Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from <i>Nectandra leucantha</i>

Costa-Silva, Thaís A.; Grecco, Simone dos Santos; Sousa, Fernanda S. de; Lago, João Henrique G.; Martins, Euder Glendes Andrade; Terrazas, César; Varikuti, Sanjay; Owens, Katherine; Beverley, Stephen M.; Satoskar, Abhay R.; Tempone, André G.

doi:10.1021/np500809a

Cited by 62 publications

(57 citation statements)

References 40 publications

(69 reference statements)

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“…The parasite burden was determined by the number of infected macrophages out of 400 cells. Compounds were tested to the highest concentration of 100 μ m and were reported as not active (>100) when the IC 50 value was above this concentration …”

Section: Methodsmentioning

confidence: 99%

Antileishmanial Activity and Immunomodulatory Effects of Tricin Isolated from Leaves of Casearia arborea (Salicaceae)

Santos

Yamamoto

Passero

et al. 2017

Chemistry & Biodiversity

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Bioactivity-guided fractionation of antileishmanial active extract from leaves of Casearia arborea led to isolation of three metabolites: tricin (1), 1',6'-di-O-β-d-vanilloyl glucopyranoside (2) and vanillic acid (3). Compound 1 demonstrated the highest activity against the intracellular amastigotes of Leishmania infantum, with an IC value of 56 μm. Tricin (1) demonstrated selectivity in mammalian cells (SI > 7) and elicited immunomodulatory effect on host cells. The present work suggests that tricin modulated the respiratory burst of macrophages to a leishmanicidal state, contributing to the parasite elimination. Therefore, the natural compound tricin could be further explored in drug design studies for leishmaniasis treatment.

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Section: Methodsmentioning

confidence: 99%

Antileishmanial Activity and Immunomodulatory Effects of Tricin Isolated from Leaves of Casearia arborea (Salicaceae)

Santos

Yamamoto

Passero

et al. 2017

Chemistry & Biodiversity

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“…Cells were treated with AmB (native drug) and nanoformulations of MTC, TC, UC and AmBisome V R equivalent to their IC 50 concentration, and untreated cells were considered as control. Supernatants were collected after 72 h of incubation at 37 C and analyzed for the concentration of cytokines (TNF-a, IL-12, and IL-6) by ELISA plate reader at 405 nm [16].…”

Section: Cytokine Elisamentioning

confidence: 99%

“…After ten min incubation, absorbance was evaluated using the ELISA plate reader at 540 nm. Results achieved were extrapolated from a standard curve plotted with NaNO 2 at different concentrations (0-400 lM) [16].…”

Section: Quantification Of Nitric Oxidementioning

confidence: 99%

Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis

Sarwar

Sohail

Saljoughian

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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The aim of this study was to evaluate mannose-anchored thiolated chitosan (MTC) based nanocarriers (NCs) for enhanced permeability, improved oral bioavailability and anti-parasitic potential of amphotericin B (AmB). Transgenic Leishmania donovani parasites expressing red fluorescent protein DsRed2 and imaging-flow cytometry was used to investigate parasitic burdens inside bone marrow-derived macrophages ex vivo. Cytokine estimation revealed that MTC nanocarriers activated the macrophages to impart an explicit immune response by higher production of TNF-α and IL-12 as compared to control. Cells treated with MTC NCs showed a significantly higher magnitude of nitrite and propidium iodide (PI) fluorescence intensity in contrast to cells treated with AmB. Concerning to apparent permeability coefficient (P) results, the MTC NCs formulation displayed more specific permeation across the Caco-2 cell monolayer as compared to AmB. The half-life of MTC NCs was about 3.3-fold persistent than oral AmB used as positive control. Also, t oral bioavailability of AmB was increased to 6.4-fold for MTC NCs compared to AmB for positive control. Acute oral evaluation indicated that MTC NCs were significantly less toxic compared to the AmB. Based on these findings, MTC NCs seems to be promising for significant oral absorption and improved oral bioavailability of AmB in leishmaniasis chemotherapy.

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“…It has also been reported that patients with active VL have higher serum levels of IL-10 and IL-6, evidencing their association with disease persistence [21]. Other studies with phenylpropanoid derivatives, demonstrated a correlation between the downregulation of IL-6 and IL-10 with the control of the infection in the Leishmania -infected macrophages [22]. Jek and co-workers [23] demonstrated that blocking NO production in rat macrophages results in an increased IL-1 and IL-6 secretion.…”

Section: Discussionmentioning

confidence: 98%

Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice

et al. 2017

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BackgroundThe leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity.Methodology/Principal FindingsIn vitro antileishmanial activity was determined in promastigotes and in L. infantum-infected macrophages. For in vivo studies, L. infantum-infected BALB/c mice were treated with CBP by oral gavage for five days and the parasite load was estimated. Trypanothione reductase activity was assessed in the soluble fraction of promastigotes of L. infantum. For evaluation of cytokines, L. infantum-infected macrophages were co-cultured with BALB/c splenocytes and treated with CBP for 48 h. The supernatant was analyzed for IL-6, IL-10, MCP-1, IFN-γ and TNF-α. CBP demonstrated an IC50 of 14.5±1.1μM and an IC90 of 74.5±1.2 μM in promastigotes and an IC50 of 12.6±1.05 μM and an IC90 of 28.7±1.3 μM in intracellular amastigotes. CBP also reduced the parasite load in L. infantum-infected mice by 40.4±10.3% and 66.7±10.5% in spleen at 24.64 and 49.28 mg/kg, respectively and by 85.6±5.0 and 89.3±4.8% in liver at 24.64 and 49.28mg/kg, after a short-term treatment. CBP inhibited the trypanothione reductase activity with a Ki of 86 ± 7.7 μM and increased the ROS production in promastigotes. CBP inhibited in 53% the production of IL-6 in infected macrophages co-culture.Conclusion/SignificanceTo the best of our knowledge, this study is the first report of the in vivo antileishmanial activity of the FDA-approved drug CBP. Modulation of immune response and induction of oxidative stress in parasite seem to contribute to this efficacy.

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Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha

Cited by 62 publications

References 40 publications

Antileishmanial Activity and Immunomodulatory Effects of Tricin Isolated from Leaves of Casearia arborea (Salicaceae)

Antileishmanial Activity and Immunomodulatory Effects of Tricin Isolated from Leaves of Casearia arborea (Salicaceae)

Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis

Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice

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