2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3- thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease

Targeting Dendritic Cells as a Good Alternative to Combat Leishmania spp

Submitted by Kamylla Nascimento ([email protected]) on 2017-11-17T13:55:45Z No. of bitstreams: 1 art. Targeting dendritic cells - freitas e silva.pdf: 471913 bytes, checksum: b4c122e7554ab17b58c72834fdfded61 (MD5)Approved for entry into archive by Kamylla Nascimento ([email protected]) on 2017-11-17T14:10:12Z (GMT) No. of bitstreams: 1 art. Targeting dendritic cells - freitas e silva.pdf: 471913 bytes, checksum: b4c122e7554ab17b58c72834fdfded61 (MD5)Made available in DSpace on 2017-11-17T14:10:12Z (GMT). No. of bitstreams: 1 art. Targeting dendritic cells - freitas e silva.pdf: 471913 bytes, checksum: b4c122e7554ab17b58c72834fdfded61 (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil

Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART

Decades of studies in antiretroviral therapy (ART) have passed, and the mechanisms that determine impaired immunological recovery in HIV-positive patients receiving ART have not been completely elucidated yet. Thus, T-lymphocytes immunophenotyping and cytokines levels were analyzed in 44 ART-treated HIV-positive patients who had a prolonged undetectable plasma viral load. The patients were classified as immunological non-responders (INR = 13) and immunological responders (IR = 31), according to their CD4+ T cell levels. Evaluating pre-CD4+ levels, we observed a statistically significant trend between lower CD4+ T cell levels and INR status (Z = 3.486, p p < 0.001). Furthermore, the INRs were associated with an elevated age at ART start; a lower pre-treatment CD4+ T cell count and a percentage that remained low even after 18 months of ART; lower levels of recent thymic emigrant (RTE) CD4+ T cell (CD45RA + CD31+) and a naïve CD4+ T cell (CD45RA + CD62L+); higher levels of central memory CD4+ T cells (CD45RA-CD62L+); and higher immune activation by CD4+ expressing HLA-DR+ or both (HLA-DR+ and CD38+) when compared with IRs. Our study demonstrates that thymic exhaustion and increased immune activation are two mechanisms substantially implicated in the impaired immune recovery of ART-treated HIV patients

Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART

Decades of studies in antiretroviral therapy (ART) have passed, and the mechanisms that determine impaired immunological recovery in HIV-positive patients receiving ART have not been completely elucidated yet. Thus, T-lymphocytes immunophenotyping and cytokines levels were analyzed in 44 ART-treated HIV-positive patients who had a prolonged undetectable plasma viral load. The patients were classified as immunological non-responders (INR = 13) and immunological responders (IR = 31), according to their CD4+ T cell levels. Evaluating pre-CD4+ levels, we observed a statistically significant trend between lower CD4+ T cell levels and INR status (Z = 3.486, p &lt; 0.001), and during 18 months of ART, the CD4+ T cell levels maintained statistical differences between the INR and IR groups (WTS = 37.252, p &lt; 0.001). Furthermore, the INRs were associated with an elevated age at ART start; a lower pre-treatment CD4+ T cell count and a percentage that remained low even after 18 months of ART; lower levels of recent thymic emigrant (RTE) CD4+ T cell (CD45RA + CD31+) and a na&iuml;ve CD4+ T cell (CD45RA + CD62L+); higher levels of central memory CD4+ T cells (CD45RA-CD62L+); and higher immune activation by CD4+ expressing HLA-DR+ or both (HLA-DR+ and CD38+) when compared with IRs. Our study demonstrates that thymic exhaustion and increased immune activation are two mechanisms substantially implicated in the impaired immune recovery of ART-treated HIV patients

Central and Effector Memory Human CD4⁺ and CD8⁺ T Cells during Cutaneous Leishmaniasis and after In Vitro Stimulation with <i>Leishmania (Viannia) braziliensis</i> Epitopes

Cutaneous Leishmaniasis (CL) is a Neglected Tropical Disease characterized by skin ulcers caused by Leishmania spp. protozoans and there is no safe and effective vaccine to reduce its negative consequences. In a previous work by our group, we identified T cell epitopes of Leishmania (Viannia) braziliensis which stimulated patients’ T cells in vitro. In the present work, the peptides were tested as two pools for their ability to rescue memory T cells during natural infection by Leishmania. We analyzed the frequency of central memory (TCM, CD45RA-CD62L+) and effector memory (TEM, CD45RA + CD62L-) cells during active CL and post-treatment. In parallel, we investigated cell proliferation levels and the cytokines produced after stimulation. Interestingly, we observed higher frequencies (%) in CD4+ TEM during CL, and CD8+ TEM and CD8+ TCM during CL and post-treatment. Cell proliferation was increased, and a significant difference in expression was observed on T-bet and RORγT. Besides that, IFN-γ, IL-2, and IL-10 were detected in patient samples. Collectively, this dataset suggests that during CL there is an increase in the frequency of TCM and TEM, especially in the CD8 compartment. These results indicate a potentially immunogenic profile of the peptide pools, which can support the development of anti-Leishmania formulations

The in vitro biological activity of the Brazilian brown seaweed Dictyota mertensii against Leishmania amazonensis

Submitted by Kamylla Nascimento ([email protected]) on 2017-11-20T14:06:24Z No. of bitstreams: 1 art. The in Vitro Biological Activity - aliança.pdf: 3586985 bytes, checksum: 5dc5a0466274bf6a18c38bc8815ef061 (MD5)Approved for entry into archive by Kamylla Nascimento ([email protected]) on 2017-11-20T14:30:32Z (GMT) No. of bitstreams: 1 art. The in Vitro Biological Activity - aliança.pdf: 3586985 bytes, checksum: 5dc5a0466274bf6a18c38bc8815ef061 (MD5)Made available in DSpace on 2017-11-20T14:30:32Z (GMT). No. of bitstreams: 1 art. The in Vitro Biological Activity - aliança.pdf: 3586985 bytes, checksum: 5dc5a0466274bf6a18c38bc8815ef061 (MD5) Previous issue date: 2014-09-09Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.Seaweeds present a wide variety of interesting bioactive molecules. In the present work we evaluated the biological activity of the dichloromethane/methanol (2:1) extract (DME) from the brown seaweed Dictyota mertensii against Leishmania amazonensis and its cytotoxic potential on mammalian cells. The extract showed significant inhibitory effect on the growth of promastigote forms (IC50=71.60 μg/mL) and low toxicity against mammalian cells (CC50=233.10 μg/mL). The DME was also efficient in inhibiting the infection in macrophages, with CC50 of 81.4 μg/mL and significantly decreased the survival of amastigote forms within these cells. The selectivity index showed that DME was more toxic to both promastigote (SI=3.25) and amastigote (SI=2.86) forms than to macrophages. Increased NO production was observed in treated macrophages suggesting that besides acting directly on the parasites, the DME also shows an immunomodulatory effect on macrophages. Drastic ultrastructural alterations consistent with loss of viability and cell death were observed in treated parasites. Confocal microscopy and cytometry analyzes showed no significant impairment of plasma membrane integrity, whereas an intense depolarization of mitochondrial membrane could be observed by using propidium iodide and rhodamine 123 staining, respectively. The low toxicity to mammalian cells and the effective activity against promastigotes and amastigotes, point to the use of DME as a promising agent for the treatment of cutaneous leishmaniasis

Comparison of serum cytokine levels in symptomatic and asymptomatic HIV-Leishmania coinfected individuals from a Brazilian visceral leishmaniasis endemic area.

BackgroundVisceral leishmaniasis (VL) remains an important infectious disease worldwide. VL-HIV coinfected individuals can present with atypical clinical forms of VL and have a high risk of VL relapse. Some cytokines have been described as potential markers to diagnose active VL and to predict the severity of the cases. However, few studies have included VL-HIV coinfected patients. We aimed to characterize the levels of several cytokines among VL-HIV coinfected individuals living in a VL-endemic area in Northeast Brazil.MethodsThis was a retrospective, cross-sectional study, aiming to estimate the levels of various cytokines in symptomatic and asymptomatic VL-HIV coinfected individuals. There were 134 study participants (35 symptomatic VL-HIV, 75 asymptomatic VL-HIV, and 24 healthy controls), all ≥ 18 years-old. Serum cytokine levels (interferon-γ, tumor necrosis factor, and interleukins 2, 4, 6, 10, and 17A) were quantified using the Becton Dickinson-BD's Cytometric Bead Array (CBA) system.ResultsThe population mainly consisted of men (64.9%), with a median age of 35 (27-41) years. Asymptomatic individuals were younger (p = 0.013), with more years of education (p ConclusionsHigher serum levels of IL-17A, IL-6, and IL-10 cytokines were observed in symptomatic coinfected individuals but not in asymptomatically infected individuals. More studies among HIV-positive persons are needed to better understand the role of serum cytokines for prognosis, to define cure and predict VL relapses in VL-HIV coinfected individuals