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Parasitic diseases affect millions of individuals worldwide, mainly in low-income regions. There is no cure for most of these diseases, and the treatment relies on drugs that have side effects and lead to drug resistance, emphasizing the urgency to find new treatments. Snake venom has been gaining prominence as a rich source of molecules with antiparasitic potentials, such as phospholipases A 2 (PLA 2 s). Here, we compile the findings involving PLA 2 s with antiparasitic activities against helminths, Plasmodium , Toxoplasma , and trypanosomatids. We indicate their molecular features, highlighting the possible antiparasitic mechanisms of action of these proteins. We also demonstrate interactions between PLA 2 s and some parasite membrane components, shedding light on potential targets for drug design that may provide better treatment for the illnesses caused by parasites. Despite treatments available (most of them inefficient), human parasitic diseases are still affecting millions of individuals worldwide. Snake venoms are a rich source of bioactive molecules (small molecules, peptides, and proteins) potentially useful for various biotechnological applications. PLA 2 s, important snake-venom components, have striking features that make this class of proteins an excellent candidate to be used as anti-infectious agents. Recent data suggest that both Asp49 and Lys49 svPLA 2 s can promote pharmacological effects regardless of their catalytic activity. [ABSTRACT FROM AUTHOR]

One-third of the world's population is estimated to be affected by toxoplasmosis. Pregnancy-related Toxoplasma gondii infection can cause vertical transmission, infect the fetus, and cause miscarriage, stillbirth, and fetal death. The current study showed that both human trophoblast cells (BeWo lineage) and human explant villous were resistant to T. gondii infection after incubation with BjussuLAAO-II, an l -amino acid oxidase isolated from Bothrops jararacussu. Almost 90% of the parasite's ability to proliferate in BeWo cells was decreased by the toxin at 1.56 μg/mL and showed an irreversible anti- T. gondii effect. Also, BjussuLAAO-II impaired the key events of adhesion and invasion of T. gondii tachyzoites in BeWo cells. BjussuLAAO-II antiparasitic properties were associated with the intracellular production of reactive oxygen species and hydrogen peroxide, since the presence of catalase restored the parasite's growth and invasion. In addition, T. gondii growth in human villous explants was decreased to approximately 51% by the toxin treatment at 12.5 μg/mL. Furthermore, BjussuLAAO-II treatment altered IL-6, IL-8, IL-10 and MIF cytokines levels, assuming a pro-inflammatory profile in the control of T. gondii infection. This study contributes to the potential use of a snake venom l -amino acid oxidase for the development of agents against congenital toxoplasmosis and the discovery of new targets in parasites and host cells. [ABSTRACT FROM AUTHOR]

Phospholipases A 2 (PLA 2 s) from snake venom possess antitumor and antiangiogenic properties. In this study, we evaluated the antimetastatic and antiangiogenic effects of MjTX-II, a Lys49 PLA 2 isolated from Bothrops moojeni venom, on lung cancer and endothelial cells. Using in vitro and ex vivo approaches, we demonstrated that MjTX-II reduced cell proliferation and inhibited fundamental processes for lung cancer cells (A549) growth and metastasis, such as adhesion, migration, invasion, and actin cytoskeleton decrease, without significantly interfering with non-tumorigenic lung cells (BEAS-2B). Furthermore, MjTX-II caused cell cycle alterations, increased reactive oxygen species production, modulated the expression of pro- and antiangiogenic genes, and decreased vascular endothelial growth factor (VEGF) expression in HUVECs. Finally, MjTX-II inhibited ex vivo angiogenesis processes in an aortic ring model. Therefore, we conclude that MjTX-II exhibits antimetastatic and antiangiogenic effects in vitro and ex vivo and represents a molecule that hold promise as a pharmacological model for antitumor therapy. [Display omitted] • PLA 2 Lys49 MjTX-II from Bothrops moojeni venom induces antimetastatic and antiangiogenic effects. • The toxin inhibits cell migration and invasion in lung cancer cells by wound healing and transwell assays. • MjTX-II modulates the expression of Angiopoietin-1, Vascular endothelial growth factor A and sFlt-1 gens. • The Toxin decreased cells in the G0-G1 phase and decreased reactive oxygen species formation in endothelial cells. • MjTX-II is a potential prototype for developing new tools and antitumor drugs in cancer therapy. [ABSTRACT FROM AUTHOR]

Angiogenesis is a process that is controlled by a delicate combination of proangiogenic and antiangiogenic molecules and can be disrupted in various illnesses, including cancer. Non-cancerous diseases can also have an abnormal or insufficient vascular growth, inflammation and hypoxia, which exacerbate angiogenesis. These conditions include atherosclerosis, psoriasis, endometriosis, asthma, obesity and AIDS. Based on that, the present work assessed the in vitro and ex vivo antiangiogenic properties stemming from BthMP, a P–I metalloproteinase from Bothrops moojeni snake venom, via the VEGF pathway. BthMP at a concentration of 5 and 40 μg/mL showed no toxicity to endothelial cells (HUVEC) in the MTT assay and was not able to induce necrosis and colony proliferation. Interestingly, BthMP inhibited adhesion, migration and invasion of HUVECs in Matrigel and arrested in vitro angiogenesis by reducing the average number of nodules in toxin-treated cells by 9.6 and 17.32 at 5 and 40 μg/mL, respectively, and the number of tubules by 15.9 at 5 μg/mL and 21.6 at 40 μg/mL in a VEGF-dependent way, an essential proangiogenic property. Furthermore, BthMP inhibited the occurrence of the angiogenic process in an ex vivo aortic ring test by decreasing new vessel formation by 52% at 5 μg/mL and by 66% at 40 μg/mL and by increasing the expression of an antiangiogenic gene, SFLT-1, and decreasing the expression of the proangiogenic genes VEGFA and ANGPT-1. Finally, this toxin reduces the production of nitric oxide, a marker that promotes angiogenesis and VEGF modulation, and decreases the protein expression of VEGFA in the supernatant of the HUVEC culture by about 30 %. These results suggest that BthMP has a promising antiangiogenic property and proves to be a biotechnological mechanism for understanding the antiangiogenic responses induced by snake venom metalloproteinases, which could be applied to a variety of diseases that exhibit an imbalance of angiogenesis mechanisms. • BthMP inhibits adhesion, migration, and invasion of endothelial cells without cytotoxicity or cell necrosis. • BthMP promotes the inhibition of in vitro and ex vivo angiogenesis by modulating nitric oxide and VEGF. • BthMP upregulates the anti-angiogenic gene SFLT-1, while it downregulates the proangiogenic genes VEGFA and ANGPT-1. [ABSTRACT FROM AUTHOR]

Herein we evaluated the genotoxic effects of BnSP-6, a Lys-49 phospholipase A 2 (PLA 2 ) from Bothrops pauloensis , on breast cancer cells. BnSP-6 was able to induce a higher cytotoxic and genotoxic activity in MDA-MB-231 cells, when compared to MCF10A (a non-tumorigenic breast cell line), suggesting that this protein presented a possible preference for cancer cells. BnSP-6 inhibited MDA-MB-231 proliferation at 24, 48 and 72 h. In addition, BnSP-6 induced significant increase in the percentage of TUNEL-positive cells, a marker of DNA damage. To obtain novel insight into the direct DNA damage interference in MDA-MB-231 survival and proliferation, we evaluated cell cycle progression. BnSP-6 produced a significant decrease in 2N (G1) and an increase in the G2/M phase and this capacity is likely related to the modulation of expression of progression cell cycle-associated genes (CCND1, CCNE1, CDC25A, CHEK2, E2F1, CDH-1 and NF-kB). Taken together, these results indicate that BnSP-6 induces DNA damage in breast cancer cells and is an attractive model for developing innovative therapeutic agents against breast cancer. [ABSTRACT FROM AUTHOR]

The present work addressed the abilities of two L-amino acid oxidases isolated from Bothrops moojeni (BmooLAAO-I) and Bothrops jararacussu (BjussuLAAO-II) snake venoms to control the growth and prevent the biofilm formation of clinically relevant bacterial pathogens. Upon S. aureus (ATCC BAA44) and S. aureus (clinical isolates), BmooLAAO-I (MIC = 0.12 and 0.24 μg/mL, respectively) and BjussuLAAO-II (MIC = 0.15 μg/mL) showed a potent bacteriostatic effect. Against E. coli (ATCC BAA198) and E. coli (clinical isolates), BmooLAAO-I (MIC = 15.6 and 62.5 μg/mL, respectively) and BjussuLAAO-II (MIC = 4.88 and 9.76 μg/mL, respectively) presented a lower extent effect. Also, BmooLAAO-I (MICB 50 = 0.195 μg/mL) and BjussuLAAO-II (MICB 50 = 0.39 μg/mL) inhibited the biofilm formation of S. aureus (clinical isolates) in 88% and 89%, respectively, and in 89% and 53% of E. coli (clinical isolates). Moreover, scanning electron microscopy confirmed that the toxins affected bacterial morphology by increasing the roughness of the cell surface and inhibited the biofilm formation. Furthermore, analysis of the tridimensional structures of the toxins showed that the surface-charge distribution presents a remarkable positive region close to the glycosylation motif, which is more pronounced in BmooLAAO-I than BjussuLAAO-II. This region may assist the interaction with bacterial and biofilm surfaces. Collectively, our findings propose that venom-derived antibiofilm agents are promising biotechnological tools which could provide novel strategies for biofilm-associated infections. [Display omitted] • BmooLAAO-I and BjussuLAAO-II impaired the biofilm formation of clinically relevant microorganisms. • The enzymes caused alterations in bacteria morphology and biofilm architecture. • The positive electrostatic surface and the glycosylation sites may interact with the bacterial and biofilm surfaces. [ABSTRACT FROM AUTHOR]

Antiangiogenic strategies are promising tools for cancer treatment and several other disorders. In this sense, phospholipases A 2 (PLA 2 s) from snake venom have been described to possess antiangiogenic properties. In this study, we evaluated both in vitro and ex vivo antiangiogenic effects induced by BnSP-7, a Lys49 PLA 2 isolated from Bothrops pauloensis snake venom. BnSP-7 was able to inhibit endothelial cell (HUVEC) proliferation, which was indeed confirmed by a modulation of cell cycle progression. Interestingly, BnSP-7 also inhibited the adhesion and migration of HUVECs and blocked in vitro angiogenesis in a VEGF-dependent manner, an important proangiogenic factor. Finally, BnSP-7 was capable of inhibiting sprouting angiogenic process through an ex vivo aortic ring assay. Taken together, these results indicate that BnSP-7 has potent in vitro and ex vivo antiangiogenic effect. • BnSP-7 inhibited cell cycle progression and colonies formation on HUVEC cells. • BnSP-7 inhibited HUVEC cells migration and adhesion. • BnSP-7 inhibited HUVEC cells vessel formation in vitro in VEGF-dependent manner. • BnSP-7 inhibited microvessel sprouting ex vivo by mouse aortic ring assay. [ABSTRACT FROM AUTHOR]

Highlights • Antitumoral activity of an acidic PLA 2 from Porthidium l. lansbergii on HeLa cells • Pllans - II induced cell cycle arrest and apoptosis by extrinsic pathway on HeLa cells. • Pllans – II inhibit cell migration on HeLa cells by interfering with α5 and β1–integrins. • Pllans - II showed negligible effects in vitro on normal cells such as MCF10A and HUVEC. • Pllans – II inhibited angiogenesis on HUVEC cells through VEGF–independent pathway. [ABSTRACT FROM AUTHOR]

Cancer cells produce abnormal levels of reactive oxygen species (ROS) that contribute to promote their malignant phenotype. In this framework, we hypothesized that the change in ROS concentration above threshold could impair key events of prostate cancer cells (PC-3) progression. Our results demonstrated that Pollonein-LAAO, a new L-amino acid oxidase obtained from Bothrops moojeni venom, was cytotoxic to PC-3 cells in two-dimensional and in tumor spheroid assays. Pollonein-LAAO was able to increase the intracellular ROS generation that culminates in cell death from apoptosis by both intrinsic and extrinsic pathways due to the up-regulation of TP53 , BAX , BAD , TNFRSF10B and CASP8. Additionally, Pollonein-LAAO reduced mitochondrial membrane potential and caused G0/G1 phase to delay, due to the up-regulation of CDKN1A and the down-regulation of the expression of CDK2 and E2F. Interestingly, Pollonein-LAAO inhibited critical steps of the cellular invasion process (migration, invasion and adhesion), due to the down-regulation of SNAI1 , VIM , MMP2 , ITGA2 , ITGAV and ITGB3. Furthermore, the Pollonein-LAAO effects were associated with the intracellular ROS production, since the presence of catalase restored the invasiveness of PC-3 cells. In this sense, this study contributes to the potential use of Pollonein-LAAO as ROS-based agent to enhance the current understanding of cancer treatment strategies. [Display omitted] • A new of L-amino acid oxidase was obtained from Bothrops moojeni venom, named as Pollonein-LAAO. • Pollonein-LAAO displayed cytotoxicity in multicellular prostate tumor spheroid. • This enzyme up-regulated TP53 triggering to PC-3 apoptosis and G0/G1 cell phase to delay. • Oxidative stress induced by Pollonein-LAAO reduced PC-3 cell adhesion, migration and invasion. • Epithelial-mesenchymal transition genes (SNAI1 , VIM , MMP2 , ITGA2 , ITGAV and ITGB3) were modulated by Pollonein-LAAO. [ABSTRACT FROM AUTHOR]

This study reports the isolation of CollinLAAO-I, a new L-amino acid oxidase from Crotalus durissus collilineatus snake venom, its biochemical characterization and leishmanicidal potential in Leishmania spp. CollinLAAO-I (63.1 kDa) was successfully isolated with high purity using two chromatographic steps and represents 2.5% of total venom proteins. CollinLAAO-I displayed high enzymatic activity (4262.83 U/mg/min), significantly reducing after 28 days. The enzymatic activity of CollinLAAO-I revealed higher affinity for hydrophobic amino acids such as L-leucine, high enzymatic activity in a wide pH range (6.0–10.0), at temperatures from 0 to 25 °C, and showed complete inhibition in the presence of Na+ and K+. Cytotoxicity assays revealed IC 50 of 18.49 and 11.66 μg/mL for Leishmania (L.) amazonensis and Leishmania (L.) infantum , respectively, and the cytotoxicity was completely suppressed by catalase. CollinLAAO-I significantly increased the intracellular concentration of reactive oxygen species (ROS) and reduced the mitochondrial potential of both Leishmania species. Furthermore, CollinLAAO-I decreased the parasite capacity to infect macrophages by around 70%, indicating that even subtoxic concentrations of CollinLAAO-I can interfere with Leishmania vital processes. Thus, the results obtained for CollinLAAO-I provide important support for developing therapeutic strategies against leishmaniasis. [Display omitted] • CollinLAAO-I increased ROS production and caused mitochondrial damage in Leishmania. • CollinLAAO-I treatment interfered in essential steps of the Leishmania infection. • L. (L.) infantum is more susceptible to the leishmanicidal effect of CollinLAAO-I. [ABSTRACT FROM AUTHOR]