Associated with Cardiac Remodeling and Fibrosis in Chagas Disease Cardiomyopathy.

Int J Mol Sci 2019 Aug 20;20(16). Epub 2019 Aug 20.

Gonçalo Moniz Institute, FIOCRUZ, 40296-710 Salvador, Brazil.

Chagas disease (CD) affects approximately 6-7 million people worldwide, from which 30% develop chronic Chagas cardiomyopathy (CCC), usually after being asymptomatic for years. Currently available diagnostic methods are capable of adequately identifying infected patients, but do not provide information regarding the individual risk of developing the most severe form of the disease. The identification of biomarkers that predict the progression from asymptomatic or indeterminate form to CCC, may guide early implementation of pharmacological therapy. Here, six circulating microRNAs (miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p and miR-208a-3p) were evaluated and compared among patients with CCC ( = 28), CD indeterminate form ( = 10) and healthy controls ( = 10). MiR-19a-3p, miR-21-5p, and miR-29b-3p were differentially expressed in CCC patients when compared to indeterminate form, showing a positive correlation with cardiac dysfunction, functional class, and fibrosis, and a negative correlation with ejection fraction and left ventricular strain. Cardiac tissue analysis confirmed increased expression of microRNAs in CCC patients. In vitro studies using human cells indicated the involvement of these microRNAs in the processes of cardiac hypertrophy and fibrosis. Our study suggests that miRNAs are involved in the process of cardiac fibrosis and remodeling presented in CD and indicate a group of miRNAs as potential biomarkers of disease progression in CCC.
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http://dx.doi.org/10.3390/ijms20164064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721092PMC
August 2019

Pharmacological and physicochemical profile of arylacetamides as tools against human cancers.

Toxicol Appl Pharmacol 2019 10 26;380:114692. Epub 2019 Jul 26.

Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil.

Arylacetamides are widely used as synthetic intermediates to obtain medicinal substances. This work evaluated in vitro antiproliferative activity of ten 2-Chloro-N-arylacetamides on human normal and cancer cells and detailed in vivo toxicological and anticancer investigations. Initially, cytotoxic colorimetric assays were performed using tumor lines, peripheral blood mononuclear cells (PBMC) and erythrocytes. Compounds 2, 3 and 4 were tested for acute toxicity (50, 150 and 300 mg/kg) and for subacute antitumoral capacity in HCT-116 colon carcinoma-bearing xenograft mice for 15 days at 25 mg/kg/day. Most compounds revealed cytotoxic action on tumor lines and PBMC, but activity on human erythrocytes were not detected. Molecular dipole moment, lipophilicity and electronic constant of aryl substituents had effects upon in vitro antiproliferative capacity. More common in vivo acute behavioral signals with compounds 2, 3 and 4 were muscle relaxation, reduction of spontaneous locomotor activity and number of entries in closed arms and increased number of falls andtime spent in open arms, suggesting diazepam-like anxiolytic properties. Decrease of grabbing strength and overall activity were common, but palpebral ptosis and deaths occurred at 300 mg/kg only. Compounds 2 and 3 reduced colon carcinoma growth (21.2 and 27.5%, respectively, p < 0.05) without causing apparent signals of organ-specific toxicity after subacute exposure. The structural chemical simplicity of arylacetamides make them cost-effective alternatives and justifies further improvements to enhance activity, selectivity and the development of pharmaceutical formulations.
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http://dx.doi.org/10.1016/j.taap.2019.114692DOI Listing
October 2019

Anti-inflammatory activity of SintMed65, an N-acylhydrazone derivative, in a mouse model of allergic airway inflammation.

Int Immunopharmacol 2019 Oct 12;75:105735. Epub 2019 Jul 12.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), CEP 40296-710 Salvador, BA, Brazil. Electronic address:

Asthma is a chronic, complex and heterogeneous inflammatory illness, characterized by obstruction of the lower airways. About 334 million people worldwide suffer from asthma, and these estimates, as well as the severity of the disease, have increased in the last decades. Glucocorticoids are currently the most widely used drugs in the treatment and control of asthma symptoms, but their prolonged use can cause serious adverse effects. N-acylhydrazone derivatives have been tested in pre-clinical studies in models of inflammatory diseases. Here we tested SintMed65 (N'-[(1E)-3-(4-nitrophenylhydrazono)]-(2E)-propan-2-ylidene-3,5-dinitrobenzohydrazide), a compound belonging to a novel class of immunosuppressive drugs, in a mouse model of allergic airway inflammation. BALB/c mice were sensitized previously and challenged with ovalbumin for five consecutive days and SintMed65 treatment was performed orally 1 h prior to challenge with ovalbumin. Administration of SintMed65, as well as the reference drug dexamethasone, reduced cellularity and the number of eosinophils in the bronchoalveolar fluid (BALF). SintMed65 also reduced the production of Th2 cytokines IL-4, IL-5 and IL-13 in the BALF, and IL-4, IL-10 and CCL8 gene expression in lung, compared to vehicle-treated mice. Importantly, a reduction in the number of leukocytes and in the mucus production in lungs of SintMed65-treated mice was found, compared to the vehicle-treated group. In contrast, IgE production was not significantly altered after treatment with SintMed65. Our results demonstrate that compound SintMed65 possesses anti-inflammatory characteristics, suggesting its therapeutic potential for the treatment of allergic diseases.
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http://dx.doi.org/10.1016/j.intimp.2019.105735DOI Listing
October 2019

2-(phenylthio)ethylidene derivatives as anti-Trypanosoma cruzi compounds: Structural design, synthesis and antiparasitic activity.

Eur J Med Chem 2019 Oct 7;180:191-203. Epub 2019 Jul 7.

Universidade Federal de Pernambuco, Laboratório de Planejamento e Síntese de Fármacos, Departamento de Ciências Farmacêuticas, 50740-520, Recife, PE, Brazil.

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16-26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC of 2.6 μM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.018DOI Listing
October 2019

Generation of an induced pluripotent stem cell line from a patient with autism spectrum disorder and SCN2A haploinsufficiency.

Stem Cell Res 2019 08 25;39:101488. Epub 2019 Jun 25.

Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, BA, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, RJ, Brazil; D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil.

Autism spectrum disorders (ASDs) are a group of diseases that affect social interaction, communication and behavior. Molecular mechanisms involved in the pathogenesis of ASDs are complex due to genetic heterogeneity. Recently, pathogenic variants of SCN2A have been strongly associated with ASDs. Here, we generated iPSCs from a patient with ASD and a heterozygous nonsense mutation in SCN2A, by reprogramming mesenchymal stromal cells with non-integrating vectors. The generated iPSC line expresses pluripotency markers, presents a normal karyotype and is able to differentiate into the three germ layers. This iPSC line is a useful tool for modeling ASD and drug screening studies.
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http://dx.doi.org/10.1016/j.scr.2019.101488DOI Listing
August 2019

Betulinic Acid Derivative BA5, Attenuates Inflammation and Fibrosis in Experimental Chronic Chagas Disease Cardiomyopathy by Inducing IL-10 and M2 Polarization.

Front Immunol 2019 11;10:1257. Epub 2019 Jun 11.

FIOCRUZ, Gonçalo Moniz Institute, Salvador, Brazil.

Chronic Chagas disease cardiomyopathy (CCC) is a major cause of heart disease in Latin America and treatment for this condition is unsatisfactory. Here we investigated the effects of BA5, an amide semi-synthetic derivative betulinic acid, in a model of CCC. Mice chronically infected with were treated orally with BA5 (10 or 1 mg/Kg), three times per week, for 2 months. BA5 treatment decreased inflammation and fibrosis in heart sections but did not improve exercise capacity or ameliorate cardiac electric disturbances in infected mice. Serum concentrations of TNF-α, IFN-γ, and IL-1β, as well as cardiac gene expression of pro-inflammatory mediators, were reduced after BA5 treatment. In contrast, a significant increase in the anti-inflammatory cytokine IL-10 concentration was observed in BA5-treated mice in both tested doses compared to vehicle-treated mice. Moreover, polarization to anti-inflammatory/M2 macrophage phenotype was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers, such as Arg1 and CHI3 in mice treated with BA5. In conclusion, BA5 had a potent anti-inflammatory activity on a model of parasite-driven heart disease related to IL-10 production and a switch from M1 to M2 subset of macrophages.
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http://dx.doi.org/10.3389/fimmu.2019.01257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579897PMC
October 2020
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