Within the phylum Cnidaria, sea anemones (class Anthozoa) express a rich diversity of ion-channel peptide modulators with biomedical applications, but corollary discoveries from jellyfish (subphylum Medusozoa) are lacking. To bridge this gap, bioactivities of previously unexplored proteinaceous and small molecular weight (~15 kDa to 5 kDa) venom components were assessed in a mouse dorsal root ganglia (DRG) high-content calcium-imaging assay, known as constellation pharmacology. While the addition of crude venom led to nonspecific cell death and Fura-2 signal leakage due to pore-forming activity, purified small molecular weight fractions of venom demonstrated three main, concentration-dependent and reversible effects on defined heterogeneous cell types found in the primary cultures of mouse DRG. These three phenotypic responses are herein referred to as phenotype A, B and C: excitatory amplification (A) or inhibition (B) of KCl-induced calcium signals, and test compound-induced disturbances to baseline calcium levels (C). Most notably, certain Alatina alata venom fractions showed phenotype A effects in all DRG neurons; Physalia physalis and Chironex fleckeri fractions predominantly showed phenotype B effects in small- and medium-diameter neurons. Finally, specific Physalia physalis and Alatina alata venom components induced direct excitatory responses (phenotype C) in glial cells. These findings demonstrate a diversity of neuroactive compounds in jellyfish venom potentially targeting a constellation of ion channels and ligand-gated receptors with broad physiological implications.

Envenomation by aquatic species is an under-investigated source of human morbidity and mortality. Increasing population density along marine and freshwater coastlines increases these incidents. Specific occupational groups - including commercial fishery workers, fisherfolk, marine tourism workers, and researchers - rely on aquatic resources for their livelihood. While diverse venomous aquatic species exhibit a broad array of habitats worldwide, they are most abundant in the tropics. Specific tropical regions present historic “hot spot” areas of concern for occupational groups with heightened risk of aquatic envenomation. Towards the overall objective of characterizing the health burden of aquatic envenomations, this review seeks to define (1) vulnerable, high-risk populations and (2) geographic hot-spot regions. To formally assess these metrics, a systematic literature review was performed where inclusion criteria requirements were peer-reviewed, published, epidemiological studies with defined denominators from January 1, 2000, to July 31, 2024, on the topic of human envenomation by aquatic species. Fifty-three articles met the inclusion criteria. Excluded articles were comprised of case reports, news and magazine articles, and those in languages aside from English, French, Portuguese, and Spanish. Most of the included articles examined emergency department and poison-control datasets that reported few overall envenomations (< 1%) from populations with physical and financial access to medical care. In contrast, datasets surveying beachgoers or fisherfolk directly, and life-guard incident reports, demonstrated that aquatic envenomation is an important source of injury for these groups and settings (envenomation frequency mean: 71%, median: 80%). Reports on additional high-risk groups, including marine and aquatic biologists, military personnel etc., and in key high-risk geographic regions including Thailand, Indonesia, and other Indo-Pacific countries were missing from the reviewed literature. Socio-demographic data were also largely missing from the literature. This systematic review highlights critical gaps where further research is needed, especially in under-represented regions and vulnerable populations.

Examination of venom constituent bioactivities from diverse venomous animals shows certain highly conserved classes, including enzymes (e.g., phospholipases and metalloproteinases) and pore-forming proteins. While antivenoms targeting other unique and lethal venom components have proven to be life-saving, venom-enzyme-driven tissue damage and morbidity persists. Broad-acting enzyme inhibitors demonstrate the potential to augment antivenom approaches. In this study, we investigate the potential utility of certain broad-acting inhibitors in cubozoa for the first time. Fluorogenic assays were used to determine the phospholipase A₂ (PLA₂) and matrix metalloproteinase (MMP) activity of the Hawaiian box jellyfish, Alatina alata, and this was compared to representative elapid, viper, and bee venoms. In vitro, evaluation of selected small-molecule inhibitors demonstrated the ability and feasibility of the broad-acting therapeutic doxycycline, which inhibited the PLA₂ and MMP activity of A. alata (approximately 50% reduction at 0.1 mM (95% CI 0.06–0.15) and 2.1 mM (95% CI 1.4–3.0), respectively), in addition to both snake venoms. Additionally, copper gluconate broadly inhibited the PLA₂ activity of bee, snake, and jellyfish venoms. While all venoms are complex mixtures of bioactive molecules, these studies demonstrate that targeting common class components with broad-acting inhibitors shows promise in clinical and preclinical management.