Quercetin Induces Apoptosis of Trypanosoma brucei gambiense and Decreases the Proinflammatory Response of Human Macrophages

Abstract

In addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-␣ and nitric oxide derivatives. In the present study, quercetin (3,3,4,5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-␣ and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.Human African trypanosomiasis (HAT), or sleeping sickness, is provoked by the inoculation of Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense into humans by a tse-tse fly. HAT is considered a reemerging disease, mainly due to the deterioration of health facilities in endemic areas. Blood monocytes and tissue macrophages play a key role in the control of parasite numbers, and an increased number of activated hematopoietic cells are observed during trypanosomiasis (33). Trypanosome-derived products were also shown to activate the generation by macrophages of various proinflammatory mediators including tumor necrosis factor alpha (TNF-␣), nitric oxide (NO), and interleukin-1 (IL-1) (7,19,28). TNF-␣ and NO fulfill important functions in host-parasite interactions as they control infections by various pathogens, including T. b. gambiense (6,21,32). In addition, chronic secretion of macrophage-derived mediators is in part responsible for the pathogenic aspects of HAT (18,20,25,27). Accordingly, a correlation can be made between high levels in serum of TNF-␣ and disease severity in HAT (25), and successful treatment with melarsoprol significantly reduced the circulating concentration of this cytokine in HAT patients (27).Only a few drugs are available to treat HAT, and some of them are effective only during the first phase of disease or are difficult to administer because of their high toxicity. These facts led us to investigate the effects of nutrition-derived flavonoids on in vitro interactions between T. b. gambiense and human leukocytes. Flavonoids are produced in plants in response to environmental stress such as adverse weather or attacks by insects, animals, or pathogens (37). For humans, the main flavonoid dietary sources are fruits, beverages, vegetables, dry legumes, and cereals. Recently, various purified polyphenolic compounds were defined as strong free-radical scavenging agents that display antitumoral, antimicrobial, and anti-inflammatory activities (3).Quercetin and its derivatives are among the most common polyphenolic flavonoids present in plants such as onions, ginkgo biloba, and tea ...

Antitrypanosomal and Antileishmanial Activities of Flavonoids and Their Analogues: In Vitro, In Vivo, Structure-Activity Relationship, and Quantitative Structure-Activity Relationship Studies

“…It is noteworthy that some flavones, such as 3-hydroxyflavone, 3,6-dihydroxyflavone, 3,7-dihydroxyflavone, 3Ј,4Ј-dihydroxyflavone, cirsimaritin, ladanein, and biochanin A, potently inhibit both T. brucei rhodesiense and L. donovani parasites with almost equivalent IC 50 s. The first four compounds are of special interest, as they are also able to kill Trypanosoma cruzi to some extent. On the other hand, some of the phenolic compounds tested (e.g., luteolin, quercetin, gallic acid, and 3,4-dihydroxybenzoic acid) are well known for their inhibitory activities against Leishmania and Trypanomosoma parasites (18,23,26); however, the IC 50 s obtained in our study are generally much lower (2-to 40-fold). We believe that these discrepancies derive from the use of different methods and different life cycle stages of the parasites.…”

The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System

“…The beneficial effects have been attributed to their antioxidant and anti-inflammatory properties. The current study shows that the anti-inflammatory effects of quercetin may be mediated by downregulating endogenous and PMA/Ca TNF-␣ production (11,17,23,24,30,(36)(37)(38)40). Previous studies from this laboratory demonstrate that quercetin inhibits interleukin 4 expression and increases gamma interferon production in PBMCs (28).…”

Untargeted metabolite analysis of healthy and Huanglongbing‐infected orange leaves by CE‐DAD

“…However, this type of HLB secondary effects need to be further researched. Naringenin [43] and quercetin [44] have been reported to have microbial inhibition properties. Therefore, the plant probably synthesizes these compounds as a defense mechanism against pathogens.…”