Mast cell degranulation induced by two phospholipase A2 homologues: Dissociation between enzymatic and biological activities

Landucci, Elen C.T.; Castro, Rogério Cardoso de; Pereira, M F; Cintra, Adélia Cristina Oliveira; Giglio, José Roberto; Marangoni, Sérgio; Oliveira, Benedito; Cirino, Giuseppe; Antunes, Edson; Nucci, Gilberto De

doi:10.1016/s0014-2999(97)01546-x

Cited by 106 publications

(67 citation statements)

References 30 publications

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“…It has been described that fucCS inhibits sialyl-Lewis and P-and L-selectins, preventing neutrophil migration, which also can contribute to this effect (Borsig et al, 2007). It all supports the observations showing that fucCS decreases neutrophil migration to EDL muscle (MPO in EDL and blood cell count) and edema formation (1 mg/kg), which indicate that this substance can prevent the complex inflammatory response induced by B. jararacussu venom, which plays an important role in myotoxicity (Landucci et al, 1998;Guti errez and Rucavado, 2000;Teixeira et al, 2003Teixeira et al, , 2005Elifio-Esposito et al, 2011;Patrão-Neto et al, 2013).…”

Section: Discussionsupporting

confidence: 78%

Occurrence of sulfated fucose branches in fucosylated chondroitin sulfate are essential for the polysaccharide effect preventing muscle damage induced by toxins and crude venom from Bothrops jararacussu snake

Monteiro-Machado

Tomaz

Fonseca

et al. 2015

Toxicon

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Snake envenoming is an important public health problem around the world, particularly in tropics. Beyond deaths, morbidity induced by snake venoms, such as myotoxicity, is of pivotal consequence to population. Bothrops jararacussu is the main venomous snake in southeast region of Brazil, and particularly presents strong myotoxic effect. The only available therapy, antibothropic antivenom, poorly affects venom-induced myotoxicity. The aim of this study is to assess the ability of fucosylated chondroitin sulfate (fucCS), a glycosaminoglycan with anticoagulant and antithrombotic properties, and its derivatives to inhibit toxic activities of B. jararacussu crude venom and its isolated toxins, named bothropstoxins (BthTX-I and BthTX-II). The in vitro myotoxic activities induced by crude venom, by BthTX-I alone and by toxins together were abolished by fucCS. Carboxyl reduction (fucCS-CR) kept this ability whereas defucosilation (defucCS) abrogates myoprotection. We observed the same pattern in the response of these polysaccharides in antagonizing the increase in plasma creatine kinase (CK) levels, the reduction of skeletal muscle CK content and the rise of myeloperoxidase (MPO) activity induced by crude venom and isolated toxins. FucCS inhibited edematogenic activity and partially prevented the reduction of total leukocytes in blood when pre-incubated with crude venom. Furthermore, the venom procoagulant effect was completely antagonized by increasing concentrations of fucCS, although this polyanion could stop neither the tail bleeding nor the skin hemorrhage induced by Bothrops jararaca venom. The B. jararacussu phospholipase, hyaluronidase, proteolytic and collagenase activities were inhibited in vitro. The results suggest that fucCS could be able to interact with both toxins, and it is able to inhibit BthTX-II phospholipase activity. Light microscopy of extensor digitorum longus muscle (EDL) muscle showed myoprotection by fucCS, once necrotic areas, edema and inflammatory cells were all decreased as compared to venom injection alone. Altogether, data show that fucCS was able to inhibit myotoxicity and inflammation induced by B. jararacussu venom and its phospholipase toxins, BthTX-I and BthTX-II. Thus, fucosylated chondroitin sulfate is a new polyanion with potential to be used as an adjuvant in the treatment of snakebites in the future.

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Section: Discussionsupporting

confidence: 78%

Occurrence of sulfated fucose branches in fucosylated chondroitin sulfate are essential for the polysaccharide effect preventing muscle damage induced by toxins and crude venom from Bothrops jararacussu snake

Monteiro-Machado

Tomaz

Fonseca

et al. 2015

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“…Our results demonstrated that the catalytically active BthTX-II (Asp 49 PLA 2 ) is more potent in promoting edema formation than BthTX-I (Lys 49 PLA 2 ) (p < 0.05 BthTX-II versus BthTX-I, Figure 1). Various enzymatically inactive Lys-49 PLA 2 s have been shown to induce edema, clearly indicating the existence of molecular regions, different from the catalytic site in these PLA 2 s homologues, which are responsible for mast cell degranulation and edema formation (13,36,37).…”

Section: Discussionmentioning

confidence: 99%

Low-level laser therapy decreases local effects induced by myotoxins isolated from Bothrops jararacussu snake venom

Barbosa¹,

Villaverde²,

Guimarães-Sousa³

et al. 2010

J. Venom. Anim. Toxins incl. Trop. Dis

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Abstract:The prominent myotoxic effects induced by Bothrops jararacussu crude venom are due, in part, to its polycationic myotoxins, BthTX-I and BthTX-II. Both myotoxins have a phospholipase A2 structure: BthTX-II is an active enzyme Asp-49 PLA2, while BthTX-I is a Lys-49 PLA2 devoid of enzymatic activity. In this study, the effect of low-level laser therapy (LLLT), 685 nm laser at a dose of 4.2 J/cm2 on edema formation, leukocyte influx and myonecrosis caused by BthTX-I and BthTX-II, isolated from Bothrops jararacussu snake venom, was analyzed. BthTX-I and BthTX-II caused a significant edema formation, a prominent leukocyte infiltrate composed predominantly by neutrophils and myonecrosis in envenomed gastrocnemius muscle. LLLT significantly reduced the edema formation, neutrophil accumulation and myonecrosis induced by both myotoxins 24 hours after the injection. LLLT reduced the myonecrosis caused by BthTX-I and BthTX-II, respectively, by 60 and 43%; the edema formation, by 41 and 60.7%; and the leukocyte influx, by 57.5 and 51.6%. In conclusion, LLLT significantly reduced the effect of these snake toxins on the inflammatory response and myonecrosis. These results suggest that LLLT should be considered a potential therapeutic approach for treatment of local effects of Bothrops species venom.

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“…PLA 2 -binding proteins, such as the M-type receptor described in skeletal muscle [126], may contribute to toxin sequestration and inhibition, since a recombinant soluble form of this receptor inhibits the enzymatic activity of PLA 2 s [127]. An interesting, albeit speculative, possibility for an inactivating mechanism occurring in vivo relates to the observation that myotoxic PLA 2 s can induce the degranulation of mast cells, with the consequent release of their mediators [128,129]. Among these, heparin could play an important inactivating role as myotoxic PLA 2 are highly basic proteins, and heparin inhibits the myotoxic effect of many PLA 2 s [130,131].…”

Section: Toxin Inactivation Tissue Repair and Regenerationmentioning

confidence: 99%

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

Montecucco

Gutiérrez

Lomonte

2008

Cell. Mol. Life Sci.

258

163

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A large variety of snake toxins evolved from PLA(2) digestive enzymes through a process of 'accelerated evolution'. These toxins have different tissue targets, membrane receptors and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA(2)s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation which promotes a large increase of the cytosolic Ca(2+) concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.

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Mast cell degranulation induced by two phospholipase A2 homologues: Dissociation between enzymatic and biological activities

Cited by 106 publications

References 30 publications

Occurrence of sulfated fucose branches in fucosylated chondroitin sulfate are essential for the polysaccharide effect preventing muscle damage induced by toxins and crude venom from Bothrops jararacussu snake

Occurrence of sulfated fucose branches in fucosylated chondroitin sulfate are essential for the polysaccharide effect preventing muscle damage induced by toxins and crude venom from Bothrops jararacussu snake

Low-level laser therapy decreases local effects induced by myotoxins isolated from Bothrops jararacussu snake venom

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

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