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Snake envenomation results in a range of clinical sequelae, and widely used animal-based conventional antivenoms exhibit several limitations including the adverse immunological effects in human snake bite victims. Therefore, human monoclonal anti-snake venom antibodies or fragments can be an alternate therapy for overcoming the existing limitations. We developed venom-neutralizing humanized scFv antibodies and analyzed biochemical mechanisms associated with the inhibition of toxicity. Tomlinson I and J human scFv antibody libraries were screened against Naja naja and Echis carinatus venoms, and seven unique scFv antibodies were obtained. Further, specific toxins of snake venom interacting with each of these scFvs were identified, and phospholipase A2 (PLA2) was found to be prominently captured by the phage-anchored scFv antibodies. Our study indicated PLA2 to be one of the abundant toxins in Naja naja and Echis carinatus venom samples. The scFvs binding to PLA2 were used to perform in vivo survival assay using the mouse model and in vitro toxin inhibition assays. scFv N194, which binds to acidic PLA2, protected 50% of mice treated with Naja naja venom. Significant prolongation of survival time and 16% survival were observed in Echis carinatus venom-challenged mice treated with scFv E113 and scFv E10, respectively. However, a combination comprised of an equal amount of two scFvs, E113 and E10, both interacting with basic PLA2, exhibited synergistically enhanced survival of 33% in Echis carinatus venom-challenged mice. No such synergistically enhanced survival was observed in the case of combinatorial treatment with anti- Naja naja scFvs, N194, and N248. These scFvs demonstrated partial inhibition of venom-induced myotoxicity, and E113 also inhibited hemolysis by 50%, which corroborates the enhanced survival during combinatorial treatment in Echis carinatus venom-challenged mice. • Conventional antivenoms exhibit adverse effects in snakebite victims. • Seven human scFvs antibody fragments against two prominent Indian snake venoms were isolated. • Majority of antibodies were specific to phospholipase A2, which is an abundant toxin in both venoms. • These antibodies partially inhibited venom-induced myotoxicity, and one of them also exhibited partial hemolysis inhibition. • Antibodies developed against PLA2 exhibited partial in vivo venom neutralization. [ABSTRACT FROM AUTHOR]

African cobras (Naja species) represent one of the most encountered medically important snakes in Africa. They are classified as African spitting (Afronaja subgenus) and non-spitting cobras (Uraeus and Boulengerina subgenera) with similar and different characteristics. Snake venom toxins including three-finger toxin (3FTx), phospholipase A2 (PLA 2), and snake venom metalloproteinase (SVMP) cause snakebite envenomation leading to morbidity and mortality. The profile of the proteome of African cobra venoms will help to develop safer and more effective antivenoms. The approval of Captopril by the US Food and Drug Administration (FDA) for the treatment of cardiovascular diseases, has led to intensified research towards possible use of venom toxins as therapeutics. In this review, we compare the venom proteome profile of 3 African Naja subgenera. In both Afronaja and Boulengerina subgenera, 3FTx (Afronaja –69.79%; Boulengerina –60.56%) followed by PLA 2 (Afronaja –21.15%; Boulengerina –20.21%) dominated the venoms compared to the Uraeus subgenus dominated by 3FTx (84.55%) with little to no PLA 2 abundance (0.8%). The venom of subgenus Uraeus was distinct from the other two subgenera by the almost total absence of PLA 2 , thus indicating little or no contribution of PLA 2 in the envenomation caused by Uraeus compared to Afronaja and Boulengerina. Furthermore, we report studies on the experimental testing of African cobra venoms and toxins against diseases including anti-cancer properties. [Display omitted] • African spitting and non-spitting cobra venoms cause severe envenomation. • 3FTxs are the most dominant toxin of spitting and non-spitting cobras venoms. • African non-spiting cobra venom of the Uraeus genus constitutes little or no PLA 2. • African cobras have potential therapeutic applications against diseases including cancer. [ABSTRACT FROM AUTHOR]

This report details a documented case of fatal King cobra (Ophiophagus hannah) envenomation in the Philippines. A 46-year-old woman from a mountainous town in Leyte was bitten on her left thigh by a snake. Despite receiving prompt medical attention, including administration of fluids and oxygen, she went into arrest and succumbed within 2.5 hours of the bite. Inadequate pre-hospital care, including endotracheal intubation and assisted ventilation, highlights a notable gap in emergency medical services. Photographic evidence, verified by a herpetologist, confirmed the involvement of a King cobra, with venom presenting with a swift and lethal systemic effect that led to the patient's demise, despite minimal local manifestations. This incident accentuates the urgent need for accessible, effective antivenom and improved snakebite management protocols in the Philippines. It also calls for heightened awareness and preparedness among pre-hospital healthcare providers and the public, alongside advocating for more research into snakebite envenomation. [Display omitted] • The report introduces a case of fatal King cobra envenomation in the Philippines. • A 46-year-old woman from Leyte experienced a cardiopulmonary arrest within 2.5 hours after being bitten on her left thigh. • Antivenom was unavailable at the time of the incident. • Photographic evidence later confirmed the snake as a King cobra. • This incident points to the need for more research on King cobra bite and improving antivenom access in the Philippines. [ABSTRACT FROM AUTHOR]

Snakebite envenomation often leads to severe visceral injuries, including acute liver injury (ALI). However, the toxicity mechanism remains unclear. Moreover, varespladib can directly inhibit phospholipase A 2 (PLA 2) in snake venom, but its protective effect on snakebite-induced ALI and the mechanism have not been clarified. Previous studies have shown that snake venom PLA 2 leads to neuron cell death via reactive oxygen species (ROS), one of the initial factors related to the mitophagy pathway. The present study group also found that ROS accumulation occurred after Naja atra envenoming. Hematoxylin and eosin (H/E) staining and immunohistochemistry (IHC) were performed to identify the expression of inflammatory factors in the liver tissue, and flow cytometry and immunofluorescence were used to detect ROS levels and mitochondrial function. Immunofluorescence and western blotting were also used for detecting mitophagy pathway-related proteins. The results showed that N. atra bite induced ALI by activating mitophagy and inducing inflammation and that varespladib had a protective effect. Collectively, these results showed the pathological mechanism of ALI caused by N. atra bite and revealed the protective effect of varespladib. [Display omitted] • N.atra venom causes acute liver injury(ALI), which accompanies with ROS generation. • Excess ROS could induce mitophagy. • Varespladib could effectively allevitate ALI caused by N.atra venom. [ABSTRACT FROM AUTHOR]

Snake bite envenomation causes tissue damage resulting in acute and chronic inflammatory responses. Inflammasome activation is one of the factors involved in tissue damage in a mouse model of snake envenomation. The present study examines the potency of Indian Big Four snake venoms in the activation of inflammasome and its role in local and systemic tissue toxicity. Among Indian Big Four snake venoms, Naja naja venom activated NLRP3 inflammasome in mouse macrophages. Activation of NLRP3 inflammasome was also observed in mouse foot paw and thigh muscle upon administration of N. naja venom. Intraperitoneal administration of N. naja venom cause systemic lung damage showed activation of NLRP3 inflammasome. Treatment with MCC950, a selective NLRP3 inflammasome inhibitor effectively inhibited N. naja venom-induced activation of caspase-1 and liberation of IL-1β in macrophages. In mice, MCC950 partially inhibited the activation of NLRP3 inflammasome in N. naja venom administered foot paw and thigh muscle. In conclusion, the present data showed that inflammasome is one of the host responses involved in N. naja snake venom-induced toxicities. The inhibition of inflammasome activation will provide new insight into better management of snake bite-induced local tissue damage. Proposed mechanism of NLRP3 inflammasome activation by N. naja venom. LPS priming as a first signal triggers the activation of NLRP3, which leads to the expression of the pro-IL-1β gene and the production of the pro-IL-1β protein. N. naja venom and DAMPs released from muscle tissue due to N. naja venom-induced edema and myotoxicity serve as the second signal for inflammasome activation. These two signals trigger the assembly and activation of the NLRP3 inflammasome complex and the liberate IL-1β cytokine. MCC950 inhibits N. naja venom-induced NLRP3 inflammasome activation by blocking pro-Caspase-1 cleavage into active Caspase-1. [Display omitted] • Naja naja snake venom activates NLRP3 inflammasome complex in macrophages. • Inflammasome pathway is activated in vivo in Naja naja venom-induced edema and myotoxicity in mice. • MCC950 an inhibitor of NLRP3 inflammasome pathway neutralizes Naja naja venom-induced inflammasome activation. [ABSTRACT FROM AUTHOR]