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The dysregulation of complement system activation usually results in acute or chronic inflammation and can contribute to the development of various diseases. Although the activation of complement pathways is essential for innate defense, exacerbated activity of this system may be harmful to the host. Thus, drugs with the potential to inhibit the activation of the complement system may be important tools in therapy for diseases associated with complement system activation. The synthetic peptides Cp40 and PMX205 can be highlighted in this regard, given that they selectively inhibit the C3 and block the C5a receptor (C5aR1), respectively. The zebrafish (Danio rerio) is a robust model for studying the complement system. The aim of the present study was to use in silico computational modeling to investigate the hypothesis that these complement system inhibitor peptides interact with their target molecules in zebrafish, for subsequent in vivo validation. For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors. [ABSTRACT FROM AUTHOR]

The systemic increase in inflammatory mediator levels can induce diverse pathological disorders, including potentially thrombus formation, which may be lethal. Among the clinical conditions in which the formation of thrombi dictates the patient's prognosis, envenomation by Bothrops lanceolatus should be emphasized, as it can evolve to stroke, myocardial infarction and pulmonary embolism. Despite their life-threatening potential, the immunopathological events and toxins involved in these reactions remain poorly explored. Therefore, in the present study, we examined the immunopathological events triggered by a PLA2 purified from B. lanceolatus venom, using an ex vivo human blood model of inflammation. Our results showed that the purified PLA2 from the venom of B. lanceolatus damages human erythrocytes in a dose dependent way. The cell injury was associated with a decrease in the levels of CD55 and CD59 complement regulators on the cell surface. Moreover, the generation of anaphylatoxins (C3a and C5a) and the soluble terminal complement complex (sTCC) indicates that human blood exposure to the toxin activates the complement system. Increased production of TNF-α, CXCL8, CCL2 and CCL5 followed complement activation. The venom PLA2 also triggered the generation of lipid mediators, as evidenced by the detected high levels of LTB4, PGE2 and TXB2. The scenario here observed of red blood cell damage, dysfunctions of the complement regulatory proteins, accompanied by an inflammatory mediator storm, suggests that B. lanceolatus venom PLA2 contributes to the thrombotic disorders present in the envenomed individuals. [ABSTRACT FROM AUTHOR]

Snake venom enzymes have a broad range of molecular targets in plasma, tissues, and cells, among which hyaluronan (HA) is outstanding. HA is encountered in the extracellular matrix of diverse tissues and in the bloodstream, and its different chemical configurations dictate the diverse morphophysiological processes in which it participates. Hyaluronidases are highlighted among the enzymes involved in HA metabolism. This enzyme has been detected along the phylogenetic tree, suggesting that hyaluronidases exert multiple biological effects on different organisms. Hyaluronidases have been described in tissues, blood and snake venoms. Snake venom hyaluronidases (SVHYA) contribute to tissue destruction in envenomations and are called spreading factors since their action potentiates venom toxin delivery. Interestingly, SVHYA are clustered in Enzyme Class 3.2.1.35 together with mammalian hyaluronidases (HYAL). Both HYAL and SVHYA of Class 3.2.1.35 act upon HA, generating low molecular weight HA fragments (LMW-HA). LMW-HA generated by HYAL becomes a damage-associated molecular pattern that is recognized by Toll-like receptors 2 and 4, triggering cell signaling cascades culminating in innate and adaptive immune responses that are characterized by lipid mediator generation, interleukin production, chemokine upregulation, dendritic cell activation and T cell proliferation. In this review, aspects of the structures and functions of HA and hyaluronidases in both snake venoms and mammals are presented, and their activities are compared. In addition, the potential immunopathological consequences of HA degradation products generated after snakebite envenoming and their use as adjuvant to enhance venom toxin immunogenicity for antivenom production as well as envenomation prognostic biomarker are also discussed. [ABSTRACT FROM AUTHOR]

The clinical manifestations of envenomation by Bothrops species are complex and characterized by prominent local effects that can progress to tissue loss, physical disability, or amputation. Systemic signs can also occur, such as hemorrhage, coagulopathy, shock, and acute kidney failure. The rapid development of local clinical manifestations is accompanied by the presence of mediators of the inflammatory process originating from tissues damaged by the bothropic venom. Considering the important role that the complement system plays in the inflammatory response, in this study, we analyzed the action of Bothrops jararaca snake venom on the complement system and cell surface receptors involved in innate immunity using an ex vivo human whole blood model. B. jararaca venom was able to induce activation of the complement system in the human whole blood model and promoted a significant increase in the production of anaphylatoxins C3a/C3a-desArg, C4a/C4a-desArg, C5a/C5a-desArg and sTCC. In leukocytes, the venom of B. jararaca reduced the expression of CD11b, CD14 and C5aR1. Inhibition of the C3 component by Cp40, an inhibitor of C3, resulted in a reduction of C3a/C3a-desArg, C5a/C5a-desArg and sTCC to basal levels in samples stimulated with the venom. Exposure to B. jararaca venom induced the production of inflammatory cytokines and chemokines such as TNF-a, IL-8/CXCL8, MCP-1/CCL2 and MIG/CXCL9 in the human whole blood model. Treatment with Cp40 promoted a significant reduction in the production of TNF-a, IL-8/CXCL8 and MCP-1/CCL2. C5aR1 inhibition with PMX205 also promoted a reduction of TNF-a and IL-8/CXCL8 to basal levels in the samples stimulated with venom. In conclusion, the data presented here suggest that the activation of the complement system promoted by the venom of the snake B. jararaca in the human whole blood model significantly contributes to the inflammatory process. The control of several inflammatory parameters using Cp40, an inhibitor of the C3 component, and PMX205, a C5aR1 antagonist, indicates that complement inhibition may represent a potential therapeutic tool in B. jararaca envenoming. [ABSTRACT FROM AUTHOR]

Recently, nuclear distribution element-like (NUDEL) has been implicated to play a role in lissencephaly and schizophrenia through interactions with the lissencephaly gene 1 (Lis1) and disrupted-in-schizophrenia 1 (DISC1) products, respectively. Interestingly, NUDEL is the same protein as endooligopeptidase A (EOPA), a thiol-activated peptidase involved in conversion and inactivation of a number of bioactive peptides. In this study, we have cloned EOPA from the human brain and have confirmed that it is equivalent to NUDEL, leading us to suggest a single name, NUDEL-oligopeptidase. In the brain, the monomeric form of NUDEL-oligopeptidase is responsible for the peptidase activity whose catalytic mechanism is likely to involve a reactive cysteine, because mutation of Cys-273 fully abolished NUDEL-oligopeptidase activity without disrupting the protein's secondary structure. Cys-273 is very close to the DISC1-binding site on NUDEL-oligopeptidase. Intriguingly, DISC1 inhibits NUDEL-oligopeptidase activity in a competitive fashion. We suggest that the activity of NUDEL-oligopeptidase is under tight regulation through protein-protein interactions and that disruption of these interactions, as postulated in a Scottish DISC1 translocation schizophrenia cohort, may lead to aberrant regulation of NUDEL-oligopeptidase, perhaps providing a substrate for the pathology of schizophrenia. endooligopeptidase A | neuropeptide metabolism | cysteine peptidase | neurodevelopmental pathology