cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The level of cumulative and detailed information provided in this review may help pharmacists, physicians, biotechnologists, pharmacologists, and scientists interested in toxinology, drug discovery, and development of toxin-based products.

Scorpion venoms are natural sources of molecules that have, in addition to their toxic function, potential therapeutic applications. In this source the neurotoxins can be found especially those that act on potassium channels. Potassium channels are responsible for maintaining the membrane potential in the excitable cells, especially the voltage-dependent potassium channels (Kv), including Kv1.3 channels. These channels (Kv1.3) are expressed by various types of tissues and cells, being part of several physiological processes. However, the major studies of Kv1.3 are performed on T cells due its importance on autoimmune diseases. Scorpion toxins capable of acting on potassium channels (KTx), mainly on Kv1.3 channels, have gained a prominent role for their possible ability to control inflammatory autoimmune diseases. Some of these toxins have already left bench trials and are being evaluated in clinical trials, presenting great therapeutic potential. Thus, scorpion toxins are important natural molecules that should not be overlooked in the treatment of autoimmune and other diseases.

Snake venom serine proteases (SVSPs) are complex and multifunctional enzymes, acting primarily on hemostasis. In this work, we report the hitherto unknown inhibitory effect of a SVSP, named collinein-1, isolated from the venom of Crotalus durissus collilineatus, on a cancer-relevant voltage-gated potassium channel (hEAG1). Among 12 voltage-gated ion channels tested, collinein-1 selectively inhibited hEAG1 currents, with a mechanism independent of its enzymatic activity. Corroboratively, we demonstrated that collinein-1 reduced the viability of human breast cancer cell line MCF7 (high expression of hEAG1), but does not affect the liver carcinoma and the non-tumorigenic epithelial breast cell lines (HepG2 and MCF10A, respectively), which present low expression of hEAG1. In order to obtain both functional and structural validation of this unexpected discovery, where an unusually large ligand acts as an inhibitor of an ion channel, a recombinant and catalytically inactive mutant of collinein-1 (His43Arg) was produced and found to preserve its capability to inhibit hEAG1. A molecular docking model was proposed in which Arg79 of the SVSP 99-loop interacts directly with the potassium selectivity filter of the hEAG1 channel.Voltage-gated potassium channels (Kv) are involved in a diversity of physiological processes, such as smooth muscle contraction 1 , cell volume control 2 , cell cycle progression 3 , cardiac repolarization 4 , and proliferation of tumor cells 5 . Several animal venom-related toxins are known to modulate Kv channel activity either by blocking 6 the ion selective pore or by modulating 7 the channel gating (i.e. opening and closing mechanisms). Pore blocking toxins bind to the external opening of the pore or to the internal cavity underneath the channel selectivity filter 8 , while gating modifiers induce conformational changes in the voltage-sensing domain of the channel, affecting the kinetics of channel opening and closing 9,10 . Most of the Kv-ligand toxins known to date are found in scorpion, spider, cone snail and sea anemone venoms 10-13 ; only relatively few snake venom toxins are known to interfere with ion channel activity, such as dendrotoxins, the B chain of β-bungarotoxin, and crotamine, acting on Kv channels [14][15][16][17][18] . Snake venom serine proteases (SVSPs) comprise a group of extensively studied toxins, widely found in the venom of terrestrial snakes from Viperidae, Elapidae, and Crotalidae families. Snake venom thrombin-like enzymes (SVTLEs) are the prevalent class of serine proteases from Viperidae venoms and present similar activity to that of human thrombin [19][20][21] . SVSPs may be considered multifunctional toxins due to their broad substrate specificity and can thus act on different systems of the prey or victim organisms 22 . Therefore, the investigation of the intrinsic pathways involved in the variety of biological activities of these molecules may contribute to open Scientific RepoRtS | (2020) 10:4476 | https://doi.org/10.1038/s41598-020-61258-x www.nature.com/scient...

Brazil is a country with a large territorial extension (approximately 8.5 million kilometers squared), which is composed of 26 states and a Federal District. The scorpion fauna of Brazil is also quite vast, highlighting the Tityus genus. The species that is considered the most dangerous and that is accounted for the highest number of accidents is Tityus serrulatus. One of the unique features of this species is its ability to reproduce by parthenogenesis, which enabled its rapid proliferation across the country. According to the records of the Ministry of Health, during the years (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012), accidents related to scorpions have increased dramatically all over the country and are recognized as a public health problem by the government. In this period, 482,479 cases of scorpion envenomation have been reported in Brazil, with the occurrence of 749 deaths for a lethal rate of 0.15 %.

Scorpionism is responsible for most accidents involving venomous animals in Brazil, which leads to severe symptoms that can evolve to death. Scorpion venoms consist of complexes cocktails, including peptides, proteins, and non-protein compounds, making separation and purification procedures extremely difficult and time-consuming. Scorpion toxins target different biological systems and can be used in basic science, for clinical, and biotechnological applications. This study is the first to explore the venom content of the unexplored scorpion species Rhopalurus crassicauda, which inhabits exclusively the northernmost state of Brazil, named Roraima, and southern region of Guyana. Here, we pioneer the fractionation of the R. crassicauda venom and isolated and characterized a novel scorpion beta-neurotoxin, designated Rc1, and a monomeric hyaluronidase. R. crassicauda venom and Rc1 (6,882 Da) demonstrated pro-inflammatory activities in vitro and a nociceptive response in vivo. Moreover, Rc1 toxin showed specificity for activating Na v 1.4, Na v 1.6, and BgNa v 1 voltage-gated ion channels. This study also represents a new perspective for the treatment of envenomings in Roraima, since the Brazilian scorpion and arachnid antivenoms were not able to recognize R. crassicauda venom and its fractions (with exception of hyaluronidase). Our work provides useful insights for the first understanding of the painful sting and pro-inflammatory effects associated with R. crassicauda envenomings.

No abstract

Identification of cross-reactive human single-chain variable fragments against phospholipases A 2 from Lachesis muta and Bothrops spp venoms, Toxicon (2020), doi:

Over 1 million cases of scorpion stings are estimated every year, whereas current treatment is limited to antivenom serum combined with supportive therapy. Tityus serrulatus scorpion venom (TsV) is composed of diverse molecules, including toxins that induce a catecholamine storm and mediate classical symptoms of scorpion envenomation. However, the same toxins promote an intense inflammatory response coordinated by innate immune cells, such as macrophages, contributing significantly to the lung edema and mortality caused by TsV injection. Macrophages sense TsV via innate immune receptors, including TLR2, TLR4, and CD14 that promote inflammation and mortality via PGE 2 /cAMP/PKA/NF-κB/IL-1β axis. The scavenger receptor CD36 also recognizes TsV, but in contrast to the other receptors, it drives the production of leukotriene B 4 (LTB 4 ). This lipid mediator operates via BLT1 receptor to reduce cAMP production and consequently IL-1β release, which results in resistance to fatal outcomes of experimental scorpion envenomation. EP80317 is an hexapeptide that serves as a ligand for CD36 and features protective effects under conditions such as atherosclerosis and vascular inflammation. In this study, we evaluated the effects of EP80317 treatment during experimental scorpion envenomation. EP80317 treatment suppressed mouse peritoneal macrophage production of IL-1β, IL-6, tumor necrosis factor (TNF-α), CCL3, and PGE 2 in vitro . EP80317 treatment also boosted the production of LTB 4 and IL-10 in response to TsV. Importantly, EP80317 restrained lung inflammation and mortality caused by TsV in vivo . Taken together, these data indicate a strong therapeutic potential of EP80317 as a supportive treatment to control inflammation induced by scorpion envenomation.