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1.
Mol Biol Evol ; 41(5)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38676945

RESUMEN

Gene duplication is a major force driving evolutionary innovation. A classic example is generating new animal toxins via duplication of physiological protein-encoding genes and recruitment into venom. While this process drives the innovation of many animal venoms, reverse recruitment of toxins into nonvenomous cells remains unresolved. Using comparative genomics, we find members of the Membrane Attack Complex and Perforin Family (MAC) have been recruited into venom-injecting cells (cnidocytes), in soft and stony corals and sea anemones, suggesting that the ancestral MAC was a cnidocyte expressed toxin. Further investigation into the model sea anemone Nematostella vectensis reveals that three members have undergone Nematostella-specific duplications leading to their reverse recruitment into endomesodermal cells. Furthermore, simultaneous knockdown of all three endomesodermally expressed MACs leads to mis-development, supporting that these paralogs have nonvenomous function. By resolving the evolutionary history and function of MACs in Nematostella, we provide the first proof for reverse recruitment from venom to organismal development.


Asunto(s)
Evolución Molecular , Perforina , Anémonas de Mar , Animales , Anémonas de Mar/genética , Perforina/metabolismo , Perforina/genética , Duplicación de Gen , Venenos de Cnidarios/genética , Venenos de Cnidarios/metabolismo , Filogenia , Familia de Multigenes
2.
Microb Pathog ; 186: 106486, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38056601

RESUMEN

In this study, we investigated the potential in vitro anti-HSV-1 activities of the Cassiopea andromeda jellyfish tentacle extract (TE) and its fractions, as well as computational work on the thymidine kinase (TK) inhibitory activity of the identified secondary metabolites. The LD50, secondary metabolite identification, preparative and analytical chromatography, and in silico TK assessment were performed using the Spearman-Karber, GC-MS, silica gel column chromatography, RP-HPLC, LC-MS, and docking methods, respectively. The antiviral activity of TE and the two purified compounds Ca2 and Ca7 against HSV-1 in Vero cells was evaluated by MTT and RT-PCR assays. The LD50 (IV, mouse) values of TE, Ca2, and Ca7 were 104.0 ± 4, 5120 ± 14, and 197.0 ± 7 (µg/kg), respectively. They exhibited extremely effective antiviral activity against HSV-1. The CC50 and MNTD of TE, Ca2, and Ca7 were (125, 62.5), (25, 12.5), and (50, 3.125) µg/ml, respectively. GC-MS analysis of the tentacle extract revealed seven structurally distinct chemical compositions. Four of the seven compounds had a steroid structure. According to the docking results, all compounds showed binding affinity to the active sites of both thymidine kinase chains. Among them, the steroid compound Pregn-5-ene-3,11-dione, 17,20:20,21 bis [methylenebis(oxy)]-, cyclic 3-(1,2-ethane diyl acetal) (Ca2) exhibited the highest affinity for both enzyme chains, surpassing that of standard acyclovir. In silico data confirmed the experimental results. We conclude that the oxosteroid Ca2 may act as a potent agent against HSV-1.


Asunto(s)
Venenos de Cnidarios , Herpesvirus Humano 1 , Chlorocebus aethiops , Animales , Ratones , Antivirales/farmacología , Antivirales/química , Células Vero , Timidina Quinasa/genética , Timidina Quinasa/química , Venenos de Cnidarios/farmacología , Esteroides/farmacología
3.
Med Sci Monit ; 30: e944265, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39074073

RESUMEN

With the surge in the human coastal population and the increasing frequency of human activities along the coast, cases of marine envenomation, particularly jellyfish envenomation, have notably risen. Jellyfish stings can induce a spectrum of symptoms that vary in severity, encompassing skin injuries, acute systemic venom effects, delayed indirect sequelae, and even fatality, causing significant distress to patients. Among these manifestations, the occurrence of skin lesions following jellyfish stings is prevalent and substantial. These lesions are characterized by evident blister formation, development of bullae, subcutaneous hemorrhage, erythema, papules, wheal, ecchymosis, and ulceration or skin necrosis. Local cutaneous manifestations may persist for several weeks or even months after the initial sting. Despite aggressive treatment, many skin injuries still result in significant pigmentation or scarring after recovery. To address this issue effectively, it is imperative to conduct comprehensive evidence-based medical research, elucidate various components within jellyfish venom, and elucidate its pathogenic mechanism to develop targeted treatment programs. This article aims to review the skin symptoms, pathophysiology, and management of jellyfish stings. Such considerations can provide comprehensive guidance to medical professionals and the public and minimize the harm caused by jellyfish stings.


Asunto(s)
Mordeduras y Picaduras , Venenos de Cnidarios , Piel , Humanos , Mordeduras y Picaduras/terapia , Mordeduras y Picaduras/fisiopatología , Mordeduras y Picaduras/complicaciones , Animales , Piel/patología , Piel/fisiopatología , Cnidarios , Enfermedades de la Piel/terapia , Enfermedades de la Piel/fisiopatología , Enfermedades de la Piel/etiología , Escifozoos
4.
Am J Emerg Med ; 75: 197.e1-197.e3, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37945412

RESUMEN

We describe a case of a young male who presented to the emergency department with unilateral eye pain, blurred vision, conjunctival injection, and ocular pH of 9, one day after direct ocular exposure to palytoxin (PTX) from coral in a home saltwater fish tank. Although uncommon, ocular PTX toxicity is a potentially vision-threatening condition that requires prompt recognition. This case report documents the successful management of presumed ocular PTX exposure and suggests additional workup and treatment considerations for future patients.


Asunto(s)
Antozoos , Venenos de Cnidarios , Animales , Humanos , Masculino , Venenos de Cnidarios/toxicidad , Acrilamidas/toxicidad , Cara
5.
Mar Drugs ; 22(10)2024 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-39452876

RESUMEN

The venom contained within cnidarian nematocysts has a complex composition and holds significant potential for biotechnological applications. In this context, one of the most effective methods for studying nematocyst contents is the proteomic approach, which can detect even trace amounts of compounds while minimizing the need for large-scale animal collection, thus helping to preserve ecosystem integrity. This study aimed to provide a comprehensive proteomic and biochemical characterization of the crude nematocyst extract from the common hydrozoan Velella velella. Despite not being harmful to humans, the analysis of the crude venom extract from V. velella brought to the identification of 783 different proteins, categorized into structural components, enzymes, and potential toxins, revealing a qualitative composition of the venom similar to that of other more toxic cnidarians. Biochemical assays confirmed the presence of various active hydrolytic enzymes within the extract, including proteases, phospholipases, hyaluronidases, DNases, and chitinases. These findings pave the road for future studies involving the pharmacological applications of Velella velella venom components through recombinant production and functional testing.


Asunto(s)
Venenos de Cnidarios , Hidrozoos , Nematocisto , Proteómica , Animales , Proteómica/métodos , Venenos de Cnidarios/química , Nematocisto/química , Hidrozoos/química
6.
Mar Drugs ; 22(2)2024 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-38393042

RESUMEN

The venoms of various sea anemones are rich in diverse toxins, which usually play a dual role in capturing prey and deterring predators. However, the complex components of such venoms have not been well known yet. Here, venomics of integrating transcriptomic and proteomic technologies was applied for the first time to identify putative protein and peptide toxins from different tissues of the representative sea anemone, Heteractis magnifica. The transcriptomic analysis of H. magnifica identified 728 putative toxin sequences, including 442 and 381 from the tentacles and the column, respectively, and they were assigned to 68 gene superfamilies. The proteomic analysis confirmed 101 protein and peptide toxins in the venom, including 91 in the tentacles and 39 in the column. The integrated venomics also confirmed that some toxins such as the ShK-like peptides and defensins are co-expressed in both the tentacles and the column. Meanwhile, a homology analysis was conducted to predict the three-dimensional structures and potential activity of seven representative toxins. Altogether, this venomics study revealed the venom complexity of H. magnifica, which will help deepen our understanding of cnidarian toxins, thereby supporting the in-depth development of valuable marine drugs.


Asunto(s)
Venenos de Cnidarios , Anémonas de Mar , Toxinas Biológicas , Animales , Ponzoñas/metabolismo , Anémonas de Mar/metabolismo , Proteómica/métodos , Péptidos/genética , Péptidos/metabolismo , Venenos de Cnidarios/química
7.
Mar Drugs ; 22(8)2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39195478

RESUMEN

The giant jellyfish Nemopilema nomurai sting can cause local and systemic reactions; however, comparative analysis of the tentacle extract (TE) and nematocyst venom extract (NV), and its toxicity, mechanism, and potential intervention are still limited. This study compared venom from TE and NV for their composition, toxicity, and efficacy in vitro and in vivo used RAW264.7 cells and ICR mice. A total of 239 and 225 toxin proteins were identified in TE and NV by proteomics, respectively. Pathological analysis revealed that TE and NV caused heart and liver damage through apoptosis, necrosis, and inflammation, while TE exhibited higher toxicity ex vivo and in vivo. Biochemical markers indicated TE and NV elevated creatine kinase, lactatedehydrogenase, and aspartate aminotransferase, with the TE group showing a more significant increase. Transcriptomics and Western blotting indicated both venoms increased cytokines expression and MAPK signaling pathways. Additionally, 1 mg/kg PACOCF3 (the phospholipase A2 inhibitor) improved survival from 16.7% to 75% in mice. Our results indicate that different extraction methods impact venom activities, tentacle autolysis preserves toxin proteins and their toxicity, and PACOCF3 is a potential antidote, which establishes a good extraction method of jellyfish venom, expands our understanding of jellyfish toxicity, mechanism, and provides a promising intervention.


Asunto(s)
Venenos de Cnidarios , Ratones Endogámicos ICR , Nematocisto , Animales , Ratones , Venenos de Cnidarios/toxicidad , Venenos de Cnidarios/farmacología , Nematocisto/química , Células RAW 264.7 , Escifozoos , Proteómica , Masculino , Apoptosis/efectos de los fármacos , Inhibidores de Fosfolipasa A2/farmacología
8.
Mar Drugs ; 22(5)2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38786608

RESUMEN

We identified a new human voltage-gated potassium channel blocker, NnK-1, in the jellyfish Nemopilema nomurai based on its genomic information. The gene sequence encoding NnK-1 contains 5408 base pairs, with five introns and six exons. The coding sequence of the NnK-1 precursor is 894 nucleotides long and encodes 297 amino acids containing five presumptive ShK-like peptides. An electrophysiological assay demonstrated that the fifth peptide, NnK-1, which was chemically synthesized, is an effective blocker of hKv1.3, hKv1.4, and hKv1.5. Multiple-sequence alignment with cnidarian Shk-like peptides, which have Kv1.3-blocking activity, revealed that three residues (3Asp, 25Lys, and 34Thr) of NnK-1, together with six cysteine residues, were conserved. Therefore, we hypothesized that these three residues are crucial for the binding of the toxin to voltage-gated potassium channels. This notion was confirmed by an electrophysiological assay with a synthetic peptide (NnK-1 mu) where these three peptides were substituted with 3Glu, 25Arg, and 34Met. In conclusion, we successfully identified and characterized a new voltage-gated potassium channel blocker in jellyfish that interacts with three different voltage-gated potassium channels. A peptide that interacts with multiple voltage-gated potassium channels has many therapeutic applications in various physiological and pathophysiological contexts.


Asunto(s)
Péptidos , Bloqueadores de los Canales de Potasio , Canales de Potasio con Entrada de Voltaje , Escifozoos , Animales , Humanos , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Péptidos/farmacología , Péptidos/química , Secuencia de Aminoácidos , Venenos de Cnidarios/farmacología , Venenos de Cnidarios/química , Alineación de Secuencia
9.
Mar Drugs ; 22(8)2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39195449

RESUMEN

The relative lack of marine venom could be attributed to the difficulty in dealing with venomous marine animals. Moreover, the venom of marine animals consists of various bioactive molecules, many of which are proteins with unique properties. In this study, we investigated the potential toxic proteins of jellyfish collected for ligand screening to understand the mechanism of the toxic effects of jellyfish. Since taxonomic identification is problematic due to the lack of proper keys, we conducted morphological and molecular mitochondrial DNA sequencing from COI and ITS regions. The venom extract from nematocysts found along the bell margins was used for protein characterization using SDS-gel electrophoresis and nano-liquid chromatography-tandem mass spectrometry. Ligand screening for the most potent toxin and antibacterial and cytotoxicity assays were carried out. The phylogenetic tree showed distinct clustering from other Catostylus sp. The proteomic analysis revealed venom with many bioactive proteins. Only 13 venom proteins were identified with molecular weights ranging from 4318 to 184,923 Da, exhibiting the venom's complexity. The overall toxin protein composition of Catostylus sp. venom was dominated by potassium channel toxin alpha-KTx. Molecular docking of toxin alpha-KTx 1.13 revealed high specificity towards the human voltage-gated potassium channel Kv3 with a high fitness score and a minimum energy barrier of -17.9 kcal/mol. Disc diffusion and cytotoxicity assays revealed potent antibacterial activity against Klebsiella pneumoniae with no cytotoxicity. Further studies on detailed characterization and therapeutic potentials are warranted.


Asunto(s)
Antibacterianos , Venenos de Cnidarios , Simulación del Acoplamiento Molecular , Péptidos , Animales , Antibacterianos/farmacología , Antibacterianos/química , Humanos , Venenos de Cnidarios/farmacología , Venenos de Cnidarios/química , Péptidos/farmacología , Péptidos/química , Escifozoos , Ligandos , Filogenia , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Proteómica/métodos
10.
Mar Drugs ; 22(3)2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38535452

RESUMEN

Sea anemone venom, abundant in protein and peptide toxins, serves primarily for predatory defense and competition. This study delves into the insulin-like peptides (ILPs) present in sea anemones, particularly focusing on their role in potentially inducing hypoglycemic shock in prey. We identified five distinct ILPs in Exaiptasia diaphana, exhibiting varied sequences. Among these, ILP-Ap04 was successfully synthesized using solid phase peptide synthesis (SPPS) to evaluate its hypoglycemic activity. When tested in zebrafish, ILP-Ap04 significantly reduced blood glucose levels in a model of diabetes induced by streptozotocin (STZ) and glucose, concurrently affecting the normal locomotor behavior of zebrafish larvae. Furthermore, molecular docking studies revealed ILP-Ap04's unique interaction with the human insulin receptor, characterized by a detailed hydrogen-bonding network, which supports a unique mechanism for its hypoglycemic effects. Our findings suggest that sea anemones have evolved sophisticated strategies to activate insulin receptors in vertebrates, providing innovative insights into the design of novel drugs for the treatment of diabetes.


Asunto(s)
Venenos de Cnidarios , Diabetes Mellitus , Anémonas de Mar , Humanos , Animales , Insulina , Hipoglucemiantes , Pez Cebra , Simulación del Acoplamiento Molecular , Péptidos Similares a la Insulina
11.
Mar Drugs ; 22(5)2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38786596

RESUMEN

The escalation of jellyfish stings has drawn attention to severe skin reactions, underscoring the necessity for novel treatments. This investigation assesses the potential of hydroxybenzoic acid derivatives, specifically protocatechuic acid (PCA) and gentisic acid (DHB), for alleviating Nemopilema nomurai Nematocyst Venom (NnNV)-induced injuries. By employing an in vivo mouse model, the study delves into the therapeutic efficacy of these compounds. Through a combination of ELISA and Western blot analyses, histological examinations, and molecular assays, the study scrutinizes the inflammatory response, assesses skin damage and repair mechanisms, and investigates the compounds' ability to counteract venom effects. Our findings indicate that PCA and DHB significantly mitigate inflammation by modulating critical cytokines and pathways, altering collagen ratios through topical application, and enhancing VEGF and bFGF levels. Furthermore, both compounds demonstrate potential in neutralizing NnNV toxicity by inhibiting metalloproteinases and phospholipase-A2, showcasing the viability of small-molecule compounds in managing toxin-induced injuries.


Asunto(s)
Venenos de Cnidarios , Hidroxibenzoatos , Piel , Animales , Hidroxibenzoatos/farmacología , Ratones , Venenos de Cnidarios/farmacología , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Gentisatos/farmacología , Nematocisto/efectos de los fármacos , Modelos Animales de Enfermedad , Citocinas/metabolismo
12.
Genomics ; 115(6): 110709, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37739021

RESUMEN

Recent studies on marine organisms have made use of third-generation sequencing technologies such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT). While these specialized bioinformatics tools have different algorithmic designs and performance capabilities, they offer scalability and can be applied to various datasets. We investigated the effectiveness of PacBio and ONT RNA sequencing methods in identifying the venom of the jellyfish species Nemopilema nomurai. We conducted a detailed analysis of the sequencing data from both methods, focusing on key characteristics such as CD, alternative splicing, long-chain noncoding RNA, simple sequence repeat, transcription factor, and functional transcript annotation. Our findings indicate that ONT generally produced higher raw data quality in the transcriptome analysis, while PacBio generated longer read lengths. PacBio was found to be superior in identifying CDs and long-chain noncoding RNA, whereas ONT was more cost-effective for predicting alternative splicing events, simple sequence repeats, and transcription factors. Based on these results, we conclude that PacBio is the most specific and sensitive method for identifying venom components, while ONT is the most cost-effective method for studying venogenesis, cnidocyst (venom gland) development, and transcription of virulence genes in jellyfish. Our study has implications for future sequencing technologies in marine jellyfish, and highlights the power of full-length transcriptome analysis in discovering potential therapeutic targets for jellyfish dermatitis.


Asunto(s)
Venenos de Cnidarios , Escifozoos , Animales , ARN , Análisis de Secuencia de ARN , ARN no Traducido , Secuenciación de Nucleótidos de Alto Rendimiento/métodos
13.
Int J Mol Sci ; 25(16)2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39201376

RESUMEN

The effects of enhanced late INa, a persistent component of the Na+ channel current, on the intracellular ion dynamics and the automaticity of the pulmonary vein cardiomyocytes were studied with fluorescent microscopy. Anemonia viridis toxin II (ATX- II), an enhancer of late INa, caused increases in the basal Na+ and Ca2+ concentrations, increases in the number of Ca2+ sparks and Ca2+ waves, and the generation of repetitive Ca2+ transients. These phenomena were inhibited by eleclazine, a blocker of the late INa; SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX); H89, a protein kinase A (PKA) inhibitor; and KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These results suggest that enhancement of late INa in the pulmonary vein cardiomyocytes causes disturbance of the intracellular ion environment through activation of the NCX and Ca2+-dependent enzymes. Such mechanisms are probably involved in the ectopic electrical activity of the pulmonary vein myocardium.


Asunto(s)
Calcio , Venenos de Cnidarios , Miocitos Cardíacos , Venas Pulmonares , Intercambiador de Sodio-Calcio , Animales , Venas Pulmonares/metabolismo , Venas Pulmonares/citología , Venas Pulmonares/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Cobayas , Calcio/metabolismo , Venenos de Cnidarios/farmacología , Intercambiador de Sodio-Calcio/metabolismo , Sodio/metabolismo , Masculino , Potenciales de Acción/efectos de los fármacos , Canales de Sodio/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Compuestos de Anilina/farmacología , Sulfonamidas/farmacología , Señalización del Calcio/efectos de los fármacos , Isoquinolinas , Éteres Fenílicos
14.
J Biol Chem ; 298(10): 102455, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36063994

RESUMEN

Pore-forming proteins perforate lipid membranes and consequently affect their integrity and cell fitness. Therefore, it is not surprising that many of these proteins from bacteria, fungi, or certain animals act as toxins. While pore-forming proteins have also been found in plants, there is little information about their molecular structure and mode of action. Bryoporin is a protein from the moss Physcomitrium patens, and its corresponding gene was found to be upregulated by various abiotic stresses, especially dehydration, as well as upon fungal infection. Based on the amino acid sequence, it was suggested that bryoporin was related to the actinoporin family of pore-forming proteins, originally discovered in sea anemones. Here, we provide the first detailed structural and functional analysis of this plant cytolysin. The crystal structure of monomeric bryoporin is highly similar to those of actinoporins. Our cryo-EM analysis of its pores showed an actinoporin-like octameric structure, thereby revealing a close kinship of proteins from evolutionarily distant organisms. This was further confirmed by our observation of bryoporin's preferential binding to and formation of pores in membranes containing animal sphingolipids, such as sphingomyelin and ceramide phosphoethanolamine; however, its binding affinity was weaker than that of actinoporin equinatoxin II. We determined bryoporin did not bind to major sphingolipids found in fungi or plants, and its membrane-binding and pore-forming activity was enhanced by various sterols. Our results suggest that bryoporin could represent a part of the moss defense arsenal, acting as a pore-forming toxin against membranes of potential animal pathogens, parasites, or predators.


Asunto(s)
Bryopsida , Porinas , Animales , Secuencia de Aminoácidos , Bryopsida/genética , Bryopsida/metabolismo , Venenos de Cnidarios/química , Citotoxinas , Porinas/genética , Porinas/metabolismo , Anémonas de Mar/química
15.
J Chem Inf Model ; 63(10): 3043-3053, 2023 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-37143234

RESUMEN

Peptide toxins that adopt the ShK fold can inhibit the voltage-gated potassium channel KV1.3 with IC50 values in the pM range and are therefore potential leads for drugs targeting autoimmune and neuroinflammatory diseases. Nuclear magnetic resonance (NMR) relaxation measurements and pressure-dependent NMR have shown that, despite being cross-linked by disulfide bonds, ShK itself is flexible in solution. This flexibility affects the local structure around the pharmacophore for the KV1.3 channel blockade and, in particular, the relative orientation of the key Lys and Tyr side chains (Lys22 and Tyr23 in ShK) and has implications for the design of KV1.3 inhibitors. In this study, we have performed molecular dynamics (MD) simulations on ShK and a close homologue, HmK, to probe the conformational space occupied by the Lys and Tyr residues, and docked the different conformations with a recently determined cryo-EM structure of the KV1.3 channel. Although ShK and HmK have 60% sequence identity, their dynamic behaviors are quite different, with ShK sampling a broad range of conformations over the course of a 5 µs MD simulation, while HmK is relatively rigid. We also investigated the importance of conformational dynamics, in particular the distance between the side chains of the key dyad Lys22 and Tyr23, for binding to KV1.3. Although these peptides have quite different dynamics, the dyad in both adopts a similar configuration upon binding, revealing a conformational selection upon binding to KV1.3 in the case of ShK. Both peptides bind to KV1.3 with Lys22 occupying the pore of the channel. Intriguingly, the more flexible peptide, ShK, binds with significantly higher affinity than HmK.


Asunto(s)
Venenos de Cnidarios , Anémonas de Mar , Animales , Canal de Potasio Kv1.3/química , Canal de Potasio Kv1.3/metabolismo , Venenos de Cnidarios/química , Venenos de Cnidarios/metabolismo , Venenos de Cnidarios/farmacología , Anémonas de Mar/química , Anémonas de Mar/metabolismo , Péptidos/química , Conformación Molecular , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Canal de Potasio Kv.1.2/metabolismo
16.
Mar Drugs ; 21(3)2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36976246

RESUMEN

Sea anemones are sessile invertebrates of the phylum Cnidaria and their survival and evolutive success are highly related to the ability to produce and quickly inoculate venom, with the presence of potent toxins. In this study, a multi-omics approach was applied to characterize the protein composition of the tentacles and mucus of Bunodosoma caissarum, a species of sea anemone from the Brazilian coast. The tentacles transcriptome resulted in 23,444 annotated genes, of which 1% showed similarity with toxins or proteins related to toxin activity. In the proteome analysis, 430 polypeptides were consistently identified: 316 of them were more abundant in the tentacles while 114 were enriched in the mucus. Tentacle proteins were mostly enzymes, followed by DNA- and RNA-associated proteins, while in the mucus most proteins were toxins. In addition, peptidomics allowed the identification of large and small fragments of mature toxins, neuropeptides, and intracellular peptides. In conclusion, integrated omics identified previously unknown or uncharacterized genes in addition to 23 toxin-like proteins of therapeutic potential, improving the understanding of tentacle and mucus composition of sea anemones.


Asunto(s)
Venenos de Cnidarios , Anémonas de Mar , Animales , Anémonas de Mar/metabolismo , Venenos de Cnidarios/química , Brasil , Multiómica , Péptidos/química , Toxinas Marinas/química
17.
Mar Drugs ; 21(3)2023 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-36976217

RESUMEN

Nowadays, major attention is being paid to curing different types of cancers and is focused on natural resources, including oceans and marine environments. Jellyfish are marine animals with the ability to utilize their venom in order to both feed and defend. Prior studies have displayed the anticancer capabilities of various jellyfish. Hence, we examined the anticancer features of the venom of Cassiopea andromeda and Catostylus mosaicus in an in vitro situation against the human pulmonary adenocarcinoma (A549) cancer cell line. The MTT assay demonstrated that both mentioned venoms have anti-tumoral ability in a dose-dependent manner. Western blot analysis proved that both venoms can increase some pro-apoptotic factors and reduce some anti-apoptotic molecules that lead to the inducing of apoptosis in A549 cells. GC/MS analysis demonstrated some compounds with biological effects, including anti-inflammatory, antioxidant and anti-cancer activities. Molecular docking and molecular dynamic showed the best position of each biologically active component on the different death receptors, which are involved in the process of apoptosis in A549 cells. Ultimately, this study has proven that both venoms of C. andromeda and C. mosaicus have the capability to suppress A549 cells in an in vitro condition and they might be utilized in order to design and develop brand new anticancer agents in the near future.


Asunto(s)
Adenocarcinoma , Cnidarios , Venenos de Cnidarios , Neoplasias Pulmonares , Escifozoos , Animales , Humanos , Venenos de Cnidarios/farmacología , Venenos de Cnidarios/química , Células A549 , Simulación del Acoplamiento Molecular , Adenocarcinoma/tratamiento farmacológico , Apoptosis , Neoplasias Pulmonares/tratamiento farmacológico
18.
Proc Natl Acad Sci U S A ; 117(44): 27481-27492, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33060291

RESUMEN

The sea anemone Nematostella vectensis (Anthozoa, Cnidaria) is a powerful model for characterizing the evolution of genes functioning in venom and nervous systems. Although venom has evolved independently numerous times in animals, the evolutionary origin of many toxins remains unknown. In this work, we pinpoint an ancestral gene giving rise to a new toxin and functionally characterize both genes in the same species. Thus, we report a case of protein recruitment from the cnidarian nervous to venom system. The ShK-like1 peptide has a ShKT cysteine motif, is lethal for fish larvae and packaged into nematocysts, the cnidarian venom-producing stinging capsules. Thus, ShK-like1 is a toxic venom component. Its paralog, ShK-like2, is a neuropeptide localized to neurons and is involved in development. Both peptides exhibit similarities in their functional activities: They provoke contraction in Nematostella polyps and are toxic to fish. Because ShK-like2 but not ShK-like1 is conserved throughout sea anemone phylogeny, we conclude that the two paralogs originated due to a Nematostella-specific duplication of a ShK-like2 ancestor, a neuropeptide-encoding gene, followed by diversification and partial functional specialization. ShK-like2 is represented by two gene isoforms controlled by alternative promoters conferring regulatory flexibility throughout development. Additionally, we characterized the expression patterns of four other peptides with structural similarities to studied venom components and revealed their unexpected neuronal localization. Thus, we employed genomics, transcriptomics, and functional approaches to reveal one venom component, five neuropeptides with two different cysteine motifs, and an evolutionary pathway from nervous to venom system in Cnidaria.


Asunto(s)
Venenos de Cnidarios/genética , Duplicación de Gen , Sistema Nervioso/metabolismo , Neuropéptidos/genética , Anémonas de Mar/fisiología , Animales , Venenos de Cnidarios/metabolismo , Evolución Molecular , Neuropéptidos/metabolismo , Filogenia
19.
Int J Mol Sci ; 24(5)2023 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-36901790

RESUMEN

Infections caused by multi-drug-resistant (MDR) bacteria are a global threat to human health. As venoms are the source of biochemically diverse bioactive proteins and peptides, we investigated the antimicrobial activity and murine skin infection model-based wound healing efficacy of a 13 kDa protein. The active component PaTx-II was isolated from the venom of Pseudechis australis (Australian King Brown or Mulga Snake). PaTx-II inhibited the growth of Gram-positive bacteria in vitro, with moderate potency (MICs of 25 µM) observed against S. aureus, E. aerogenes, and P. vulgaris. The antibiotic activity of PaTx-II was associated with the disruption of membrane integrity, pore formation, and lysis of bacterial cells, as evidenced by scanning and transmission microscopy. However, these effects were not observed with mammalian cells, and PaTx-II exhibited minimal cytotoxicity (CC50 > 1000 µM) toward skin/lung cells. Antimicrobial efficacy was then determined using a murine model of S. aureus skin infection. Topical application of PaTx-II (0.5 mg/kg) cleared S. aureus with concomitant increased vascularization and re-epithelialization, promoting wound healing. As small proteins and peptides can possess immunomodulatory effects to enhance microbial clearance, cytokines and collagen from the wound tissue samples were analyzed by immunoblots and immunoassays. The amounts of type I collagen in PaTx-II-treated sites were elevated compared to the vehicle controls, suggesting a potential role for collagen in facilitating the maturation of the dermal matrix during wound healing. Levels of the proinflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10), factors known to promote neovascularization, were substantially reduced by PaTx-II treatment. Further studies that characterize the contributions towards efficacy imparted by in vitro antimicrobial and immunomodulatory activity with PaTx-II are warranted.


Asunto(s)
Antiinfecciosos , Venenos de Cnidarios , Colubridae , Humanos , Animales , Ratones , Staphylococcus aureus , Australia , Cicatrización de Heridas , Antiinfecciosos/farmacología , Venenos de Cnidarios/farmacología , Colágeno/farmacología , Péptidos/farmacología , Citocinas/farmacología , Mamíferos
20.
Int J Mol Sci ; 24(10)2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37240317

RESUMEN

Jellyfish stings pose a major threat to swimmers and fishermen worldwide. These creatures have explosive cells containing one large secretory organelle called a nematocyst in their tentacles, which contains venom used to immobilize prey. Nemopilema nomurai, a venomous jellyfish belonging to the phylum Cnidaria, produces venom (NnV) comprising various toxins known for their lethal effects on many organisms. Of these toxins, metalloproteinases (which belong to the toxic protease family) play a significant role in local symptoms such as dermatitis and anaphylaxis, as well as systemic reactions such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Hence, a potential metalloproteinase inhibitor (MPI) could be a promising candidate for reducing the effects of venom toxicity. For this study, we retrieved the Nemopilema nomurai venom metalloproteinase sequence (NnV-MPs) from transcriptome data and modeled its three-dimensional structure using AlphaFold2 in a Google Colab notebook. We employed a pharmacoinformatics approach to screen 39 flavonoids and identify the most potent inhibitor against NnV-MP. Previous studies have demonstrated the efficacy of flavonoids against other animal venoms. Based on our analysis, Silymarin emerged as the top inhibitor through ADMET, docking, and molecular dynamics analyses. In silico simulations provide detailed information on the toxin and ligand binding affinity. Our results demonstrate that Silymarin's strong inhibitory effect on NnV-MP is driven by hydrophobic affinity and optimal hydrogen bonding. These findings suggest that Silymarin could serve as an effective inhibitor of NnV-MP, potentially reducing the toxicity associated with jellyfish envenomation.


Asunto(s)
Cnidarios , Venenos de Cnidarios , Escifozoos , Silimarina , Toxinas Biológicas , Animales , Venenos de Cnidarios/química , Escifozoos/química , Proteínas/análisis , Metaloproteasas/metabolismo
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