Melatonin attenuates <i><scp>L</scp>eishmania (L.) amazonensis</i> infection by modulating arginine metabolism

Laranjeira-Silva, Maria Fernanda; Zampieri, Ricardo Andrade; Muxel, Sandra Márcia; Flöeter-Winter, Lucile Maria; Markus, Regina Pekelmann

doi:10.1111/jpi.12279

Cited by 57 publications

(74 citation statements)

References 54 publications

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“…( L .) amazonensis , probably by reducing the uptake of L-arginine and polyamine production, then supplementation with putrescine allow the infectivity44. Indeed, the deprivation of L-arginine decreases ornithine and putrescine levels but does not change the levels of spermidine, spermidine or agmatine in promastigotes45.…”

Section: Discussionmentioning

confidence: 99%

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

Muxel

Laranjeira-Silva

Zampieri

et al. 2017

Sci Rep

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Leishmania (Leishmania) amazonensis is an intracellular protozoan parasite responsible for the cutaneous leishmaniasis. The parasite replicates inside mammalian macrophage to establish infection. Host-pathogen interactions result in microRNA-mediated post-transcriptional regulation of host genes involved in inflammatory immune response. We analyzed macrophage miRNA profiles during L. (L.) amazonensis infection. The regulation of macrophage miRNA expression by the parasite correlates with/depends on parasite arginase activity during infection. L. (L.) amazonensis (La-WT) presented significant miRNA profile alteration (27%) compared to L. (L.) amazonensis arginase knockout (La-arg−) (~40%) in relation to uninfected-macrophages. We observed that 78% of the altered miRNAs were up-regulated in La-WT infection, while only 32% were up-regulated in La-arg−-infected macrophages. In contrast to La-WT, the lack of L. (L.) amazonensis arginase led to the inhibition of miR-294 and miR-721 expression. The expression of miR-294 and miR-721 was recovered to levels similar to La-WT in La-arg− addback mutant. The inhibition of miR-294/Nos2 and miR721/Nos2 interactions increased NOS2 expression and NO production, and reduced L. (L.) amazonensis infectivity, confirming Nos2 as target of these miRNAs. The role of miR-294 and miR-721 in the regulation of NOS2 expression during Leishmania replication in infected macrophages pointing these miRNAs as potential new targets for drug development.

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Section: Discussionmentioning

confidence: 99%

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

Muxel

Laranjeira-Silva

Zampieri

et al. 2017

Sci Rep

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120

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“…Human colostrum monocytes, incubated with Escherichia coli enteropathogenic or zymosan, synthesize melatonin after a time lag of 20 min . RAW 264.7 macrophages also synthesize melatonin after incubation with LPS, zymosan, or the parasite Leishmania amazonensis . The common step for all this experimental models is that melatonin synthesis is driven by NF‐ κ B nuclear translocation and is dependent on Aa‐nat transcription.…”

Section: Discussionmentioning

confidence: 99%

The RelA/cRel nuclear factor‐κB (NF‐κB) dimer, crucial for inflammation resolution, mediates the transcription of the key enzyme in melatonin synthesis in RAW 264.7 macrophages

Muxel

Laranjeira-Silva

Carvalho-Sousa

et al. 2016

Journal of Pineal Research

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Lipopolysaccharide (LPS) modulates the transcription of the gene that codifies the enzyme arylalkylamine-N-acetyltransferase (AA-NAT) through nuclear translocation of the transcription factor nuclear factor-κ-light-chain-enhancer of activated B cells (NF-κB). AA-NAT converts serotonin to N-acetylserotonin, the ultimate precursor of melatonin. Activation of kappa B elements (aa-nat-κB), localized in the promoter (nat-κB1 and nat-κB2), leads to Aa-nat transcription in RAW 264.7 macrophages. Competitive electrophoretic mobility shift assay (EMSA) with oligonucleotide probes corresponding to each of the two elements, as well as a NF-κB consensus corresponding probe, revealed different specificities for each κB element. In addition, activator protein-1 (AP-1) as well as signal transducers and activator of transcription-1 and 3 (STAT-1; STAT-3) competed with NF-κB for binding to nat-κB1, while only STAT-3 competed with NF-κB for binding to nat-κB2. According to co-immunoprecipitation (ChiP) assays, these two sites are able to distinguish NF-κB subunits. The sequence nat-κB1 bound dimers containing p52, RelA, and cRel, while nat-κB2 bound preferentially p50, p52, and RelA, and did not bind cRel. The expression of RelA and cRel is essential for the induction of Aa-nat expression and melatonin synthesis. Considering that the expression of cRel is induced by the earlier expressed p50/RelA, the differential effects of NF-κB dimers may be intimately associated with the temporal regulation of inflammatory responses, with the resolution phase being associated with paracrine and autocrine melatonin effects. Such data suggest that the proven effects of exogenous melatonin in the resolution phase of inflammation are paralleled by the effects of locally synthesized melatonin in immune cells.

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“…Recently, it was shown that the effect of darkness on endothelial cells primes the expression of microRNAs that negatively regulate cell adhesiveness, inflammatory response, and proliferation [44]. Melatonin synthesized by phagocytes acts in a paracrine manner favouring the phagocytosis of bacteria, fungi, parasites, and cellular debris [17, 41, 45, 46]. The synthesis of melatonin by the pineal gland is restored before the end of the acute inflammatory response, due to the inhibition of NF- κ B by glucocorticoids released from the adrenal gland [29, 47, 48].…”

Section: Melatoninergic Systemmentioning

confidence: 99%

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

Mack

Schamne

Sampaio

et al. 2016

Oxidative Medicine and Cellular Longevity

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Melatonin is synthesized by several tissues besides the pineal gland, and beyond its regulatory effects in light-dark cycle, melatonin is a hormone with neuroprotective, anti-inflammatory, and antioxidant properties. Melatonin acts as a free-radical scavenger, reducing reactive species and improving mitochondrial homeostasis. Melatonin also regulates the expression of neurotrophins that are involved in the survival of dopaminergic neurons and reduces α-synuclein aggregation, thus protecting the dopaminergic system against damage. The unbalance of pineal melatonin synthesis can predispose the organism to inflammatory and neurodegenerative diseases such as Parkinson's disease (PD). The aim of this review is to summarize the knowledge about the potential role of the melatoninergic system in the pathogenesis and treatment of PD. The literature reviewed here indicates that PD is associated with impaired brain expression of melatonin and its receptors MT1 and MT2. Exogenous melatonin treatment presented an outstanding neuroprotective effect in animal models of PD induced by different toxins, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, and maneb. Despite the neuroprotective effects and the improvement of motor impairments, melatonin also presents the potential to improve nonmotor symptoms commonly experienced by PD patients such as sleep and anxiety disorders, depression, and memory dysfunction.

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Melatonin attenuates Leishmania (L.) amazonensis infection by modulating arginine metabolism

Cited by 57 publications

References 54 publications

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

The RelA/cRel nuclear factor‐κB (NF‐κB) dimer, crucial for inflammation resolution, mediates the transcription of the key enzyme in melatonin synthesis in RAW 264.7 macrophages

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

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