Search Results (289)

Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types. Full article

Many vertebrates have evolved resistance to snake venom as a result of coevolutionary chemical arms races. In Australian skinks (family Scincidae), who often encounter venomous elapid snakes, the frequency, diversity, and molecular basis of venom resistance have been unexplored. This study investigated the evolution of neurotoxin resistance in Australian skinks, focusing on mutations in the muscle nicotinic acetylcholine receptor (nAChR) α1 subunit’s orthosteric site that prevent pathophysiological binding by α-neurotoxins. We sampled a broad taxonomic range of Australian skinks and sequenced the nAChR α1 subunit gene. Key resistance-conferring mutations at the toxin-binding site (N-glycosylation motifs, proline substitutions, arginine insertions, changes in the electrochemical state of the receptor, and novel cysteines) were identified and mapped onto the skink organismal phylogeny. Comparisons with other venom-resistant taxa (amphibians, mammals, and reptiles) were performed, and structural modelling and binding assays were used to evaluate the impact of these mutations. Multiple independent origins of α-neurotoxin resistance were found across diverse skink lineages. Thirteen lineages evolved at least one resistance motif and twelve additional motifs evolved within these lineages, for a total of twenty-five times of α-neurotoxic venoms resistance. These changes sterically or electrostatically inhibit neurotoxin binding. Convergent mutations at the orthosteric site include the introduction of N-linked glycosylation sites previously known from animals as diverse as cobras and mongooses. However, an arginine (R) substitution at position 187 was also shown to have evolved on multiple occasions in Australian skinks, a modification previously shown to be responsible for the Honey Badger’s iconic resistance to cobra venom. Functional testing confirmed this mode of resistance in skinks. Our findings reveal that venom resistance has evolved extensively and convergently in Australian skinks through repeated molecular adaptations of the nAChR in response to the enormous selection pressure exerted by elapid snakes subsequent to their arrival and continent-wide dispersal in Australia. These toxicological findings highlight a remarkable example of convergent evolution across vertebrates and provide insight into the adaptive significance of toxin resistance in snake–lizard ecological interactions. Full article

Ant venoms are rich sources of bioactive molecules, including peptide toxins with potent and selective activity on ion channels, which makes them valuable for pharmacological research and therapeutic development. Voltage-dependent potassium (Kv) channels, critical for regulating cellular excitability or cell cycle progression control, are targeted by a diverse array of venom-derived peptides. This study focuses on MYRTX_A4-Tb11a, a peptide from Tetramorium bicarinatum venom, which was previously shown to have a strong paralytic effect on dipteran species without cytotoxicity on insect cells. In the present study, we show that Tb11a exhibited no or low cytotoxicity toward mammalian cells either, even at high concentrations, while electrophysiological studies revealed a blockade of hKv1.3 activity. Additionally, Ta11a, an analog of Tb11a from the ant Tetramorium africanum, demonstrated similar Kv1.3 inhibitory properties. Structural analysis supports that the peptide acts on Kv1.3 channels through the functional dyad Y21-K25 and that the disulfide bridge is essential for biological activity, as reduction seems to disrupt the peptide conformation and impair the dyad. These findings highlight the importance of three-dimensional structure in channel modulation and establish Tb11a and Ta11a as promising Kv1.3 inhibitors. Future research should investigate their selectivity across additional ion channels and employ structure-function studies to further enhance their pharmacological potential. Full article

A large majority of cone snails (a species in the genus Conus) are vermivorous (worm-hunting), but the diversity and bioactivity of their venom peptides remain largely unexplored. In this study, we report the first venom gland transcriptomes from two species in the Rhizoconus clade, Conus capitaneus and Conus mustelinus, and a new Conus miles transcriptome from a specimen collected in the Philippines. From the set of assembled sequences, a total of 225 C. capitaneus, 121 C. miles, and 168 C. mustelinus putative peptide toxin transcripts were identified, which were assigned to 27 canonical gene superfamilies in C. capitaneus and 24 in C. miles and in C. mustelinus. Most of these venom peptides are novel, and some exhibit new cysteine patterns. Clustering also revealed 12 putative novel gene superfamilies, highlighting the diversity of uncharacterized venom peptides in this group. The O1-, M-, O2-, and con-ikot-ikot superfamilies were the most abundant, while gene superfamilies such as D and G2 were highly expressed. Several hormone-like conopeptides were also identified in this study, revealing the vast diversity of conopeptides from the Rhizoconus species. Full article

Conus venoms are both highly powerful and complex, exhibiting a remarkably intriguing molecular variability. The biologic reasons behind such astonishing molecular diversity are yet to be fully understood. We hypothesized that the current knowledge has been hampered by a lack of studies targeting the whole Conus genus backed by a feeding habit analysis, as opposed to the abundant studies focused on single species or at the individual level. We aim to enlighten the understanding of the remarkable venom variability in cone snails while pushing to deliver novel peptides for biomedical applications through a broad transcriptomics approach. Here, we assessed 76 publicly available venom-related and unrelated transcriptomes from a total of 20 different Conus species. The shared transcriptomic repertoire revealed several gene variations in accordance with predatory diets (e.g., gene loss in piscivorous species), indicating that feeding habit largely influences venom evolution. Furthermore, evidences of ubiquitous symbiotic relationships within the venom organs were depicted, as biological processes alien to Conus species (e.g., Sorocarp morphogenesis) were found in all analyzed transcriptomes. Moreover, 88 potential anti-microbial peptides were bioinformatically detected, including one showing similarity with the human ACE2 receptor. Our study highlights the importance of in-depth comparative transcriptomic analyses, fostering cross-field synergic assessments by relying on informatic, biologic, and pharmacologic resources. Full article

Reliable assessment of protection in venom immunotherapy (VIT) patients remains a clinical challenge, especially due to the limitations of conventional sting challenge tests (SCTs), which require complex insect handling and may compromise test accuracy. This study introduces StingReady, a novel, user-friendly device designed to streamline the SCT process by enabling safe, efficient, and minimally manipulative exposure to hymenopteran stings. For the first time, StingReady was applied to conduct SCTs with Vespa velutina, an invasive hornet species of increasing clinical relevance. The device was tested in a real-world setting at Belvís Park in Santiago de Compostela, Spain, where hornets were successfully captured and transported to the hospital without anesthesia or limb removal. The design features adjustable mesh sizes, allowing compatibility with various hymenopteran taxa. Using StingReady, nine patients underwent SCTs with no need for direct insect handling during the hospital procedure. The process improved patient safety and comfort while preserving the insect’s natural stinging behavior, thereby enhancing test reliability. This study demonstrates that StingReady significantly improves SCT methodology, offering a practical, reproducible, and ethically sound alternative for evaluating VIT efficacy across diverse hymenopteran species. Full article

Snakebite envenoming constitutes a significant global health issue, particularly in Africa, where venomous species such as Echis vipers and Dendroaspis mambas pose substantial risks to human health. This study employs a standardized venomics workflow to comprehensively characterize and comparatively quantify the venom composition of nine medically relevant snake species chosen from among the deadliest in Africa. Utilizing shotgun venom proteomics and venom gland transcriptomics, we report detailed profiles of venom complexity, highlighting the relative abundance of dominant toxin families such as three-finger toxins and Kunitz-type proteins in Dendroaspis, and metalloproteinases and phospholipases A₂ in Echis. We delineate here the relative abundance and structural diversity of venom components. Key to our proteomic approach is the implementation of Multi-Enzymatic Limited Digestion (MELD), which improved protein sequence coverage and enabled the identification of rare toxin families such as hyaluronidases and renin-like proteases, by multiplying the overlap of generated peptides and enhancing the characterization of both toxin and non-toxin components within the venoms. The culmination of these efforts resulted in the construction of a detailed toxin database, providing insights into the biological roles and potential therapeutic targets of venom proteins and peptides. The findings here compellingly validate the MELD technique, reinforcing its reproducibility as a valuable characterization approach applied to venomics. This research significantly advances our understanding of venom complexity in African snake species, including representatives of both Viperidae and Elapidae families. By elucidating venom composition and toxin profiles, our study paves the way for the development of targeted therapies aimed at mitigating the morbidity and mortality associated with snakebite envenoming globally. Full article

New genes play a critical role in phenotypic diversity and evolutionary innovation. Parasitoid wasps, a highly abundant and diverse group of insects, parasitize other arthropods and exhibit remarkable evolutionary adaptations, such as evading host immune responses and exploiting host resources. However, the specific contributions of new genes to their unique traits remain poorly understood. Here, we identified 480 new genes that emerged after the Nasonia-Pteromalus divergence. Among these, 272 (56.7%) originated through DNA-mediated duplication, representing the largest proportion, followed by 77 (16.0%) derived from RNA-mediated duplication and 131 (27.3%) that arose de novo. Comparative analysis revealed that these new genes generally have shorter coding sequences and fewer exons compared to single-copy older genes conserved in the seven parasitoid wasps. These new genes are predominantly expressed in the reproductive glands and exhibit venom gland-biased expression. Notably, gene co-expression network analysis further identified that a new gene may act as a hub by interacting with older genes to regulate venom-related networks rather than directly encoding venom proteins. Together, our findings provide novel insights into the role of new genes in driving venom innovation in parasitoid wasps. Full article

Background/Objectives: Breast cancer remains the most prevalent malignancy among women worldwide. Innovative therapies are essential to address its diverse subtypes and treatment resistance. Scorpion venom and its bioactive proteins have gained attention as potential anticancer agents owing to their multitargeted cellular effects. This review systematically evaluates their anticancer properties and mechanisms in breast cancer, highlighting therapeutic potential. Methods: A systematic search was conducted in five databases (PubMed, Science Direct, EMBASE, OVID, and KISS) up to September 2024. Only in vitro studies using breast cancer cell lines and investigating scorpion venom or its bioactive proteins were included. Extracted data covered study characteristics, intervention types, control groups, dose range, duration, and key outcomes. Results: In total, 19 studies met the eligibility criteria. Crude scorpion venom showed broad cytotoxicity against hormone receptor-positive, triple-negative, and HER2-positive breast cancer subtypes. The primary mechanisms included apoptosis induction, DNA fragmentation, oxidative stress modulation, and cell cycle regulation. Bioactive proteins, such as chlorotoxin (CTX) and Neopladine 1/2, exhibited selective anticancer effects by targeting signaling pathways, inhibiting migration and invasion, and promoting apoptosis. Conclusion: These findings support scorpion venom’s potential as a multitargeted anticancer agent. The complementary actions of crude venom and its proteins highlight their promise for combination therapies. Further research is needed to clarify their synergistic interactions and optimize preclinical and clinical applications. Full article

The occurrence of antibiotic-resistant bacteria is a serious global health issue, and it emphasizes the need for novel antimicrobial agents. This review explores the potential of snake venom as another alternative strategy against antimicrobial resistance. Snake venoms are complex combinations of bioactive peptides and proteins, including metalloproteases (MPs), serine proteases (SPs), phospholipase A₂ (PLA₂) enzymes, three-finger toxins (3FTXs), cysteine-rich secretory proteins (CRISPs), L-amino acid oxidases (LAAOs), and antimicrobial peptides (AMPs). The antibacterial products possess wide-spectrum antibacterial activity against resistant microbes via diverse mechanisms such as cell membrane disruption, enzymatic hydrolysis of microbial structures, generation of oxidative stress, inhibition of biofilms, and immunomodulation. Strong antimicrobial activity is reported by most studies, but these are mostly restricted to in vitro testing with low translational use. Although preliminary insights into molecular targets and physiological effects exist, further studies are needed to clarify long-term safety and therapeutic potential. Special attention is given to snake venom-derived extracellular vesicles (SVEVs), which enhance the therapeutic potential of venom toxins by protecting them from degradation, improving bioavailability, and facilitating targeted delivery. Furthermore, innovative delivery strategies such as PEGylation, liposomes, hydrogels, microneedle patches, biopolymer films, and nanoparticles are discussed for their role in reducing systemic toxicity and enhancing antimicrobial efficacy. The rational modification of venom-derived peptides further expands their therapeutic utility by improving pharmacokinetics and minimizing off-target effects. Together, these approaches highlight the translational potential of snake venom-based therapies as next-generation antimicrobials in the fight against resistant infections. By outlining these challenges and directions, this review positions snake venom as an overlooked but fertile resource in the battle against antibiotic resistance. Full article

Over millions of years of evolution, natural selection has driven the specialization of predatory and defensive mechanisms in various animal species through the development of poisons and venoms. These venoms contain highly specific and selective molecules for several different targets according to the habitat and behavior of each species. In this work, we performed a comprehensive proteomic analysis of Tityus obscurus venom, identifying 45 proteins, including 8 toxins targeting K⁺ channels, 22 targeting Na⁺ channels, and 15 other venom components. Our study reveals seven novel isoforms of ion channel-targeting peptides characterized by amino acid substitutions which may influence their bioactivity and pharmacological properties. These findings contribute to our understanding of venom molecular diversity and evolution, providing new insights into peptide structure–function relationships. Considering the biomedical relevance of ion channel-modulating toxins, our work expands the repertoire of potential candidates for future drug development, particularly in the context of neuropharmacology and ion channel disorders. Full article

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. Full article

The Philippines has a high diversity of venomous snake species, but there is minimal information on their envenomation effects. This is evidenced by the small number of case reports, the poor reporting of envenomation cases, and the absence of specific antivenoms apart from one against the Philippine cobra (Naja philippinensis). This study sought to profile the action of selected Philippine pit viper venoms on blood coagulation and to investigate whether commercially available non-specific antivenoms can provide adequate protection against these venoms. Venom from the pit vipers Trimeresurus flavomaculatus and Trimeresurus mcgregori were subjected to coagulation assays, antivenom cross-neutralization tests, and thromboelastography. Venoms from both species were able to clot human plasma and isolated human fibrinogen. Consistent with pseudo-procoagulant/thrombin-like activity, the resulting fibrin clots were weak and transient, thereby contributing to net anticoagulation through the depletion of fibrinogen levels. Clotting factors fIXa and fXa were also inhibited by the venoms, further contributing to the net anticoagulant activity. Monovalent and polyvalent antivenoms from the Thai Red Cross Society were effective against both venoms, indicating cross-neutralization of venom toxins; the polyvalent antivenom was able to rescue fibrinogen clotting to a greater degree than the monovalent antivenom. Our findings highlight the coagulopathic effects of these pit viper venoms and suggest the utility of procuring the non-specific antivenoms for areas in the Philippines with a high risk for pit viper envenomation. Full article

Research on viper venom has expanded into diverse medical applications, including cancer treatment. This study investigates the potential of Vipera ammodytes venom in oncology, evaluating its cytotoxicity and chemosensitising effects on malignant melanoma cells. Proteomic analysis identified 125 proteins in the venom, with Phospholipases A2, C-type lectins, and metalloproteinases among the most abundant components. These proteins are associated with cytotoxic, anti-proliferative, and tumor-inhibiting properties. Three melanoma cell lines (M001, Me501, and A375) were used to assess venom cytotoxicity. The IC50 values demonstrated consistent venom sensitivity across cell lines (approximately 1.1 µg/mL). Combined treatment with venom and cisplatin significantly increased the cytotoxicity compared to single-agent treatments. Notably, venom enhanced the sensitivity of cisplatin in resistant cell lines (M001 and Me501), increasing cell mortality by up to 40%. The A375 cell line, inherently more sensitive to cisplatin, exhibited additional cytotoxic effects only at higher venom doses. The morphological changes observed under microscopy confirmed venom-induced cellular changes, further supporting its potential as an anti-cancer agent. The selective targeting of melanoma cells by venom components, particularly in muscle-associated metastases, suggests a unique therapeutic niche. While cisplatin was chosen for this pilot study due to its established cytotoxicity, future research will explore venom combinations with contemporary treatments such as immunotherapy and targeted therapies. Although preliminary, these findings provide a foundation for integrating venom-based strategies into advanced melanoma protocols, aiming to improve outcomes in resistant or metastatic cases. Full article

The escalating global health crisis of antibiotic resistance, driven by the rapid emergence of multidrug-resistant (MDR) bacterial pathogens, necessitates urgent and innovative countermeasures. This review comprehensively examines the diverse mechanisms employed by bacteria to evade antibiotic action, including alterations in cell membrane permeability, efflux pump overexpression, biofilm formation, target site modifications, and the enzymatic degradation of antibiotics. Specific focus is given to membrane transport systems such as ATP-binding cassette (ABC) transporters, resistance–nodulation–division (RND) efflux pumps, major facilitator superfamily (MFS) transporters, multidrug and toxic compound extrusion (MATE) systems, small multidrug resistance (SMR) families, and proteobacterial antimicrobial compound efflux (PACE) families. Additionally, the review explores the global burden of MDR pathogens and evaluates emerging therapeutic strategies, including quorum quenching (QQ), probiotics, postbiotics, synbiotics, antimicrobial peptides (AMPs), stem cell applications, immunotherapy, antibacterial photodynamic therapy (aPDT), and bacteriophage. Furthermore, this review discusses novel antimicrobial agents, such as animal-venom-derived compounds and nanobiotics, as promising alternatives to conventional antibiotics. The interplay between clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) in bacterial adaptive immunity is analyzed, revealing opportunities for targeted genetic interventions. By synthesizing current advancements and emerging strategies, this review underscores the necessity of interdisciplinary collaboration among biomedical scientists, researchers, and the pharmaceutical industry to drive the development of novel antibacterial agents. Ultimately, this comprehensive analysis provides a roadmap for future research, emphasizing the urgent need for sustainable and cooperative approaches to combat antibiotic resistance and safeguard global health. Full article