Schistosoma mansoni venom allergen-like protein (SmVAL) is a gene family composed of 29 members divided into group 1 encoding proteins potentially secreted, and group 2 encoding intracellular components. Some members were found to be upregulated in the transition of germ ball - cercariae - day 3 schistosomula, suggesting that group 1 SmVAL proteins are associated with the invasion of the human host, although their functions are not completely established. Recently, we have described the localization of SmVAL7 (group 1) and SmVAL6 (group 2) transcripts in the oesophageal gland and in the oral and ventral suckers of adult parasites, respectively. The expression patterns of the two genes suggest that SmVAL7 protein plays a role in the blood-feeding process while SmVAL6 is associated with the parasite attachment and movement in the vasculature. In this way, searching for additional secreted SmVAL proteins that could be involved in key processes from skin penetration to the beginning of blood-feeding, we investigated the tissue localization of SmVAL4, 13, 16 and 24 by whole-mount in situ hybridization (WISH). We report here the localization of group 1 SmVAL4 and 24 transcripts in the pre-acetabular glands of developing germ balls. Time course experiments of in vitro cultured schistosomula after cercariae transformation demonstrated that SmVAL4 protein is secreted during the first 3 h of in vitro culture, correlating with the emptying of acetabular glands as documented by confocal microscopy. In addition, the localization of SmVAL13 transcripts in adult male anterior oesophageal gland suggests that the respective protein may be involved in the first steps of the blood-feeding process. SmVAL16 was localized close to the neural ganglia and requires further investigation. Our findings demonstrate that SmVAL proteins have localizations that place them in strategic positions to be considered as potential vaccine candidates as some members are exposed to interaction with the immune system and may participate in key processes of mammalian invasion and parasitism establishment.

Emerging tolerance of Schistosoma mansoni to praziquantel, the only drug available for schistosomiasis treatment, highlights the need for new therapeutic targets. Snake venoms contain pharmacologically active proteins and peptides that can decrease the viability of S. mansoni worms in vitro. Long non-coding RNAs (lncRNAs) play important roles in S. mansoni and are promising new therapeutic targets. However, new candidates still need to be identified, as only four S. mansoni lncRNAs have been functionally characterized to date. Therefore, we investigated lncRNA expression changes in S. mansoni following incubation with Bothrops venoms. Adult worms were incubated with eight venoms at a sublethal dose, and phenotypic parameters were evaluated. RNA-Seq was conducted on worms incubated with Bothrops jararacussu or Bothrops moojeni venoms, followed by Weighted Gene Co-expression Network Analysis for each sex. B. moojeni venom reduced all phenotypic measurements, while B. jararacussu reduced oviposition. Both venoms altered global gene expression, including lncRNAs. Females showed two lncRNA hub genes in two venom-associated co-expression modules, while males showed 61 lncRNA hub genes in nine venom-associated modules. RT-qPCR validated six out of seven selected hub lncRNAs in male worms. These results reveal the involvement of lncRNAs in S. mansoni gene expression modulation induced by Bothrops venoms and point to lncRNAs that should be prioritized in future functional studies, such as SmLINC121220-IBu, SmLINC152105-IBu and SmLNCA123831-IBu.

Schistosomiasis is a neglected tropical disease that affects over 240 million people worldwide. Currently, praziquantel is the only drug recommended by the World Health Organization for treatment. However, cases of drug resistance have been reported, which indicates an urgent need for new therapeutics. In this context, natural compounds represent valuable sources of pharmacological substances. Plant-derived natural products have been greatly explored for their potential antischistosomal activity, while animal-derived compounds have received little attention. Recent advances in the biotechnology field allow the wide exploration of animal-derived compounds in drug discovery, which may represent a cost-effective option to find bioactive molecules also against Schistosoma mansoni and other parasites. This review highlights the research into animal-derived products and compounds that have already been tested against schistosomes. Phenotypic effects on schistosomes have been observed upon incubation with some of these substances, which may, therefore, represent possible candidates to be used in the development of new drugs. Overall, these studies advance the discovery of antischistosomal compounds by exploring a yet understudied natural resource. The present review also discusses the challenges of testing animal-derived products and provides examples of the experimental in vitro testing of different selected animal natural products against S. mansoni.

Crotalphine (CRP) is a structural analogue to a peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. This peptide induces a potent and long-lasting antinociceptive effect that is mediated by the activation of peripheral opioid receptors. The opioid receptor activation regulates a variety of intracellular signaling, including the mitogen-activated protein kinase (MAPK) pathway. Using primary cultures of sensory neurons, it was demonstrated that crotalphine increases the level of activated ERK1/2 and JNK-MAPKs and this increase is dependent on the activation of protein kinase Cζ (PKCζ). However, whether PKCζ-MAPK signaling is critical for crotalphine-induced antinociception is unknown. Here, we biochemically demonstrated that the systemic crotalphine activates ERK1/2 and JNK and decreases the phosphorylation of p38 in the lumbar spinal cord. The in vivo pharmacological inhibition of spinal ERK1/2 and JNK, but not of p38, blocks the antinociceptive effect of crotalphine. Of interest, the administration of a PKCζ pseudosubstrate (PKCζ inhibitor) prevents crotalphine-induced ERK activation in the spinal cord, followed by the abolishment of crotalphine-induced analgesia. Together, our results demonstrate that the PKCζ-ERK signaling pathway is involved in crotalphine-induced analgesia. Our study opens a perspective for the PKCζ-MAPK axis as a target for pain control.