Immune cells and mediators involved in the inflammatory responses induced by a P-I metalloprotease and a phospholipase A2 from Bothrops atrox venom

Menaldo, Danilo L.; Bernardes, Carolina P.; Zoccal, Karina Furlani; Jacob-Ferreira, Anna L.; Costa, Tássia R.; Lama, Maria Perpetua Freire de Morais Del; Naal, Rose Mary Zumstein Georgetto; Frantz, Fabiani Gai; Faccioli, Lúcia Helena; Sampaio, Suely Vilela

doi:10.1016/j.molimm.2017.03.008

Cited by 36 publications

(38 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additional non-neurogenic and neurogenic inflammations induced by PLA2s use more complex mechanisms still not fully understood. For example, leukocyte recruitment (De Castro et al, 2000), mastocytes degranulation (Menaldo et al, 2017), and macrophage activation (Triggiani et al, 2000;Granata et al, 2006;Giannotti et al, 2013) were demonstrated to occur independently of the generic PLA2s lipid hydrolysis catalytic activity. Furthermore, substance-P mediated neurogenic inflammation has been described to be induced by PLA2s from Crotalus durissus cascavella (Camara et al, 2003) and from Naja mossambica .…”

Section: Phospholipases (Pla2s)mentioning

confidence: 99%

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

et al. 2019

View full text Add to dashboard Cite

Animal venoms have evolved over millions of years for prey capture and defense from predators and rivals. Snake venoms, in particular, have evolved a wide diversity of peptides and proteins that induce harmful inflammatory and neurotoxic effects including severe pain and paralysis, hemotoxic effects, such as hemorrhage and coagulopathy, and cytotoxic/myotoxic effects, such as inflammation and necrosis. If untreated, many envenomings result in death or severe morbidity in humans and, despite advances in management, snakebite remains a major public health problem, particularly in developing countries. Consequently, the World Health Organization recently recognized snakebite as a neglected tropical disease that affects ∼2.7 million p.a. The major protein classes found in snake venoms are phospholipases, metalloproteases, serine proteases, and three-finger peptides. The mechanisms of action and pharmacological properties of many snake venom toxins have been elucidated, revealing a complex multifunctional cocktail that can act synergistically to rapidly immobilize prey and deter predators. However, despite these advances many snake toxins remain to be structurally and pharmacologically characterized. In this review, the multifunctional features of the peptides and proteins found in snake venoms, as well as their evolutionary histories, are discussed with the view to identifying novel modes of action and improving snakebite treatments.

show abstract

Section: Phospholipases (Pla2s)mentioning

confidence: 99%

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…SVMPs present in the venoms of Bothrops snakes are responsible for several inflammatory responses such as edema formation, leukocyte infiltration and the release of mediators such as cytokines and chemokines, which play an important role in the inflammatory process [17]. To compare the proinflammatory action of SVMPs, we tested the local effects of one representative of PI-class (ATXL) and one of the PIII-class (BATXH) SVMPs, both recently isolated by our group from B. atrox venom.…”

Section: Discussionmentioning

confidence: 99%

“…A pool of low-molecular-mass proteinases was able to induce the formation of edema and leukocyte infiltrate [16]. Considering isolated toxins, Batroxase, a PI-class SVMP isolated from the venom of Bothrops atrox, was capable of inducing leukocyte migration, as well as the release of proinflammatory mediators, such as IL-1β, IL-6 and PGE 2 , involved in these events [17].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Reaction Induced by Two Metalloproteinases Isolated from Bothrops atrox Venom and by Fragments Generated from the Hydrolysis of Basement Membrane Components

Almeida

Freitas-de-Sousa

Colombini

et al. 2020

Toxins

View full text Add to dashboard Cite

Snake venom metalloproteinases (SVMPs) play an important role in local tissue damage of snakebite patients, mostly by hydrolysis of basement membrane (BM) components. We evaluated the proinflammatory activity of SVMPs Atroxlysin-Ia (ATXL) and Batroxrhagin (BATXH) from Bothrops atrox venom and their hydrolysis products of Matrigel. BALB/c mice were injected with SVMPs (2 μg), for assessment of paw edema and peritoneal leukocyte accumulation. Both SVMPs induced edema, representing an increase of ~70% of the paw size. Leukocyte infiltrates reached levels of 6 × 106 with ATXL and 5 × 106 with BATXH. TNF-α was identified in the supernatant of BATXH—or venom-stimulated MPAC cells. Incubation of Matrigel with the SVMPs generated fragments, including peptides from Laminin, identified by LC–MS/MS. The Matrigel hydrolysis peptides caused edema that increased 30% the paw size and promoted leukocyte accumulation (4–5 × 106) to the peritoneal cavity, significantly higher than Matrigel control peptides 1 and 4 h after injection. Our findings suggest that ATXL and BATXH are involved in the inflammatory reaction observed in B. atrox envenomings by direct action on inflammatory cells or by releasing proinflammatory peptides from BM proteins that may amplify the direct action of SVMPs through activation of endogenous signaling pathways.

show abstract

“…All SVSPs identified to date present a catalytic triad comprising histidine (His), aspartate (Asp), and serine (Ser), essential for their enzyme activity [2,5]. Recent studies strongly suggested that serine proteases BpirSP27 and BpirSP41, purified from Bothrops pirajai (Bpir), were able to activate the complement system, potentially inducing edema under experimental conditions, and may include proinflammatory features, as well as being significantly inhibited by nonsteroidal anti-inflammatory drugs [6,7,8]. Other SVSPs purified from Bothrops alternatus , Bothrops mooeni [9], Trimeresurus elegans , and Trimeresurus jerdonni venom revealed the ability to release kinin, as well as fibrinolytic and edematogenic activities [10].…”

Section: Introductionmentioning

confidence: 99%

Edema Induced by a Crotalus durissus terrificus Venom Serine Protease (Cdtsp 2) Involves the PAR Pathway and PKC and PLC Activation

Costa

Belchor

Rodrigues

et al. 2018

IJMS

View full text Add to dashboard Cite

Snake venom serine proteases (SVSPs) represent an essential group of enzymatic toxins involved in several pathophysiological effects on blood homeostasis. Some findings suggest the involvement of this class of enzymatic toxins in inflammation. In this paper, we purified and isolated a new gyroxin isoform from the Crotalus durissus terrificus (Cdt) venom, designated as Cdtsp 2, which showed significant proinflammatory effects in a murine model. In addition, we performed several studies to elucidate the main pathway underlying the edematogenic effect induced by Cdtsp 2. Enzymatic assays and structural analysis (primary structure analysis and three-dimensional modeling) were closely performed with pharmacological assays. The determination of edematogenic activity was performed using Cdtsp 2 isolated from snake venom, and was applied to mice treated with protein kinase C (PKC) inhibitor, phospholipase C (PLC) inhibitor, dexamethasone (Dexa), antagonists for protease-activated receptors (PARs), or saline (negative control). Additionally, we measured the levels of cyclooxygenase 2 (COX-2), malondialdehyde (MDA), and prostaglandin E2 (PGE2). Cdtsp 2 is characterized by an approximate molecular mass of 27 kDa, an isoelectric point (pI) of 4.5, and significant fibrinolytic activity, as well as the ability to hydrolyze Nα-benzoyl-l-arginine 4-nitroanilide (BAPNA). Its primary and three-dimensional structures revealed Cdtsp 2 as a typical snake venom serine protease that induces significant edema via the metabolism of arachidonic acid (AA), involving PARs, PKC, PLC, and COX-2 receptors, as well as inducing a significant increase in MDA levels. Our results showed that Cdtsp 2 is a serine protease with significant enzymatic activity, and it may be involved in the degradation of PAR1 and PAR2, which activate PLC and PKC to mobilize AA, while increasing oxidative stress. In this article, we provide a new perspective for the role of SVSPs beyond their effects on blood homeostasis.

show abstract

Immune cells and mediators involved in the inflammatory responses induced by a P-I metalloprotease and a phospholipase A2 from Bothrops atrox venom

Cited by 36 publications

References 52 publications

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

Inflammatory Reaction Induced by Two Metalloproteinases Isolated from Bothrops atrox Venom and by Fragments Generated from the Hydrolysis of Basement Membrane Components

Edema Induced by a Crotalus durissus terrificus Venom Serine Protease (Cdtsp 2) Involves the PAR Pathway and PKC and PLC Activation

Contact Info

Product

Resources

About