Publications by authors named "Ivan da Rocha Pitta"

71 Publications

Interleukin-18 in Brazilian Rheumatoid Arthritis Patients: Can Leflunomide Reduce It?

Autoimmune Dis 2021 10;2021:6672987. Epub 2021 May 10.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Research Group on Immunomodulation and New Therapeutic Approaches Suely Galdino (Nupit SG), Federal University of Pernambuco, Recife, Brazil.

Objectives: Rheumatoid arthritis affects about 1% of the world's population. This is a chronic autoimmune disease. It is predominant in females with progressive joint damage. Immune cells are involved, especially Th1/Th17 lymphocytes and their inflammatory cytokines. These proteins have different functions in the immune system, such as IL-16 is a chemotactic factor; IL-18 can activate NFB transcription producing inflammatory proteins; IL-31 can activate the JAK/STAT pathway which leads to the production of inflammatory factors in chronic diseases; IL-33 promotes IL-16 secretion which causes lymphocyte recruitment, and IL-32 and IL-34 appear to increase TNF secretion by macrophages activation in AR. The aim of this study was to evaluate serum levels of IL-16, IL-18, IL-31, IL-32, IL-33, and IL-34 and compare them with the severity and treatment of RA patients if there are any correlations.

Methods: A total of 140 RA patients and 40 healthy donors were recruited from the Department of Rheumatology at Hospital das Clínicas from the Federal University of Pernambuco. 60 AR patients were naïve for any treatment. Serum cytokine levels were determined using an ELISA kit.

Results: Serum IL-16 ( = 0.0491), IL-18 ( < 0.0001), IL-31 ( = 0.0004), and IL-32 ( = 0.0040) levels were significantly increased in RA patients compared with healthy donors. It was observed that patients using leflunomide had the lowest IL-18 levels, close to controls levels ( = 0.0064).

Conclusion: IL-16, IL-18, IL-31, and IL-32 are increased in the serum of RA patients. IL-18 is at lower levels in those AR who are taking leflunomide as treatment.
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http://dx.doi.org/10.1155/2021/6672987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131162PMC
May 2021

New Trends On Biological Activities And Clinical Studies Of Quinolinic Analogues: A Review.

Curr Drug Targets 2021 Apr 14. Epub 2021 Apr 14.

Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife. Brazil.

The quinolinic ring, present in several molecules, has a great diversity of biological activities. Therefore, this ring is in the structure composition of several candidates of drugs in preclinical and clinical studies, thus, it is necessary the grouping of these results to facilitate the design of new drugs. For this reason, some of the activities were selected for this review, such as: antimalarial, antimicrobial, anticancer, anti-inflammatory, antidiabetic, anti-rheumatic and antiviral. All publications of scientific articles chosen are dated between 2000 and 2020. In addition to presenting the structures of some natural and synthetic compounds with their activities, we list the clinical studies of phases III and IV of antimalarial drugs containing the quinoline nucleus and phase III clinical studies of hydroxychloroquine and chloroquine to assess their possible role in COVID-19. Finally, we show some of the mechanisms of action, as well as the side effects of some of the quinolinic derivatives.
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http://dx.doi.org/10.2174/1389450122666210415100151DOI Listing
April 2021

Immunopositivity for Siglec-15 in gastric cancer and its association with clinical and pathological parameters.

Eur J Histochem 2021 Mar 4;65(1). Epub 2021 Mar 4.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.

The sialic acid-binding immunoglobulin-type lectin Siglec-15 is a promising target to cancer immunotherapy in several tumor types. The present study aimed to investigate Siglec-15 expression in gastric cancer (GC) patient tissue and to evaluate its clinical value. Siglec-15 expression was evaluated by immunohistochemistry with 71 patients. Siglec-15 staining was observed in tumor cells of 53 (74.64%) patients, with significant association with histologic classification and angiolymphatic invasion (p<0.05). Immunohistochemistry analysis also detected Siglec-15 in tumor-associated stroma cells (macrophages/myeloid cells). There was no significant association with outcomes parameters. Siglec-15 expression in well differentiated histological GC tissues and in the tumor microenvironment are potential targets to be further investigated as a novel prognostic factor for GC.
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http://dx.doi.org/10.4081/ejh.2021.3174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967265PMC
March 2021

Investigation of a new oxazolidine derivative in human resistance acute leukemia cells: deciphering its mechanism of action by label-free proteomic.

Naunyn Schmiedebergs Arch Pharmacol 2021 06 21;394(6):1153-1166. Epub 2021 Jan 21.

Research Center for Therapeutic Innovation (NUPIT-SG), Federal University of Pernambuco, Professor Moraes Rêgo s/n, Cidade Universitária, Recife, Pernambuco, 50670-901, Brazil.

The present study aimed to evaluate the mechanism of action of the antineoplastic activity of an oxazolidine derivative, LPSF/NB-3 (5-(4-cloro-benzilideno)-3-etil-2-tioxo-oxazolidin-4-ona). Cytotoxicity assays were performed in peripheral blood mononuclear cells (PBMCs) and resistant acute leukemia cell line (HL-60/MX1) by the MTT method. LPSF/NB-3 exhibited cytotoxicity in HL-60/MX1, but it was not toxic to healthy cells in the highest dose tested (100 μM). The protein extract of HL-60/MX1 cells treated with LPSF/NB-3 was subjected to proteomic analysis using two-dimensional chromatography coupled to mass spectrometry. We could identify a total of 2652 proteins, in which 633 were statistically modulated. Within the group of protein considered for the quantitative analysis with the established criteria, 262 were differentially expressed, 146 with increased expression and 116 with decreased expression in the sample treated with LPSF/NB-3 compared to the control. The following differentially expressed pathways were found: involving regulation of the cytoskeleton, DNA damage, and transduce cellular signals. Networks that were highlighted are related to the immune system. The ELISA technique was used to assess the immunomodulatory potential of LPSF/NB-3 in PBMCs. We observed significant decrease of IFNγ (p < 0.01) and dose-response pattern of the cytokines IL-6, IL-17A, IL-22, and IL-10. Therefore, results suggest that LPSF/NB-3 appears to modulate important pathways, including cell cycle and immune system regulatory pathways.
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http://dx.doi.org/10.1007/s00210-020-02024-8DOI Listing
June 2021

New Oxazolidines Inhibit the Secretion of IFN-γ and IL-17 by PBMCS from Moderate to Severe Asthmatic Patients.

Med Chem 2021 ;17(3):289-297

Laboratorio de Imunomodulacao e Novas Abordagens Terapeuticas (LINAT), Nucleo de Pesquisa em Inovacao Terapeutica Suely Galdino (NUPIT-SG), Universidade Federal de Pernambuco, Recife, PE, Brazil.

Background: Moderate to severe asthma could be induced by diverse proinflammatory cytokines, as IL-17 and IFN-γ, which are also related to treatment resistance and airway hyperresponsiveness. Oxazolidines emerged as a novel approach for asthma treatment, since some chemical peculiarities were suggested by previous studies.

Objective: The present study aimed to evaluate the IL-17A and IFN-γ modulatory effect of two new oxazolidine derivatives (LPSF/NB-12 and -13) on mononucleated cells of patients with moderate and severe asthma.

Methods: The study first looked at potential targets for oxazolidine derivatives using SWISS-ADME. After the synthesis of the compounds, cytotoxicity and cytokine levels were analyzed.

Results: We demonstrated that LPSF/NB-12 and -13 reduced IFN-γ and IL-17 production in peripheral blood mononucleated cells from asthmatic patients in a concentrated manner. Our in silico analysis showed the neurokinin-1 receptor as a common target for both compounds, which is responsible for diverse proinflammatory effects of moderate and severe asthma.

Conclusion: The work demonstrated a novel approach against asthma, which deserves further studies of its mechanisms of action.
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http://dx.doi.org/10.2174/1573406416666200910151950DOI Listing
June 2021

Increased serum levels of galectin-9 in patients with chikungunya fever.

Virus Res 2020 09 18;286:198062. Epub 2020 Jun 18.

Programa de Pós-Graduação em Inovação Terapêutica (PPGIT)/ UFPE, Brazil; Núcleo de Pesquisa em Inovação Terapêutica - Sueli Galdino (Nupit-SG), Brazil.

Chikungunya fever (CHIKF) is an arboviral disease that has caused an epidemic burst of chronic inflammatory joint disease in Latin America in the last few years. Efforts are being spent in understanding the mechanisms by which it may cause such articular damage and in determining possible biomarkers of the disease. Galectins (GAL) are a family of animal lectins with an affinity for beta-galactosides. They have multiple functions including working as receptors in innate immunity and as a control for inflammatory responses in both innate and adaptive immunity. They regulate functions of immune cells, such as lymphocytes and macrophages, which have a main role in the chikungunya inflammatory process. Galectins are also involved in chronification of viral diseases, participate in the immunopathogenesis of chronic joint diseases such as rheumatoid arthritis, and have a role in inflammation in other arboviral diseases, such as dengue. Thus, we intended to determine the serum levels of galectin-1, -3, -4, -7, and -9 in patients with subacute and chronic articular manifestations of CHIKF and to evaluate their associations with clinical manifestations. We evaluated 44 patients with clinical manifestations of CHIKF and serological confirmation with IgM and/or IgG chikungunya virus (CHIKV) antibodies. Forty-nine age- and gender-matched healthy individuals served as controls. Anti-CHIKV IgM and IgG antibodies and galectins serum levels were measured by ELISA. We found higher levels of GAL-9 (patients median 2192 [1500-2631] pg/mL, controls median 46.88 [46.88-46.88] pg/mL, p < 0.0001) and lower levels of GAL-3 (patients median 235.5 [175.5-351.8] pg/mL, controls median 2236.0 [1256.0-2236.0] pg/mL, p < 0.0001) in patients than in controls. There was no statistical difference in levels of GAL-1, -4 and -7 between patients and control groups. There was no difference in GAL-9 serum levels between patients with subacute or chronic symptoms (median 2148 [1500-2722] pg/mL x 2212 [1844-2500] pg/mL, p = 0.3626). A significant association of GAL-9 with joint stiffness, both in its duration and intensity, was found. These results may reflect the participation of GAL-9 in the immunopathogenesis of the inflammatory process in chikungunya fever, as morning stiffness may reflect the systemic inflammatory process.
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http://dx.doi.org/10.1016/j.virusres.2020.198062DOI Listing
September 2020

Increased levels of the soluble oncostatin M receptor (sOSMR) and glycoprotein 130 (sgp130) in systemic sclerosis patients and associations with clinical parameters.

Immunobiology 2020 05 22;225(3):151964. Epub 2020 May 22.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica, Universidade Federal de Pernambuco, Recife, PE, Brazil. Electronic address:

Objective: The objective of the present study was to evaluate the serum levels of soluble oncostatin M (OSM), OSM receptor (sOSMR) and glycoprotein130 (sgp130) in patients with systemic sclerosis (SSc), and the possible associations and correlations with clinical parameters.

Methods: Serum levels of OSM, sOSMR and sgp130 were evaluated by ELISA in eighty-four SSc patients and eighty-four healthy volunteers.

Results: SSc patients had significantly elevated levels of sOSMR and sgp130 when compared with healthy individuals (p < 0.0001 and p = 0.025, respectively). Diffuse cutaneous SSc and limited cutaneous SSc patients also presented higher levels of sOSMR when compared with healthy individuals (p = 0.003 and p = 0.0001, respectively). Patients with digital ulcers presented higher levels of sOSMR when compared to those without ulcers (p = 0.034). However, sOSMR levels were lower in patients with esophageal dysfunction than patients without this involvement (p = 0.038). OSM levels were undetectable in serum from SSc patients and healthy volunteers.

Conclusion: Serum levels of sOSMR and sgp130 are elevated in patients with systemic sclerosis. In addition, associations were observed with important clinical manifestations, suggesting that sOSMR is a candidate biomarker of this disease. More studies are needed to clarify the functions of IL-6 family cytokines in systemic sclerosis.
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http://dx.doi.org/10.1016/j.imbio.2020.151964DOI Listing
May 2020

Atorvastatin inhibits IL-17A, TNF, IL-6, and IL-10 in PBMC cultures from patients with severe rheumatoid arthritis.

Immunobiology 2020 05 30;225(3):151908. Epub 2020 Jan 30.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Suely-Galdino Therapeutic Innovation Research Center (NUPIT-SG), Federal University of Pernambuco (UFPE), Recife, PE, Brazil.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage, and it may present with comorbidities at the systemic level. The Th1/Th2/Th17 CD4 lymphocyte imbalance produces inflammatory cytokines, which begin to act, injuring joint tissue. Atorvastatin is a cholesterol- lowering drug with a range of biological effects including anti-inflammatory potential. Patients with rheumatoid arthritis who used statins exhibited clinical improvement. However, the mechanism is not fully understood. Therefore, we aimed to evaluate the RA immunomodulatory activity of atorvastatin.

Methods: Peripheral blood mononuclear cells (PBMCs) of RA patients and healthy donors were exposed to atorvastatin in different concentrations following a cytotoxicity assay. Th1, Th2, and Th17 cytokines profiles were evaluated in the culture supernatant by cytometric bead array (CBA). Data were analyzed using the Wilcoxon test, and differences were considered significant when p < 0.05.

Results: Atorvastatin showed no toxicity at the tested doses in RA PBMC cultures, and at 10μM, it showed the most significant results, reducing IL-17A (p = 0.002), TNF (p = 0.002), and IL-6 (p = 0.008) supernatant levels. The outcomes also revealed that only patients with more severe disease activity and those sensitive to corticoid treatments were responders to atorvastatin in vitro.

Conclusion: These findings suggest the potential immunomodulatory action of atorvastatin as a mechanism in rheumatoid arthritis treatment.
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http://dx.doi.org/10.1016/j.imbio.2020.151908DOI Listing
May 2020

Sensitivity and specificity of Interleukin 29 in patients with rheumatoid arthritis and other rheumatic diseases.

Immunol Lett 2020 04 16;220:38-43. Epub 2020 Jan 16.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica, Universidade Federal de Pernambuco, Recife-PE, Brazil. Electronic address:

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and progressive inflammation that can cause a high degree of disability in affected individuals. Proinflammatory cytokines play central roles in the development of degradative and inflammatory responses in RA. IL-29 has been identified in RA and reported as a biomarker of the disease.

Objective: To analyze serum levels and accuracy of IL-29 in RA patients compared to healthy subjects and patients with other rheumatic diseases.

Methods: IL-29 serum levels were measured in 121 patients with RA, 53 patients with systemic lupus erythematosus (SLE), 60 patients with systemic sclerosis (SSc), 29 patients with fibromyalgia (FM), 50 patients with osteoarthritis (OA) and 68 healthy individuals as controls. IL-29 levels in serum were investigated by ELISA. Sensitivity, specificity and likelihood ratios (LR) for having RA were calculated.

Results: Serum levels of IL-29 were increased in RA patients 113.6 (IQR = 31.25-308.5) pg/ml compared to non-RA patients (SLE, SSc, OA, and FM) (31.25 pg/ml) and healthy controls (31.25 pg/ml, p < 0.001). The IL-29 cut-off values to distinguish patients with RA from non-RA patients were 61.11 pg/ml (sensitivity 57.02, specificity 92.71, LR: 7.82) and for all subjects 32.96 pg/ml (sensitivity 64.46, specificity 87.31, LR: 5.08). Additionally, IL-29 correlated negatively with age (r=-0189, p = 0.038) and disease duration (-0.192, p = 0.037). Interestingly, IL-29 correlated positively with neutrophil count in RA patients positive for rheumatoid factor (r = 0.259, p = 0.022).

Conclusion: IL-29 is higher in the serum of patients with RA compared to non-RA subjects and may have potential for use as a biological marker.
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http://dx.doi.org/10.1016/j.imlet.2020.01.004DOI Listing
April 2020

GQ-130, a novel analogue of thiazolidinedione, improves obesity-induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway.

Clin Exp Pharmacol Physiol 2020 05 24;47(5):798-808. Epub 2020 Jan 24.

Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Brazil.

The present investigation aimed to characterize the effect of a short-time treatment with a new thiazolidinedione (TZD) derivative, GQ-130, on metabolic alterations in rats fed a high-fat diet (HFD). We investigated whether metabolic alterations induced by GQ-130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ-130 were examined through cell transactivation, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8-week-old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ-130 (10 mg/kg/d) during the last week (HFD-GQ group). In 293T cells, unlike rosiglitazone, GQ-130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ-130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ-130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ-130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ-130 was effective in improving HFD-induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation.
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http://dx.doi.org/10.1111/1440-1681.13252DOI Listing
May 2020

Overexpression of UDP-Glucose 4-Epimerase Is Associated with Differentiation Grade of Gastric Cancer.

Dis Markers 2019 20;2019:6325326. Epub 2019 Nov 20.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas-LINAT/Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino-NUPIT SG, Universidade Federal de Pernambuco, Recife, PE, Brazil.

The UDP-glucose 4-epimerase (GALE) is a glycosyltransferase, which acts on protein and lipid glycosylation in normal and neoplastic cells. This study is aimed at investigating the differential tissue expression of GALE and its possible association with clinical-pathological parameters and the outcome of gastric adenocarcinoma patients. Seventy-one patients were evaluated in relation to GALE expression by immunohistochemistry. Our results showed that 48 (67.6%) patients were GALE positive and 23 (32.4%) negative. Positive staining was present on well-differentiated and moderate-differentiated histological grade of gastric adenocarcinomas ( < 0.0001). There was no significant association with outcome parameters ( > 0.05). Besides that, our results corroborated with the validation cohort analysis, where the expression of GALE mRNA was also associated with the histological grade ( < 0.001). These results suggest a possible use of this enzyme as a biomarker for well and moderately differentiated tumors.
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http://dx.doi.org/10.1155/2019/6325326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886318PMC
May 2020

Galectin-9 gene (LGALS9) polymorphisms are associated with rheumatoid arthritis in Brazilian patients.

PLoS One 2019 10;14(10):e0223191. Epub 2019 Oct 10.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Suely-Galdino Therapeutic Innovation Research Center (NUPIT-SG), Federal University of Pernambuco (UFPE), Recife, Pernambuco, Brazil.

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia, as well as cartilage and bone destruction. Several proteins are associated with the pathogenesis of the disease. Galectin-9 belongs to the family of lectins that are involved in various biological processes and have anti-inflammatory activity.

Objective: To investigate associations between the SNPs of the GAL-9 gene (LGALS9) and serum levels in rheumatoid arthritis patients. We extracted DNA from 356 subjects, 156 RA patients and 200 healthy controls from northeastern Brazil. Three polymorphisms (rs4795835, rs3763959, and rs4239242) in the LGALS9 gene were selected and genotyped using TaqMan SNP genotyping assay. Serum concentrations of galectin-9 were analyzed by ELISA.

Results: The rs4239242 TT genotype showed a positive association with RA (p = 0.0032, odds ratio = 0.28), and heterozygous TC were prevalent in the control group compared to RA patients (p = 0.0001, odds ratio = 7.99). Galectin-9 serum levels were significantly increased in RA patients compared to the control group (p<0.0001). Patients in remission had high levels of galectin compared to the moderate activity group (p<0.0001). Regarding the Clinical Disease Activity Index (CDAI), patients in remission or low activity presented high levels of galectin when compared to patients in severity (p<0.0001). Patients performing moderate activity had a significant value compared to patients who were in high disease severity (p = 0.0064). Interestingly, the AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients (p = 0.0436). The SNP rs4239242 TT genotype showed a positive association with RA in comparison to the control group. The AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786579PMC
March 2020

Galectin-1, -4, and -7 Were Associated with High Activity of Disease in Patients with Rheumatoid Arthritis.

Autoimmune Dis 2019 22;2019:3081621. Epub 2019 Jul 22.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Suely-Galdino Therapeutic Innovation Research Center (NUPIT-SG), Federal University of Pernambuco (UFPE), Recife, PE, Brazil.

Background: Due to the variety of functions that galectins (Gal) possess, it is clear that they participate in the pathogenesis of rheumatoid arthritis (RA). Although some studies demonstrate their functions, there is still no correlation with the clinical data of the disease, having the physiological meaning still unknown.

Objectives: To compare serum levels of Gal-1, -4, and -7 in patients with RA and healthy controls and to correlate them with clinical parameters.

Methods: Serum samples were collected from patients with RA and healthy donors to determine the serum levels of Gal-1, -4, and -7.

Results: Serum levels of Gal-1, -4, and -7 were significantly higher in RA patients compared to controls. We evaluated disease activity (CDAI) with serum levels of galectins and found that patients who were high in disease activity had high levels of galectin compared to the moderate activity group. Galectin-4 had higher levels in patients who were in high activity when compared to the group in remission or low activity. Evaluating the activity of the individual disease (DAS28), patients in high individual activity had high levels of Gal-4 when compared to the group in remission or low activity. We also found an association between positive rheumatoid factor and Gal-1 and Gal-4 levels.

Conclusion: Our results show for the first time the relationship between serum levels of galectin and the clinical parameters of patients with RA. Demonstrating their role in pathogenesis, new studies with galectins are needed to assess how they function as a biomarker in RA.
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http://dx.doi.org/10.1155/2019/3081621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681614PMC
July 2019

PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice.

Behav Pharmacol 2019 10;30(7):574-587

Department of Raw Material Production, Federal University of Rio Grande do Sul, Porto Alegre.

Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.
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http://dx.doi.org/10.1097/FBP.0000000000000494DOI Listing
October 2019

CCL3, IL-7, IL-13 and IFNγ transcripts are increased in skin's biopsy of systemic sclerosis.

Exp Dermatol 2019 10 3;28(10):1172-1175. Epub 2019 Jul 3.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica, Universidade Federal de Pernambuco, Recife, Brazil.

Although several cytokines and chemokines have been investigated as possible mediators of fibrosis in systemic sclerosis (SSc), specific correlation between cytokines and organ involvement have not been found yet, and a cytokine profile characteristic of SSc is far to be identified. We studied the profile of antifibrotic and profibrotic transcripts involved in skin of SSc patients. The mRNA expression was detected by fluorescence-based quantitative real-time PCR (qPCR) in skin's biopsies from 14 patients with SSc and 5 healthy controls. PDGF-A, CTGF, CCL3, IL-6, IL-13, IL-7, IFNγ, IL-17, IL-22 and RORc were analysed in these samples. CCL3, IL-7, IL-13 and IFN-γ were more expressed in skin's biopsy of patients with SSc (P = 0.0002, P = 0.0082, P = 0.0243, P = 0.0335, respectively) when compared with healthy controls. We also found a positive correlation between CCL3 and IL-7 transcripts (P = 0.0050 r = 0.7187). Furthermore, we observed that patients with lung involvement had lower expression of PDGF-A (P = 0.0385). We found an increase in IL-7, IFN-γ, CCL3 and IL-13 relative mRNA expressions on the skin's biopsy of patients with SSc, and a positive correlation between IL-7 and CCL3. These molecules are involved in the pathogenesis of SSc, and how their interactions occur should be the subject of further studies.
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http://dx.doi.org/10.1111/exd.13982DOI Listing
October 2019

IL-27 in patients with Chikungunya fever: A possible chronicity biomarker?

Acta Trop 2019 Aug 7;196:48-51. Epub 2019 May 7.

Serviço de Reumatologia - Hospital das Clínicas da Universidade Federal de Pernambuco, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (Nupit-SG)/ UFPE, Endereço: Av. Prof. Moraes Rego, 1235 - Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil.

Background/purpose: Although many patients with chikungunya virus disease (CHIKVD), an arboviral disease characterized by sudden fever and incapacitating poliartralgia, develop chronic articular symptoms, the mechanisms involved in CHIKVD's chronification and its possible biomarkers remain poorly understood. Interleukin (IL)-17A, IL-21, IL-22, IL-29, and transforming growth factor (TGF)-β have been implicated in the pathogenesis of other inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Since chronic manifestations of CHIKVD share many clinical and immunological characteristics with those diseases, we assessed the serum levels of those cytokines and analyzed their associations with clinical manifestations in patients with CHIKVD.

Methods: We evaluated 45 patients (36 female, mean age: 55.2 ± 13.8 years) with CHIKVD serologically confirmed by enzyme-linked immunosorbent assay (ELISA), articular manifestations upon evaluation, and no previous history of inflammatory rheumatologic diseases, along with 49 healthy age- and sex-matched controls. We tested anti-Chikungunya IgM and IgG antibodies and measured IL-17A, IL-21, IL-22, IL-27, IL-29, and TGF-β serum levels with specific ELISA kits.

Results: IL-27, IL-17A, and IL-29 appeared in most patients but not in controls. IL-27 serum levels were higher in patients with chronic symptoms (median: 523.0 pg/mL [62.5-1,048]) than in ones in the acute or subacute stage (median: 62.5 pg/mL [62.5-483.8], p = .008). In patients with CHIKVD, we found significant correlations between IL-27 levels and tender joint counts (r = .32, p = .006), along with associations between IL-17A levels and swollen joint counts (r = .315, p = .0352). Furthermore, patients with arthritis had higher IL-17A levels (median: 23.14 pg/mL [20.6-25.86]) than ones without (median: 20.29 pg/mL [3.91-22.43], p = .0352). We did not detect IL-22 in either group or IL-21 in patients with CHIKVD.

Conclusion: Serum levels of IL-17A, IL-27, and IL-29 were high in patients with CHIKVD and had important associations with articular manifestations, which might indicate the inflammatory nature of Chikungunya infection in patients with joint symptoms and the roles of those cytokines in the disease's pathophysiology.
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http://dx.doi.org/10.1016/j.actatropica.2019.05.005DOI Listing
August 2019

Dexamethasone inhibits cytokine production in PBMC from systemic sclerosis patients.

Inflammopharmacology 2019 Aug 8;27(4):723-730. Epub 2019 May 8.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica, Universidade Federal de Pernambuco, Avenida Professor Moraes Rêgo, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.

Glucocorticoids (GC) are widely used in the treatment of SSc, although there is not much evidence to prove the benefits offered by these drugs in this disease. In this study, we evaluated the effects of a GC on cytokine production in peripheral blood mononuclear cells (PBMC) of SSc patients. The effect of dexamethasone (DEX) was evaluated in PBMC of 21 SSc patients and 10 healthy volunteers after stimulation of cells with anti-CD3 and anti-CD28. Cytokines IL-2, IL-4, IL-6, IL-10, IL-17A, IL-17F, IFN-γ, TNF, and IL-1β were quantified in the culture supernatant by CBA or ELISA. Of the patients evaluated in this study, 8 (38%) were taking corticosteroids, and esophageal dysfunction was more frequent in these patients when compared to those who did not take corticosteroids. DEX (1.000 nM) treatment in PBMC of SSc patients stimulated with anti-CD3 and anti-CD28 promoted a significant reduction in IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF, IL-1β (p < 0.001 for all), and IL-17F (p = 0.023) cytokines levels. We did not observe differences in response to in vitro treatment with DEX between groups of patients taking or not taking corticosteroids. In PBMC from healthy volunteers, we observed that DEX treatment significantly reduced IL-4, IFN-γ (p = 0.003 for both), IL-6, IL-10, IL-17A, and TNF (p = 0.002 for all) cytokines. These results show that DEX treatment in PBMC of SSc patients reduced the production of important cytokines involved in the pathogenesis of the disease, suggesting a possible mechanism of action of the CG in the treatment of SSc.
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http://dx.doi.org/10.1007/s10787-019-00600-wDOI Listing
August 2019

Novel betulin derivatives inhibit IFN-γ and modulates COX-2 expression.

Nat Prod Res 2020 Jun 22;34(12):1702-1711. Epub 2018 Dec 22.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Research Center Innovation Therapeutics Suely Galdino (NUPIT-SG), Federal University of Pernambuco, Recife, Brazil.

Betulin () is a pentacyclic triterpenes, obtained from natural sources and with several biological activities described, such as anti-tumoral and anti-inflammatory activities. The esterification at hydroxyl group (C-3 and C-28) resulted in five new ester derivatives with different numbers of carbons or halogens (chlorine and fluorine). Among these derivatives, two ( e ) were able to significantly decrease IFN-g (*p = 0.0391; **p = 0.0156) and modulated the expression of COX-2 better than Dexamethasone (). Regarding to cytotoxic assay, the best results were obtained for without modifications, with emphasis on tumoral cell lines Raji and MCF-7. The derivatives and showed immunomodulation activity (for the cytokines IFN-g). The presence of chorine in seems to be important for the ability of modulate COX-2 expression, since the ester chloride derivative at 100 μM is more powerful inhibitor of COX-2 than .
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http://dx.doi.org/10.1080/14786419.2018.1528581DOI Listing
June 2020

Correction to: Statins Inhibit Cytokines in a Dose-Dependent Response in Patients with Systemic Sclerosis.

Inflammation 2019 04;42(2):412

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas Suely Galdino, Universidade Federal de Pernambuco, Recife, Brazil.

One of the author's surname was incorrect. Anderson Ferreira de Almeida should be captured as Anderson Rodrigues de Almeida. The correct name is now presented above.
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http://dx.doi.org/10.1007/s10753-018-0916-2DOI Listing
April 2019

Statins Inhibit Cytokines in a Dose-Dependent Response in Patients with Systemic Sclerosis.

Inflammation 2019 Apr;42(2):407-411

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas Suely Galdino, Universidade Federal de Pernambuco, Recife, Brazil.

Although statins have been successfully administered in the treatment of hypercholesterolemia and cardiovascular disease due to their lipid-lowering and anti-atherosclerotic action, they have shown immunomodulatory effects in several studies with immune-mediated diseases. The aim of this study was to investigate the effects of statins treatment on Th1, Th2, and Th17 cytokines production from stimulated peripheral blood mononuclear cells (PBMCs) obtained from Systemic Sclerosis (SSc) patients. We recruited 21 patients classified according to the American College of Rheumatology criteria for SSc for PBMCs culture analysis. Cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, IL-17A, and IL-17F) were quantified by ELISA or CBA, and patients were assessed for clinical and exam's variables. Simvastatin and atorvastatin at 50 μM promoted reduction in all cytokine levels with statistical significance, except for IL-6, which had its reduction only induced by the use of simvastatin. Statins, particularly simvastatin, appear to have an immunosuppressive effect in reducing all cytokine secretion levels from PBMCs of SSc in a dose-dependent manner.
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http://dx.doi.org/10.1007/s10753-018-0907-3DOI Listing
April 2019

Losartan, but not Enalapril and Valsartan, Inhibits the Expression of IFN-γ, IL-6, IL-17F and IL-22 in PBMCs from Rheumatoid Arthritis Patients.

Open Rheumatol J 2018 18;12:160-170. Epub 2018 Sep 18.

Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Nucleus of Research in Immunomodulation and New Therapeutic Approaches Suely Galdino (Nupit SG), Federal University of Pernambuco (UFPE), Recife, Brazil.

Background: Rheumatoid Arthritis (RA) is a chronic and inflammatory disease that affects about 1% of the world's population. Almost 70% of RA patients have a cardiovascular disease such as Systemic Arterial Hypertension (SAH). Inflammatory cytokines are clearly involved in the pathogenesis of RA and correlated with SAH.

Objective: It is necessary to understand whether the antihypertensive drugs have a dual effect as immunomodulators and which one is the best choice for RA SAH patients.

Methods: Peripheral Blood Mononuclear Cells (PBMCs) from 16 RA patients were purified and stimulated or not stimulated with anti-CD3 and anti-CD28 mAB and were treated with Enalapril, Losartan and Valsartan at 100μM. Patients were evaluated for clinical and laboratory variables including measures of disease activity by Clinical Disease Activity Index (CDAI) and Disease Activity Score (DAS28). Cytokines were quantified by ELISA sandwich.

Results: Losartan was able to reduce levels of IFN-γ ( = 0.0181), IL-6 ( = 0.0056), IL-17F (0.0046) and IL-22 ( = 0.0234) in RA patients. In addition, patients in remission and mild score (DAS28<3.2 and CDAI<10) had a better response to treatment. On the other hand, patients in moderate and severe activity had poor response to Losartan in cytokine inhibition.

Conclusion: PBMCs from RA patients are responsive in inhibiting proinflammatory cytokines using Losartan better than Enalapril and Valsartan and it could be a better antihypertensive choice for patients with RA and systemic arterial hypertension treatment.
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http://dx.doi.org/10.2174/1874312901812010160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151964PMC
September 2018

Thermodynamic Characterization of Mixed Monolayers of a Novel Oxazolidine Derivative and Phospholipids.

J Membr Biol 2018 12 3;251(5-6):723-733. Epub 2018 Oct 3.

Departamento de Bioquímica, Universidade Federal de Pernambuco - UFPE, Recife, PE, 50670-901, Brazil.

Oxazolidine derivatives (OxD) are five ring-membered compounds that contain at least one oxygen and nitrogen in their molecular structure. OxD are known due to several therapeutic activities such as anticancer and antibiotic properties. In this paper, we performed a thermodynamic analysis of the mixed films composed by dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphoethanolamine (DPPE), dipalmitoyl phosphatidylcholine (DPPC) or L-α phosphatidylcholine (PC) with a novel oxazolidine derivate (OxD). Relevant thermodynamic parameters such as excess areas (ΔAE), excess free energies (ΔG), and Gibbs free energy of mixing (AG) were derived from the surface pressure data. The topographical analysis was performed using atomic force microscopy. Based on the calculated values of the thermodynamic parameters, we observed that the miscibility of the mixed films was directly dependent on their composition. DPPG/OxD and DPPE/OxD systems present the best-mixed character at low pressures at OxD molar fraction equivalent to 0.25.
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http://dx.doi.org/10.1007/s00232-018-0049-4DOI Listing
December 2018

Organic Extract of Jacq. Leaf Inhibits Interferon-γ Secretion and Has Bacteriostatic Activity against and .

Evid Based Complement Alternat Med 2018 23;2018:5762368. Epub 2018 Aug 23.

Laboratory of Immunomodulation and New Therapeutical Approaches, Research Centre for Therapeutic Innovation-SuelyGaldino (NUPIT-SG), Federal University of Pernambuco, Recife, PE, Brazil.

Jacq. (Acanthaceae) leaves currently found in the Brazilian north-east are widely used to treat diabetes, menstrual pains, asthma, and other disorders. This work aimed to identify the phytochemical characterization and biological activities of leaf extracts. The plant material was ground and the crude extracts were obtained with water or acetone: water (7:3 v/v), yielding aqueous (JPA), and organic (JPO) extracts. Phytochemical characterization was performed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and trypan blue (TB) exclusion assay in peripheral blood mononuclear cells (PBMCs), BALB/c splenocytes, and neoplastic cells (TOLEDO, K562, DU-145, and PANC-1) at 1, 10, and 100 g/mL. Antibacterial activity was evaluated using the microdilution test to obtain the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Cytokines, IFN-, and IL-17A from culture supernatants of BALB/c mice splenocytes were measured by sandwich ELISA. In the TLC analysis, both JPA and JPO extracts presented coumarin and flavonoids. In addition, HPLC was able to identify coumarin, apigenin, and ellagic acid in both extracts. JPO IC was 57.59 ± 1.03 g/mL (MTT) and 69.44 ± 8.08 g/mL (TB) in TOLEDO. MIC value of JPO against and was 500 g/mL. JPO (100 g/mL) significantly inhibited IFN- levels (p=0.03). is a potential candidate to be further investigated as an IFN- inhibitory agent and against and .
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http://dx.doi.org/10.1155/2018/5762368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126107PMC
August 2018

Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

Medchemcomm 2018 Jun 17;9(6):995-1010. Epub 2018 Apr 17.

Laboratório de Síntese Orgânica Medicinal/LaSOM , Faculdade de Farmácia , Universidade Federal do Rio Grande do Sul , Avenida Ipiranga , 2752 , Porto Alegre/RS , Brazil . Email:

An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called and , with an anti-proliferative effects, achieving IC values of about half that of the IC of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the and compounds induced cell cycle arrest in the G/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to .
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http://dx.doi.org/10.1039/c8md00095fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072436PMC
June 2018

Role of an indole-thiazolidiene PPAR pan ligand on actions elicited by G-protein coupled receptor activated neutrophils.

Biomed Pharmacother 2018 Sep 19;105:947-955. Epub 2018 Jun 19.

Laboratory of Experimental Toxicology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Neutrophils are the first line of defence during inflammatory processes; nevertheless, exacerbated influx and actions of neutrophils in terms of uncontrolled inflammation are harmful to the host. Hence, neutrophil activity is the target of drugs seeking to address undesired inflammation. Here, we investigated the mechanisms of action of a ligand of the three isoforms of peroxisome proliferator-activated receptors (PPAR; (5Z)-5-[(5-bromo-1H-indole-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione), dubbed LYSO-7, on neutrophils activated by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), an agonist of G-protein coupled receptors (GPCRs) that binds to membrane-formylated peptide and activates intracellular inflammation pathways. Neutrophils were collected from the peritoneal cavity of male Wistar rats four hours after oyster glycogen injection. Afterwards, the neutrophils were incubated with saline or LYSO-7 (1 or 10 μM, 30 min), washed and stimulated with fMLP (10 μM, 1 h). LYSO-7 treatment inhibited gene and protein expression of adhesion molecules, CD62 L and CD18, abolished adhesion of neutrophils to endothelial cells, impaired chemotaxis, blocked the enhancement of intracellular calcium levels, induced the expression of PPARγ as well as PPARβδ and reduced nuclear translocation of nuclear factor κB (NF-κB). Moreover, topical application of LYSO-7 (10 mM) prior to local application of fMLP (10 μM) diminished the in vivo leukocyte-endothelial interactions in the mesentery microcirculation of rats. Together, our data highlight the effectiveness of anti-inflammatory actions of LYSO-7 on neutrophils activated by GPCRs, depending, at least in part, on impaired of NF-κB activation and induction of PPAR expression.
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http://dx.doi.org/10.1016/j.biopha.2018.06.056DOI Listing
September 2018

Different profile of cytokine production in patients with systemic sclerosis and association with clinical manifestations.

Immunol Lett 2018 06 27;198:12-16. Epub 2018 Mar 27.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - Núcleo de Pesquisa em Inovação Terapêutica (LINAT-NUPIT) - UFPE, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil.

Immune dysregulation is a central process in the pathogenesis of systemic sclerosis (SSc). Cytokines produced by lymphocytes and monocytes are important mediators and induce tissue damage, recruit additional inflammatory cells, and promote extracellular matrix production and fibrosis. In the present research, we aimed to study the associations between levels of cytokines in serum and culture supernatants from peripheral blood mononuclear cells (PBMCs) and clinical manifestations in SSc patients. Serum samples were obtained from 56 SSc patients and 56 unrelated age- and gender-matched healthy individuals. Resting and anti-CD3/CD28-stimulated PBMC cultures were obtained from 19 SSc patients and 8 healthy controls. IL-2, IL-4, IL-6, IL-10, IL-17A, TNF, and IFN-γ levels were measured by ELISA or CBA. Serum cytokines, except IL-17A, were below the kit detection limit in most of the patients and controls. In unstimulated PBMC, the production of TNF(p = 0.004), IL-10(p = .048), IL-2(p < 0.001), and IL-6 (p = 0.01) was higher in SSc patients than in healthy controls. After anti-CD3/CD28 stimulation, scleroderma PBMCs had lower concentrations of TNF(p = 0.009), IL-10(p = .018), and IL-2(p = .002) than HC. In unstimulated PBMC, IL-2 concentration was higher in patients with esophageal dysmotility (p = 0.04), and IL-10 levels had a positive correlation with modified Rodnan score (p = 0.03). After anti-CD3/CD28 stimulation, higher levels of IL-2 and IL-4 were observed in SSc patients with lung fibrosis (p = 0.01 and 0.006, respectively), and higher levels of IL-10 (p = 0.04) and IL-4 (p = 0.04) in patients with digital ulcers. In conclusion, SSc patients have a different profile of cytokine production and this was associated with clinical manifestations.
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http://dx.doi.org/10.1016/j.imlet.2018.03.011DOI Listing
June 2018

Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells.

Anticancer Drugs 2018 Feb;29(2):157-166

aLaboratory for Immunomodulation and New Therapeutic Approaches bLaboratory for Planning and Drug Synthesis, Federal University of Pernambuco (UFPE), Recife, Pernambuco cLaboratory Synthesis and Vectoring Molecules, Department of Biological Sciences, State University of Paraíba (UFPB), João Pessoa, Paraíba, Brazil.

Substitutions in thiophene structure give rise to new derivatives with different biological and pharmacological activities. The present study investigated the cytotoxicity activity of some thiophene derivatives in breast cancer cells maintained in two-dimensional (2D) or in three-dimensional (3D) culture and evaluated the anticancer mechanism of these compounds. Cytotoxicity assays were performed against untransformed cells and against breast cancer cell MCF-7. Apoptosis analysis and in-vitro migration assay were also performed to evaluate the mechanism of induction of cell death. All thiophene derivatives reduced the cell viability in breast cancer cells, showing cytotoxic activity (IC50<30 µmol/l), and SB-200 compound showed the best selectivity index in MCF-7 cells compared with doxorubicin in 2D culture. All thiophene derivatives significantly induced G0/G1 phase cell cycle arrest. However, only SB-83 treatment was effective against motility of MCF-7 cells in 2D culture (P=0.0059). The SB-200 derivative treatment induced an increased proportion of acridine orange/Hoechst double-stained cells (35.35 vs. 3.14%, P=0.0002) compared with nontreated cells, with apoptosis morphological alterations independent of caspase 7 activation (P>0.05). MCF-7 cells became less responsive to SB-200 and to doxorubicin in 3D culture compared with cells in 2D culture (higher IC50 values); however, SB-200 showed a better cytotoxic effect compared with doxorubicin in 3D culture. Therefore, the current study provides an insight into anticancer potential of thiophene derivatives, and further studies should be conducted to understand the mechanism by which thiophene derivatives act on cancer cells.
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http://dx.doi.org/10.1097/CAD.0000000000000581DOI Listing
February 2018

Antinociception induced by a novel α adrenergic receptor agonist in rodents acute and chronic pain models.

Eur J Pharmacol 2017 Nov 19;815:210-218. Epub 2017 Sep 19.

Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil.

The mechanisms and antinociceptive effects of a novel α adrenoceptor agonist, 3-(2-chloro-6-fluorobenzil)-imidazolinide-2,4-dione (PT-31) were investigated using animal models of acute and chronic pain. The effects of PT-31 on pain responses were examined using hot plate and formalin tests in mice and spinal nerve ligation (SNL)-induced hyperalgesia in rats. The effects of antagonists acting on α adrenoceptor were assessed to investigate the interaction of these pathways upon PT-31 induced antinociception. PT-31 effects on motor activity/skills and on hemodynamic parameters were also evaluated. PT-31 had dose-dependent antinociception effects on hot-plate and formalin-injection induced pain responses. Thermal hyperalgesia and mechanical allodynia were reduced following a 7 d treatment with PT-31 (1, 5, and 10mg/kg/d, p.o.), and those effects were attenuated by yohimbine (5mg/kg), atropine (2mg/kg), L-nitro arginine methyl ester (L-NAME; 30mg/kg), or naloxone (2mg/kg). In contrast to clonidine, PT-31 did not have locomotor or hemodynamic effects in rats. The present results suggest that PT-31 represents a candidate for pain treatment with advantages over clonidine, namely no locomotor or hemodynamic impairments.
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http://dx.doi.org/10.1016/j.ejphar.2017.09.018DOI Listing
November 2017

Corticosteroid inhibits chemokines production in systemic sclerosis patients.

Steroids 2017 11 1;127:24-30. Epub 2017 Sep 1.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas, Núcleo de Pesquisa em Inovação Terapêutica (NUPIT), Universidade Federal de Pernambuco, Recife, PE, Brazil.

In this study, we evaluated glucocorticoids (GC) effects on cytokine/chemokine levels in serum samples and peripheral blood mononuclear cell (PBMC) production from systemic sclerosis (SSc) patients. We evaluated cytokine and chemokine levels in serum samples from SSc patients taking or not taking systemic glucocorticoids. PBMCs response to methylprednisolone (MP) was examined from 15 SSc patients and 8 healthy control subjects following PBMC stimulation with anti-CD3/CD28. Cytokine (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17A) and chemokine (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in serum and in PBMC culture supernatants by CBA or ELISA. Compared with patients not taking corticosteroids, we did not observe any significant differences in cytokines/chemokines serum levels in patients using systemic corticosteroids. After stimulation with anti-CD3/CD28, PBMCs treated with MP (100μM), showed a significant reduction of CCL2/MCP-1 (p=0.001), CCL5/RANTES (p=0.04), and CXCL8/IL-8 (p=0.003) levels in SSc patients. In PBMC from healthy controls, we observed decreased IFN-γ, TNF, IL-2, and IL-10 levels after MP treatment, compared with stimulated condition (p<0.01 for all). However in SSc patients, we did not find any significant reduction in these cytokine levels after MP treatment. In conclusion, CCL2/MCP-1, CCL5/RANTES, and CXCL8/IL-8 are chemokines that are potentially modulated by corticosteroids in vitro in SSc patients, but no effect was observed on IL-2, IL-4, IL-6, IL-10, IL-17A, TFN, and IFN-γ secretion. These results suggest a potential effect of GCs on SSc treatment and may reflect the benefit of their use in some patients.
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http://dx.doi.org/10.1016/j.steroids.2017.08.012DOI Listing
November 2017

Synthesis of novel indole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I activities.

Eur J Med Chem 2017 Aug 4;136:511-522. Epub 2017 May 4.

Laboratório de Química e Inovação Terapêutica, Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil.

Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy H NMR, C NMR, COSY H-H and HSQC H-C. The antitumor activity was evaluated against different cancer cell lines using the antiproliferative MTT assay. DNA binding ability was analyzed by absorption spectroscopy and fluorescence technique using ethidium bromide (EB) as a fluorescent probe. Changes were observed in spectroscopic properties of the compounds after interacting with ctDNA (calf thymus DNA), with hypochromic and hyperchromic effects, besides blue or red shifts in the maxima of spectra. The indole derivative 5-(1H-Indol-3-ylmethylene)-thiazolidin-2,4-dione (4c) presented the best results in antitumor assay against the breast line tested (T47D), with IC value lower than the positive control, doxorubicin (1.93 and 4.61 μM, respectively). On the other hand, the compound 3-amino-5-(1H-indol-3-ylmethylene)-2-thioxo-thiazolidin-4-one (4a) was active against leukemia cell lines (HL60 and K562) with the high value of the DNA binding constant, Kb of 5.69 × 10. However, this compound (4a) did not inhibit the topoisomerase-I activity evaluated by relaxation assay. These results show that the indole nucleus contribute to the incorporation of molecules into the DNA. Moreover, it was highlighted that basic side chains, such as thiazolidines and imidazolidines, and free amino group, are relevant for design of promising antitumor and DNA binding compounds.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.012DOI Listing
August 2017