RESUMEN

Rotavirus A is a leading cause of non-bacterial gastroenteritis in humans and domesticated animals. Despite the vast diversity of bovine Rotavirus A strains documented in South Asian countries, there are very few whole genomes available for phylogenetic study. A cross-sectional study identified a high prevalence of the G6P[11] genotype of bovine Rotavirus A circulating in the commercial cattle population in Bangladesh. Next-generation sequencing and downstream phylogenetic analysis unveiled all 11 complete gene segments of this strain (BD_ROTA_CVASU), classifying it under the genomic constellation G6P[11]-I2-R2-C2-M2-A13-N2-T6-E2-H3, which belongs to a classical DS-1-like genomic backbone. We found strong evidence of intragenic recombination between human and bovine strains in the Non-structural protein 4 (NSP4) gene, which encodes a multifunctional enterotoxin. Our analyses highlight frequent zoonotic transmissions of rotaviruses in diverse human-animal interfaces, which might have contributed to the evolution and pathogenesis of this dominant genotype circulating in the commercial cattle population in Bangladesh.

Asunto(s)

Enfermedades de los Bovinos , Genoma Viral , Genotipo , Filogenia , Recombinación Genética , Infecciones por Rotavirus , Rotavirus , Toxinas Biológicas , Proteínas no Estructurales Virales , Animales , Bovinos , Rotavirus/genética , Rotavirus/clasificación , Rotavirus/aislamiento & purificación , Bangladesh/epidemiología , Proteínas no Estructurales Virales/genética , Humanos , Infecciones por Rotavirus/virología , Infecciones por Rotavirus/veterinaria , Infecciones por Rotavirus/epidemiología , Enfermedades de los Bovinos/virología , Enfermedades de los Bovinos/epidemiología , Estudios Transversales , Toxinas Biológicas/genética , Glicoproteínas/genética

RESUMEN

Various animal toxins pose a significant threat to human safety, necessitating urgent attention to their treatment and research. The clinical potential of programmed cell death (PCD) is widely regarded as a target for envenomation, given its crucial role in regulating physiological and pathophysiological processes. Current research on animal toxins examines their specific components in pathomechanisms and injuries, as well as their clinical applications. This review explores the relationship between various toxins and several types of PCD, such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis, to provide a reference for future understanding of the pathophysiology of toxins and the development of their potential clinical value.

Asunto(s)

Apoptosis , Autofagia , Toxinas Biológicas , Animales , Apoptosis/efectos de los fármacos , Humanos , Autofagia/efectos de los fármacos , Toxinas Biológicas/toxicidad , Necroptosis/efectos de los fármacos , Piroptosis/efectos de los fármacos , Ferroptosis/efectos de los fármacos

RESUMEN

Biological weapons, primarily dispersed as aerosols, can spread not only to the targeted area but also to adjacent regions following the movement of air driven by wind. Thus, there is a growing demand for toxin analysis because biological weapons are among the most influential and destructive. Specifically, such a technique should be hand-held, rapid, and easy to use because current methods require more time and well-trained personnel. Our study demonstrates the use of a novel lateral flow immunoassay, which has a confined structure like a double barbell in the detection area (so called c-LFA) for toxin detection such as staphylococcal enterotoxin B (SEB), ricinus communis (Ricin), and botulinum neurotoxin type A (BoNT-A). Additionally, we have explored the integration of machine learning (ML), specifically, a toxin chip boosting (TOCBoost) hybrid algorithm for improved sensitivity and specificity. Consequently, the ML powered c-LFA concurrently categorized three biological toxin types with an average accuracy as high as 95.5%. To our knowledge, the sensor proposed in this study is the first attempt to utilize ML for the assessment of toxins. The advent of the c-LFA orchestrated a paradigm shift by furnishing a versatile and robust platform for the rapid, on-site detection of various toxins, including SEB, Ricin, and BoNT-A. Our platform enables accessible and on-site toxin monitoring for non-experts and can potentially be applied to biosecurity.

Asunto(s)

Toxinas Botulínicas Tipo A , Enterotoxinas , Aprendizaje Automático , Ricina , Ricina/análisis , Inmunoensayo/métodos , Enterotoxinas/análisis , Toxinas Botulínicas Tipo A/análisis , Límite de Detección , Toxinas Biológicas/análisis

RESUMEN

Bioactive substances found in plants, microorganisms and animals have fascinated mankind since time immemorial. This review will focus on the progress that has been made over the centuries and our growing insights. The developments relate to both the discovery and characterization of novel bioactive substances, as well as the ceaseless implementation of refined techniques, the use of high-end instruments and breakthroughs in artificial intelligence with deep learning-based computational methods. As these approaches possess great translational potential, with many applications in different fields, such as therapeutic, diagnostic and agrochemical use, there is a good rationale to continue investing in toxinology-related research.

Asunto(s)

Inteligencia Artificial , Toxinas Biológicas , Animales , Historia del Siglo XX , Historia Antigua , Historia del Siglo XXI , Humanos , Historia del Siglo XIX , Historia del Siglo XVIII , Historia del Siglo XVII , Aprendizaje Profundo

RESUMEN

Pyrrolizidine alkaloids (PAs) are toxic compounds that occur naturally in certain plants, however, there are many secondary pathways causing PA contamination of other plants, including medicinal herbs and plant-based food products, which pose a risk of human intoxication. It is proven that chronic exposure to PAs causes serious adverse health consequences resulting from their cytotoxicity and genotoxicity. This review briefly presents PA occurrence, structures, chemistry, and toxicity, as well as a set of analytical methods. Recently developed sensitive electrochemical and chromatographic methods for the determination of PAs in honey, teas, herbs, and spices were summarized. The main strategies for improving the analytical efficiency of PA determination are related to the use of mass spectrometric (MS) detection; therefore, this review focuses on advances in MS-based methods. Raising awareness of the potential health risks associated with the presence of PAs in food and herbal medicines requires ongoing research in this area, including the development of sensitive methods for PA determination and rigorous legal regulations of PA intake from herbal products. The maximum levels of PAs in certain products are regulated by the European Commission; however, the precise knowledge about which products contain trace but significant amounts of these alkaloids is still insufficient.

Asunto(s)

Productos Biológicos , Alcaloides de Pirrolicidina , Alcaloides de Pirrolicidina/análisis , Humanos , Productos Biológicos/análisis , Productos Biológicos/química , Plantas Medicinales/química , Espectrometría de Masas/métodos , Contaminación de Alimentos/análisis , Toxinas Biológicas/análisis

RESUMEN

Cerebral stroke is a pressing global health concern, ranking as the second leading cause of mortality and resulting in persistent neurobehavioral impairments. Cerebral strokes, triggered by various embolic events, initiate complex signaling pathways involving neuroexcitotoxicity, ionic imbalances, inflammation, oxidative stress, acidosis, and mitochondrial dysfunction, leading to programmed cell death. Currently, the FDA has approved tissue plasminogen activator as a relatively benign intervention for cerebral stroke, leaving a significant treatment gap. However, a promising avenue has emerged from Earth's toxic creatures. Animal venoms harbor bioactive molecules, particularly neuropeptides, with potential in innovative healthcare applications. These venomous components, affecting ion channels, receptors, and transporters, encompass neurochemicals, amino acids, and peptides, making them prime candidates for treating cerebral ischemia and neurological disorders. This review explores the composition, applications, and significance of toxin-derived peptides as viable therapeutic agents. It also investigates diverse toxins from select venomous creatures, with the primary objective of shedding light on current stroke treatments and paving the way for pioneering therapeutic strategies capable of addressing neurobehavioral deficits.

Asunto(s)

Péptidos , Accidente Cerebrovascular , Humanos , Animales , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Toxinas Biológicas , Ponzoñas/uso terapéutico , Ponzoñas/farmacología

RESUMEN

Natural toxins (NTs) are poisonous secondary metabolites produced by living organisms developed to ward off predators. Especially low molecular weight NTs (MW<∼1 kDa), such as mycotoxins, phycotoxins, and plant toxins, are considered an important and growing food safety concern. Therefore, accurate risk assessment of food and feed for the presence of NTs is crucial. Currently, the analysis of NTs is predominantly performed with targeted high pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) methods. Although these methods are highly sensitive and accurate, they are relatively expensive and time-consuming, while unknown or unexpected NTs will be missed. To overcome this, novel on-site screening methods and non-targeted HPLC high resolution mass spectrometry (HRMS) methods have been developed. On-site screening methods can give non-specialists the possibility for broad "scanning" of potential geographical regions of interest, while also providing sensitive and specific analysis at the point-of-need. Non-targeted chromatography-HRMS methods can detect unexpected as well as unknown NTs and their metabolites in a lab-based approach. The aim of this chapter is to provide an insight in the recent advances, challenges, and perspectives in the field of NTs analysis both from the on-site and the laboratory perspective.

Asunto(s)

Contaminación de Alimentos , Toxinas Biológicas , Toxinas Biológicas/análisis , Contaminación de Alimentos/análisis , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Humanos , Animales

RESUMEN

In biological membranes, lipids often interact with membrane proteins (MPs), regulating the localization and activity of MPs in cells. Although elucidating lipid-MP interactions is critical to comprehend the physiological roles of lipids, a systematic and comprehensive identification of lipid-binding proteins has not been adequately established. Therefore, we report the development of lipid-immobilized beads where lipid molecules were covalently immobilized. Owing to the detergent tolerance, these beads enable screening of water-soluble proteins and MPs, the latter of which typically necessitate surfactants for solubilization. Herein, two sphingolipid species-ceramide and sphingomyelin-which are major constituents of lipid rafts, were immobilized on the beads. We first showed that the density of immobilized lipid molecules on the beads was as high as that of biological lipid membranes. Subsequently, we confirmed that these beads enabled the selective pulldown of known sphingomyelin- or ceramide-binding proteins (lysenin, p24, and CERT) from protein mixtures, including cell lysates. In contrast, commercial sphingomyelin beads, on which lipid molecules are sparsely immobilized through biotin-streptavidin linkage, failed to capture lysenin, a well-known protein that recognizes clustered sphingomyelin molecules. This clearly demonstrates the applicability of our beads for obtaining proteins that recognize not only a single lipid molecule but also lipid clusters or lipid membranes. Finally, we demonstrated the screening of lipid-binding proteins from Neuro2a cell lysates using these beads. This method is expected to significantly contribute to the understanding of interactions between lipids and proteins and to unravel the complexities of lipid diversity.

Asunto(s)

Esfingomielinas , Esfingomielinas/química , Animales , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Ratones , Ceramidas/química , Toxinas Biológicas

RESUMEN

Porcine rotavirus (PoRV) is one of the main pathogens causing diarrhea in piglets, and multiple genotypes coexist. However, an effective vaccine is currently lacking. Here, the potential adjuvant of nonstructural protein 4 (NSP4) and highly immunogenic structural protein VP4 prompted us to construct recombinant NSP486-175aa (NSP4*) and VP426-476aa (VP4*) proteins, combine them as immunogens to evaluate their efficacy. Results indicated that NSP4* enhanced systemic and local mucosal responses induced by VP4*. The VP4*-IgG, VP4*-IgA in feces and IgA-secreting cells in intestines induced by the co-immunization were significantly higher than those induced by VP4* alone. Co-immunization of NSP4* and VP4* also induced strong cellular immunity with significantly increased IFN-λ than the single VP4*. Summarily, the NSP4* as a synergistical antigen exerted limited effects on the PoRV NAbs elevation, but conferred strong VP4*-specific mucosal and cellular efficacy, which lays the foundation for the development of a more effective porcine rotavirus subunit vaccine.

Asunto(s)

Anticuerpos Antivirales , Proteínas de la Cápside , Inmunidad Mucosa , Infecciones por Rotavirus , Rotavirus , Proteínas no Estructurales Virales , Animales , Porcinos , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/inmunología , Rotavirus/inmunología , Rotavirus/genética , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Infecciones por Rotavirus/virología , Infecciones por Rotavirus/inmunología , Infecciones por Rotavirus/veterinaria , Infecciones por Rotavirus/prevención & control , Anticuerpos Antivirales/inmunología , Vacunas contra Rotavirus/inmunología , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/genética , Toxinas Biológicas/genética , Toxinas Biológicas/inmunología , Glicoproteínas/genética , Glicoproteínas/inmunología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/genética , Inmunoglobulina A/inmunología , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Heces/virología , Inmunoglobulina G/inmunología , Antígenos Virales/inmunología , Antígenos Virales/genética

RESUMEN

Food-borne biotoxins from microbes, plants, or animals contaminate unclean, spoiled, and rotten foods, posing significant health risks. Neutralizing such toxins is vital for human health, especially after food poisoning. Nanobodies (Nbs), a type of single-domain antibodies derived from the genetic cloning of a variable domain of heavy chain antibodies (VHHs) in camels, offer unique advantages in toxin neutralization. Their small size, high stability, and precise binding enable effective neutralization. The use of Nbs in neutralizing food-borne biotoxins offers numerous benefits, and their genetic malleability allows tailored optimization for diverse toxins. As nanotechnology continues to evolve and improve, Nbs are poised to become increasingly efficient and safer tools for toxin neutralization, playing a pivotal role in safeguarding human health and environmental safety. This review not only highlights the efficacy of these agents in neutralizing toxins but also proposes innovative solutions to address their current challenges. It lays a solid foundation for their further development in this crucial field and propels their commercial application, thereby contributing significantly to advancements in this domain.

Asunto(s)

Anticuerpos de Dominio Único , Animales , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/genética , Humanos , Contaminación de Alimentos/análisis , Contaminación de Alimentos/prevención & control , Anticuerpos Neutralizantes/inmunología , Toxinas Biológicas/inmunología , Enfermedades Transmitidas por los Alimentos/prevención & control , Enfermedades Transmitidas por los Alimentos/inmunología , Camelus/inmunología

RESUMEN

Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.

Asunto(s)

Antineoplásicos , Venenos de Serpiente , Humanos , Venenos de Serpiente/química , Antineoplásicos/farmacología , Antineoplásicos/química , Animales , Neoplasias/tratamiento farmacológico , L-Aminoácido Oxidasa/química , L-Aminoácido Oxidasa/farmacología , Apoptosis/efectos de los fármacos , Fosfolipasas A2/metabolismo , Fosfolipasas A2/química , Toxinas Biológicas/química , Toxinas Biológicas/farmacología

RESUMEN

Small membranes known as exosomes surround them and are released by several cell types both in vitro and in vivo. These membranes are packed with a variety of biomolecules, including proteins, lipids, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and non-coding RNA (ncRNA). As a source of biological nanomaterials, exosomes play a role in information and substance transmission between cells and have been identified as a general method of facilitating communication during interactions between the body, target organs, and toxins.. In order to understand the changes and mechanism of the composition and level of exosomes after biotoxin infection, this review focuses on current findings on the exosomes and highlights their novel uses in the toxicity mechanism. Exosomes are mainly used as a delivery carrier or mediated by receptors, and play an immune role after the toxin enters the body. This review expounds on the importance of exosomes in the toxicological mechanism of biotoxins and provides new insights for further diagnosis of toxic biomarkers, detoxification, and treatment development.

Asunto(s)

Exosomas , Exosomas/metabolismo , Humanos , Animales , Toxinas Biológicas/toxicidad , Toxinas Biológicas/metabolismo , Transducción de Señal/efectos de los fármacos , Biomarcadores/metabolismo

RESUMEN

The dynamic interface between invading viral pathogens and programmed cell death (PCD) of the host is a finely regulated process. Host cellular demise at the end of the viral life cycle ensures the release of progeny virions to initiate new infection cycles. Rotavirus (RV), a diarrheagenic virus with double-stranded RNA genome, has been reported to trigger different types of PCD such as apoptosis and pyroptosis in a highly regulated way to successfully disseminate progeny virions. Recently our lab also showed that induction of MLKL-driven programmed necroptosis by RV. However, the host cellular machinery involved in RV-induced necroptosis and the upstream viral trigger responsible for it remained unaddressed. In the present study, the signalling upstream of MLKL-driven necroptosis has been delineated where the involvement of Receptor interacting serine/threonine kinase 3 (RIPK3) and 1 (RIPK1) from the host side and RV non-structural protein 4 (NSP4) as the viral trigger for necroptosis has been shown. Interestingly, RV-NSP4 was found to be an integral component of the necrosome complex by interacting with RIPK1, thereby bypassing the requirement of RIPK1 kinase activity. Subsequently, NSP4-driven elevated cytosolic Ca2+ concentration and Ca2+-binding to NSP4 lead further to RHIM domain-dependent RIPK1-RIPK3 interaction, RIPK3-dependent MLKL phosphorylation, and eventual necroptosis. Overall, this study presents the interplay between RV-NSP4 and the host cellular necrosome complex to induce necroptotic death of host cells.

Asunto(s)

Necroptosis , Proteínas Quinasas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Rotavirus , Proteínas no Estructurales Virales , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Humanos , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Rotavirus/metabolismo , Animales , Interacciones Huésped-Patógeno , Toxinas Biológicas/metabolismo

RESUMEN

PURPOSE OF REVIEW: This narrative review will discuss how the intake of specific protein sources (animal and vegetable) providing specific amino acids can modulate the gut microbiota composition and generate toxins. A better understanding of these interactions could lead to more appropriate dietary recommendations to improve gut health and mitigate the risk of complications promoted by the toxic metabolites formed by the gut microbiota. RECENT FINDINGS: Gut microbiota is vital in maintaining human health by influencing immune function and key metabolic pathways. Under unfavorable conditions, the gut microbiota can produce excess toxins, which contribute to inflammation and the breakdown of the integrity of the intestinal barrier. Genetic and environmental factors influence gut microbiota diversity, with diet playing a crucial role. Emerging evidence indicates that the gut microbiota significantly metabolizes amino acids from dietary proteins, producing various metabolites with beneficial and harmful effects. Amino acids such as choline, betaine, l-carnitine, tyrosine, phenylalanine, and tryptophan can increase the production of uremic toxins when metabolized by intestinal bacteria. The type of food source that provides these amino acids affects the production of toxins. Plant-based diets and dietary fiber are associated with lower toxin formation than animal-based diets due to the high amino acid precursors in animal proteins.

Asunto(s)

Aminoácidos , Proteínas en la Dieta , Microbioma Gastrointestinal , Humanos , Proteínas en la Dieta/metabolismo , Aminoácidos/metabolismo , Dieta , Animales , Tóxinas Urémicas , Fibras de la Dieta , Proteínas de Vegetales Comestibles , Toxinas Biológicas

RESUMEN

The Gram-positive bacterium, Filifactor alocis is an oral pathogen, and approximately 50% of known strains encode a recently identified repeat-in-toxin (RTX) protein, FtxA. By assessing a longitudinal Ghanaian study population of adolescents (10-19 years of age; mean age 13.2 years), we recently discovered a possible correlation between deep periodontal pockets measured at the two-year follow-up, presence of the ftxA gene, and a high quantity of F. alocis. To further understand the contribution of F. alocis and FtxA in periodontal disease, we used qPCR in the present study to assess the carriage loads of F. alocis and the prevalence of its ftxA gene in subgingival plaque specimens, sampled at baseline from the Ghanaian cohort (n=500). Comparing these results with the recorded clinical attachment loss (CAL) longitudinal progression data from the two-year follow up, we concluded that carriers of ftxA-positive F. alocis typically exhibited higher loads of the bacterium. Moreover, high carriage loads of F. alocis and concomitant presence of the ftxA gene were two factors that were both associated with an enhanced prevalence of CAL progression. Interestingly, CAL progression appeared to be further promoted upon the simultaneous presence of F. alocis and the non-JP2 genotype of Aggregatibacter actinomycetemcomitans. Taken together, our present findings are consistent with the notion that F. alocis and its ftxA gene promotes CAL during periodontal disease.

Asunto(s)

Clostridiales , Enfermedades Periodontales , Toxinas Biológicas , Adolescente , Humanos , Aggregatibacter actinomycetemcomitans/genética , Pérdida de la Inserción Periodontal/microbiología , Ghana

RESUMEN

Animal venoms and toxins hold promise as sources of novel drug candidates, therapeutic agents, and biomolecules. To fully harness their potential, it is crucial to develop reliable testing methods that provide a comprehensive understanding of their effects and mechanisms of action. However, traditional rodent assays encounter difficulties in mimicking venom-induced effects in human due to the impractical venom dosage levels. The search for reliable testing methods has led to the emergence of zebrafish (Danio rerio) as a versatile model organism for evaluating animal venoms and toxins. Zebrafish possess genetic similarities to humans, rapid development, transparency, and amenability to high-throughput assays, making it ideal for assessing the effects of animal venoms and toxins. This review highlights unique attributes of zebrafish and explores their applications in studying venom- and toxin-induced effects from various species, including snakes, jellyfish, cuttlefish, anemones, spiders, and cone snails. Through zebrafish-based research, intricate physiological responses, developmental alterations, and potential therapeutic interventions induced by venoms are revealed. Novel techniques such as CRISPR/Cas9 gene editing, optogenetics, and high-throughput screening hold great promise for advancing venom research. As zebrafish-based insights converge with findings from other models, the comprehensive understanding of venom-induced effects continues to expand, guiding the development of targeted interventions and promoting both scientific knowledge and practical applications.

Asunto(s)

Modelos Animales , Ponzoñas , Pez Cebra , Animales , Pez Cebra/genética , Ponzoñas/farmacología , Toxinas Biológicas/farmacología

RESUMEN

The multidrug and toxin efflux (MATE) family participates in numerous biological processes and plays important roles in abiotic stress responses. However, information about the MATE family genes in Torreya grandis remains unclear. In this study, our genome-wide investigation identified ninety MATE genes in Torreya grandis, which were divided into five evolutionary clades. TgMATE family members are located on eleven chromosomes, and a total of thirty TgMATEs exist in tandem duplication. The promoter analysis showed that most TgMATEs contain the cis-regulatory elements associated with stress and hormonal responses. In addition, we discovered that most TgMATE genes responded to abiotic stresses (aluminum, drought, high temperatures, and low temperatures). Weighted correlation network analysis showed that 147 candidate transcription factor genes regulated the expression of 14 TgMATE genes, and it was verified through a double-luciferase assay. Overall, our findings offer valuable information for the characterization of the TgMATE gene mechanism in responding to abiotic stress and exhibit promising prospects for the stress tolerance breeding of Torreya grandis.

Asunto(s)

Taxaceae , Toxinas Biológicas , Fitomejoramiento , Aluminio , Bioensayo , Estrés Fisiológico/genética

RESUMEN

Protein toxins are defense mechanisms and adaptations found in various organisms and microorganisms, and their use in scientific research as therapeutic candidates is gaining relevance due to their effectiveness and specificity against cellular targets. However, discovering these toxins is time-consuming and expensive. In silico tools, particularly those based on machine learning and deep learning, have emerged as valuable resources to address this challenge. Existing tools primarily focus on binary classification, determining whether a protein is a toxin or not, and occasionally identifying specific types of toxins. For the first time, we propose a novel approach capable of classifying protein toxins into 27 distinct categories based on their mode of action within cells. To accomplish this, we assessed multiple machine learning techniques and found that an ensemble model incorporating the Light Gradient Boosting Machine and Quadratic Discriminant Analysis algorithms exhibited the best performance. During the tenfold cross-validation on the training dataset, our model exhibited notable metrics: 0.840 accuracy, 0.827 F1 score, 0.836 precision, 0.840 sensitivity, and 0.989 AUC. In the testing stage, using an independent dataset, the model achieved 0.846 accuracy, 0.838 F1 score, 0.847 precision, 0.849 sensitivity, and 0.991 AUC. These results present a powerful next-generation tool called MultiToxPred 1.0, accessible through a web application. We believe that MultiToxPred 1.0 has the potential to become an indispensable resource for researchers, facilitating the efficient identification of protein toxins. By leveraging this tool, scientists can accelerate their search for these toxins and advance their understanding of their therapeutic potential.

Asunto(s)

Algoritmos , Toxinas Biológicas , Benchmarking , Análisis Discriminante , Aprendizaje Automático , Proyectos de Investigación

RESUMEN

Earthworms, long utilized in traditional medicine, serve as a source of inspiration for modern therapeutics. Lysenin, a defensive factor in the coelom fluid of the earthworm Eisenia fetida, has multiple bioactivities. However, the inherent toxicity of Lysenin as a pore-forming protein (PFP) restricts its application in therapy. Here, a gene therapy strategy based on Lysenin for cancer treatment is presented. The formulation consists of polymeric nanoparticles complexed with the plasmid encoding Lysenin. After transfection in vitro, melanoma cells can express Lysenin, resulting in necrosis, autophagy, and immunogenic cell death. The secretory signal peptide alters the intracellular distribution of the expressed product of Lysenin, thereby potentiating its anticancer efficacy. The intratumor injection of Lysenin gene formulation can efficiently kill the transfected melanoma cells and activate the antitumor immune response. Notably, no obvious systemic toxicity is observed during the treatment. Non-viral gene therapy based on Lysenin derived from Eisenia foetida exhibits potential in cancer therapy, which can inspire future cancer therapeutics.

Asunto(s)

Terapia Genética , Melanoma , Oligoquetos , Animales , Ratones , Línea Celular Tumoral , Modelos Animales de Enfermedad , Terapia Genética/métodos , Melanoma/terapia , Melanoma/genética , Nanopartículas/química , Oligoquetos/genética , Toxinas Biológicas/genética , Femenino , Humanos

RESUMEN

Mechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12 induced a pro-inflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12 succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12 was dependent on the presence of the TLR4 receptor. Overall, the data suggests that failure of a timely resolution of the early inflammation by the ΔvapC12 infected mice led to hyperinflammation, altered T-cell response and high bacterial load. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the innate immune response of the host in ways that favor the long-term survival of the pathogen inside the host.

Asunto(s)

Mycobacterium tuberculosis , Ribonucleasas , Tuberculosis , Animales , Ratones , Inmunidad Innata , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Toxinas Biológicas , Tuberculosis/inmunología , Tuberculosis/metabolismo , Ribonucleasas/genética , Ribonucleasas/metabolismo