Effects of a marine serine protease inhibitor on viability and morphology of Trypanosoma cruzi, the agent of Chagas disease

Nogueira, Natália Pereira de Almeida; Morgado‐Díaz, José Andrés; Menna-Barreto, Rubem Figueiredo Sadok; Paes, Márcia Cristina; Silva-López, Raquel Elisa da

doi:10.1016/j.actatropica.2013.05.013

Cited by 22 publications

(12 citation statements)

References 71 publications

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“…Many studies have claimed that the postoperative complications of cardiac surgery are associated with the activation of inflammatory mediators and the occurrence of systemic inflammatory response syndrome (SIRS). Protease inhibitors have been used clinically to treat many diseases, such as HCV [62] , HIV [63] , and H1N1 virus [64] , and also have a potential role as anti-tumor agents [65] , [66] and parasiticides [67] . Ulinastatin is a multivalent serine protease inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Effect of Urinary Protease Inhibitor (Ulinastatin) on Cardiopulmonary Bypass: A Meta-Analysis for China and Japan

et al. 2014

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ObjectivesA meta-analysis was conducted to investigate the effects of ulinastatin treatment on adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB).MethodsSeven electronic databases were searched for reports of randomized, controlled trials conducted up to February 2014 in which patients undergoing cardiac surgery with CPB were administered ulinastatin in the perioperative period.ResultsFifty-two studies with 2025 patients were retained for analysis. The results showed that the ulinastatin can attenuate the plasma levels of pro-inflammatory cytokines and enhance the anti-inflammatory cytokine levels in patients undergoing cardiac surgery with CPB. Meanwhile, the ulinastatin had a significant beneficial effect on myocardial injury. The mean differences (MD) and 95% confidence intervals (95% CI) of biochemical markers were −63.54 (−79.36, −47.72) for lactate dehydrogenase, −224.99 (−304.83, −145.14) for creatine kinase, −8.75 (−14.23, −3.28) for creatine kinase-MB, and −0.14 (−0.20, −0.09] for troponin I (all P<0.01). However, neither hemodynamics nor cardiac function improved significantly, except that the MD and 95% CI of mean arterial pressure were 2.50 (0.19, 4.80) (P = 0.03). There were no statistically significant differences in the use of inotropes, postoperative bleeding, postoperative complications, the intensive care unit (ICU) stay, and the hospital stay; however, the frequency of auto resuscitation increased significantly (OR 1.98, 95%CI 1.19 to 3.30, P<0.01), the duration of intubation (MD −1.58, 95%CI −2.84 to −0.32, P<0.01) and the duration of mechanical ventilation (MD −3.29, 95%CI −4.41 to −2.17, P<0.01) shortened significantly in patients who were treated with ulinastatin.ConclusionsUlinastatin can reduce the plasma levels of pro-inflammatory cytokines and elevate anti-inflammatory cytokine in patients from China and Japan undergoing cardiac surgery with CPB. Ulinastatin treatment may have protective effects on myocardial injury, and can increase the frequency of auto resuscitation, shorten the duration of intubation and mechanical ventilation.

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Section: Discussionmentioning

confidence: 99%

Effect of Urinary Protease Inhibitor (Ulinastatin) on Cardiopulmonary Bypass: A Meta-Analysis for China and Japan

et al. 2014

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“…In addition a native Kunitz-type serine protease inhibitor was recently proven to affect viability of T . cruzi [ 74 ] and Leishmania [ 75 ]. The unique aspect of our study is that we chose to create transgenic parasite lines with the PPI.…”

Section: Discussionmentioning

confidence: 99%

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

et al. 2015

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Regulated proteolysis is known to control a variety of vital processes in apicomplexan parasites including invasion and egress of host cells. Serine proteases have been proposed as targets for drug development based upon inhibitor studies that show parasite attenuation and transmission blockage. Genetic studies suggest that serine proteases, such as subtilisin and rhomboid proteases, are essential but functional studies have proved challenging as active proteases are difficult to express. Proteinaceous Protease Inhibitors (PPIs) provide an alternative way to address the role of serine proteases in apicomplexan biology. To validate such an approach, a Neospora caninum Kazal inhibitor (NcPI-S) was expressed ectopically in two apicomplexan species, Toxoplasma gondii tachyzoites and Plasmodium berghei ookinetes, with the aim to disrupt proteolytic processes taking place within the secretory pathway. NcPI-S negatively affected proliferation of Toxoplasma tachyzoites, while it had no effect on invasion and egress. Expression of the inhibitor in P. berghei zygotes blocked their development into mature and invasive ookinetes. Moreover, ultra-structural studies indicated that expression of NcPI-S interfered with normal formation of micronemes, which was also confirmed by the lack of expression of the micronemal protein SOAP in these parasites. Our results suggest that NcPI-S could be a useful tool to investigate the function of proteases in processes fundamental for parasite survival, contributing to the effort to identify targets for parasite attenuation and transmission blockage.

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“…Most morphological studies of drug treatment emphasize the direct effect of compounds on the isolated parasites, mainly T. cruzi epimastigotes. Ultrastructural changes were also evidenced in T. cruzi treated with serine and cysteine protease inhibitors 33,34 . A Kunitz-type serine protease inhibitor from Caribbean Sea anemone Stichodactyla helianthus induced the formation of concentric membrane structures and endoplasmic reticulum surrounding vesicles in the cytoplasm of epimastigotes, suggesting the autophagic cell death as its mechanism of action 33 .…”

Section: Ultrastructural Analysis Of the Effect Of Had1 Inhibitor Agamentioning

confidence: 88%

“…Ultrastructural changes were also evidenced in T. cruzi treated with serine and cysteine protease inhibitors 33,34 . A Kunitz-type serine protease inhibitor from Caribbean Sea anemone Stichodactyla helianthus induced the formation of concentric membrane structures and endoplasmic reticulum surrounding vesicles in the cytoplasm of epimastigotes, suggesting the autophagic cell death as its mechanism of action 33 . Cysteine protease inhibitors (morpholinecarbonyl-phenylalanine-homophenylalanine-vinyl sulphone phenyl and morpholineureaphenylalanine-homophenylalaninefluoromethyl ketone) induced severe alterations in the Golgi complex with chagasin accumulation in enlarged cisternae, suggesting a disturbance in the transport within the ER-Golgi system 34 .…”

Section: Ultrastructural Analysis Of the Effect Of Had1 Inhibitor Agamentioning

confidence: 88%

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

Menezes

Calvet

Rodrigues

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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This work describes the antitrypanocidal activity of two hydroxamic acid derivatives containing o-ethoxy (HAD1) and p-ethoxy (HAD2) as substituent in the aromatic ring linked to the isoxazoline ring. HAD1 and HAD2 induced a significant reduction in the number of intracellular parasites and consequently showed activity on the multiplication of the parasite. Treatment of cardiomyocytes and macrophages with the compounds revealed no significant loss in cell viability. Ultrastructural alterations after treatment of cardiomyocytes or macrophages infected by Trypanosoma cruzi with the IC 50 value of HAD1 revealed alterations to amastigotes, showing initial damage seen as swelling of the kinetoplast. This gave a good indication of the ability of the drug to permeate through the host cell membrane as well as its selectivity to the parasite target. Both compounds HAD1 and 2 were able to reduce the cysteine peptidases and decrease the activity of metallopeptidases KeywordsChagas disease, hydroxamic acid derivatives, Trypanosoma cruzi History

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Effects of a marine serine protease inhibitor on viability and morphology of Trypanosoma cruzi, the agent of Chagas disease

Cited by 22 publications

References 71 publications

Effect of Urinary Protease Inhibitor (Ulinastatin) on Cardiopulmonary Bypass: A Meta-Analysis for China and Japan

Effect of Urinary Protease Inhibitor (Ulinastatin) on Cardiopulmonary Bypass: A Meta-Analysis for China and Japan

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

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