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1.
An Acad Bras Cienc ; 94(4): e20200976, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35946746

RESUMO

The scorpionfish Scorpaena plumieri is one of the most venomous fish species in the Brazilian coast. Amongst many biological activities, the S. plumieri fish venom (SpV) promotes hemagglutination. Although this activity appears to be associated to the presence of C-type lectins in the venom, it has not yet been chemically or functionally characterized. In the present work we sought to advance the characterization of the hemagglutinating activity associated to this venom. By fractionating SpV through saline precipitation followed by size exclusion chromatography we obtained two purified fractions - HF1 and HF3 - with Ca2+-dependent agglutinating activity against rabbit erythrocytes, which remained stable upon storage at 4 and -80oC. HF1 and HF3 were bacteriostatic against Gram-positive bacteria (Staphylococcus aureus), displaying minimum inhibitory concentration (MIC) of 50 and 200 µg/mL, respectively. In addition, a resazurin-based viability assay revealed that both fractions, at doses up to 370 µg/mL, were cytotoxic against tumor and non-tumor cell lines. Finally, a tendency towards edema formation could be detected when the fractions - particularly HF1 - were injected into mice footpads. We believe our data contribute to a better understanding of the biological properties of the so often neglected fish venoms.


Assuntos
Venenos de Peixe , Perciformes , Animais , Eritrócitos , Venenos de Peixe/farmacologia , Peixes , Camundongos , Coelhos , Pele
2.
Int J Mol Sci ; 23(7)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35408954

RESUMO

Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1ß/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulting in self-DNA leaks into the cytosol, and whether the DNA sensor cGAS and STING pathway participate in triggering the innate immune response. Employing a peritonitis mouse model, we found that the deficiency of the tlr2/tlr4, myd88 and trif results in decreased neutrophil influx to peritoneal cavities of mice, indicative that in addition to MyD88, TRIF contributes to neutrophilia triggered by TLR4 engagement by Natterin. Next, we demonstrated that gpcr91 deficiency in mice abolished the neutrophil recruitment after Natterin injection, but mice pre-treated with 2-deoxy-d-glucose that blocks glycolysis presented similar infiltration than WT Natterin-injected mice. In addition, we observed that, compared with the WT Natterin-injected mice, DPI and cyclosporin A treated mice had a lower number of neutrophils in the peritoneal exudate. The levels of dsDNA in the supernatant of the peritoneal exudate and processed IL-33 in the supernatant of the peritoneal exudate or cytoplasmic supernatant of the peritoneal cell lysate of WT Natterin-injected mice were several folds higher than those of the control mice. The recruitment of neutrophils to peritoneal cavity 2 h post-Natterin injection was intensely impaired in ifnar KO mice and partially in il-28r KO mice, but not in ifnγr KO mice. Finally, using cgas KO, sting KO, or irf3 KO mice we found that recruitment of neutrophils to peritoneal cavities was virtually abolished in response to Natterin. These findings reveal cytosolic DNA sensors as critical regulators for Natterin-induced neutrophilia.


Assuntos
Fator 88 de Diferenciação Mieloide , Receptor 4 Toll-Like , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , DNA , Venenos de Peixe , Proteínas de Membrana/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas Citotóxicas Formadoras de Poros , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
3.
BMC Genomics ; 23(1): 123, 2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35151271

RESUMO

BACKGROUND: The Natterin protein family was first discovered in the venom of the medically significant fish Thalassophryne nattereri, and over the last decade natterin-like genes have been identified in various organisms, notably performing immune-related functions. Previous findings support natterin-like genes as effector defense molecules able to activate multiprotein complexes driving the host innate immune response, notably due to the pore-forming function of the aerolysin superfamily members. Herein, employing a combination of the CRISPR/Cas9 depletion system, phenotype-based screening, and morphometric methods, we evaluated the role of one family member, LOC795232, in the embryonic development of zebrafish since it might be implicated in multiple roles and characterization of the null mutant is central for analysis of gene activity. RESULTS: Multiple sequence alignment revealed that the candidate natterin-like has the highest similarity to zebrafish aep1, a putative and better characterized fish-specific defense molecule from the same family. Compared to other species, zebrafish have many natterin-like copies. Whole-mount in situ hybridization confirmed the knockout and mutant embryos exhibited epiboly delay, growth retardation, yolk sac and heart edema, absent or diminished swim bladder, spinal defects, small eyes and head, heart dysfunction, and behavioral impairment. As previously demonstrated, ribonucleoproteins composed of Cas9 and duplex guide RNAs are effective at inducing mutations in the F0 zebrafish. CONCLUSIONS: The considerably high natterin-like copies in zebrafish compared to other species might be due to the teleost-specific whole genome duplication and followed by subfunctionalization or neofunctionalization. In the present work, we described some of the natterin-like features in the zebrafish development and infer that natterin-like proteins potentially contribute to the embryonary development and immune response.


Assuntos
Venenos de Peixe , Peixe-Zebra , Animais , Sistemas CRISPR-Cas , Desenvolvimento Embrionário/genética , Proteínas Citotóxicas Formadoras de Poros , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
4.
Toxins (Basel) ; 14(2)2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35202177

RESUMO

Tetrodotoxin (TTX)-bearing fish ingest TTX from their preys through the food chain and accumulate TTX in their bodies. Although a wide variety of TTX-bearing organisms have been reported, the missing link in the TTX supply chain has not been elucidated completely. Here, we investigated the composition of TTX and 5,6,11-trideoxyTTX in juveniles of the pufferfish, Chelonodon patoca, and toxic goby, Yongeichthys criniger, using LC-MS/MS, to resolve the missing link in the TTX supply chain. The TTX concentration varied among samples from different localities, sampling periods and fish species. In the samples from the same locality, the TTX concentration was significantly higher in the toxic goby juveniles than in the pufferfish juveniles. The concentration of TTX in all the pufferfish juveniles was significantly higher than that of 5,6,11-trideoxyTTX, whereas the compositional ratio of TTX and 5,6,11-trideoxyTTX in the goby was different among sampling localities. However, the TTX/5,6,11-trideoxyTTX ratio in the goby was not different among samples collected from the same locality at different periods. Based on a species-specific PCR, the detection rate of the toxic flatworm (Planocera multitentaculata)-specific sequence (cytochrome c oxidase subunit I) also varied between the intestinal contents of the pufferfish and toxic goby collected at different localities and periods. These results suggest that although the larvae of the toxic flatworm are likely to be responsible for the toxification of the pufferfish and toxic goby juveniles by TTX, these fish juveniles are also likely to feed on other TTX-bearing organisms depending on their habitat, and they also possess different accumulation mechanisms of TTX and 5,6,11-trideoxyTTX.


Assuntos
Venenos de Peixe/análise , Venenos de Peixe/química , Venenos de Peixe/toxicidade , Peixes , Tetraodontiformes , Tetrodotoxina/análise , Tetrodotoxina/toxicidade , Animais , Cromatografia Líquida , Japão , Espectrometria de Massas em Tandem
5.
Clin Toxicol (Phila) ; 60(3): 392-396, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34374612

RESUMO

BACKGROUND: Ciguatera fish poisoning (CFP) is the most common poisoning from seafood consumption with an estimated 50,000 cases per year worldwide. Attention to this malady in the English language literature has grown over the past five decades. Endemic areas include the South Pacific Ocean and the Caribbean Sea. It is likely that CFP has been present since ancient times, but records to substantiate this are scarce. OBJECTIVE: This historical review looks for clues in earlier writings about potential encounters with CFP as Europeans sailed farther from home into these endemic regions with little idea of what awaited them. We divide these records into the Age of Discovery and the Age of Enlightenment. METHODS: Review of available historical texts written by or about early European explorers with descriptions of illness attributed to eating fish. RESULTS: Fish poisonings appear in translated writings of early Spanish and Portuguese explorers in the 1500s, the writings of Captain James Cook's voyages to the South Pacific, and in Captain William Bligh's fateful voyage after the Mutiny on the Bounty. The most credible description of CFP comes from an early author in the Spanish colony of Cuba in the late 1700s. CONCLUSIONS: Although the quality of the observations varies, Parra in Cuba likely experienced CFP. Plausible CFP for Cook in the South Pacific and Locke in the Bahamas as both have elements of CFP. The descriptions from Quiros, Anghira, and Bligh lack sufficient detail to verify or to refute completely the possibility of CFP.


Assuntos
Intoxicação por Ciguatera , Venenos de Peixe , Doenças Transmitidas por Alimentos , Animais , Região do Caribe , Intoxicação por Ciguatera/epidemiologia , Peixes , Doenças Transmitidas por Alimentos/etiologia , Humanos
6.
Peptides ; 148: 170686, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34774923

RESUMO

Antimicrobial peptides (AMPs) are known to play an important role in natural immunity. Moreover, the diverse biological activities of AMPs showed great potency in treating many diseases. Thus, in this study, we used an AMP, that is, pardaxin, from a marine fish (Pardachirus marmoratus), which has been reported to possess antibacterial and antitumor activities. We first investigated the mechanisms of pardaxin in promoting osteogenic differentiation in vitro and in vivo. As per our data, it was determined that pardaxin could stimulate bone morphogenetic protein-2 (BMP-2) and downstream cascade. The activation of BMP-2 could further induce the phosphorylation of Akt and extracellular signal-regulated kinase (ERK). Additionally, the activation of p-Akt and p-ERK could prompt the elevation and translocation of runt-related transcription factor 2 (runx-2), which is associated with osteoblast differentiation. The translocation of runx-2 initiated transcription and translation of osteogenesis-related markers, including alkaline phosphatase (ALP), osterix, and osteocalcin. Pardaxin significantly facilitated preosteoblast cells in mineralization and reversed dexamethasone- (DM-) induced zebrafish bone formation deficiency by activating the osteogenesis pathway. Therefore, we suggest that pardaxin could be a possible candidate for osteoporosis treatment and a promising therapeutic agent.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Calcificação Fisiológica , Venenos de Peixe/farmacologia , Osteogênese , Fosfatase Alcalina/genética , Animais , Peptídeos Antimicrobianos/farmacologia , Linhagem Celular , Regulação da Expressão Gênica , Camundongos , Osteocalcina/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia
7.
Appl Biochem Biotechnol ; 194(1): 354-367, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34843077

RESUMO

Gastric cancer is a pathological condition induced by the bacteria Helicobacter pylori. Targeting the key virulence factors of H. pylori causing gastric cancer is a promising method for treating gastric cancer. Recently, research has been focused on analyzing the adrenergic, cholinergic, and anti-cancer properties of their venom proteins. Testing the anti-cancer activity of the lethal proteins in the venom of P. volitans provides a bioactive compound for cancer treatment. Still, it is also helpful to eliminate the ecological imbalance caused by these fish in the marine environment. This study focuses on an in silico approach using Z-dock to analyze the bioactive prospective of the venom proteins of P. volitans against the essential virulence proteins of H. pylori responsible for inducing cancer. Our in silico docking study using a computational model of the venom proteins and H. pylori proteins has displayed the possible interactions between these proteins. The results revealed that P. volitans hyaluronidase and PV toxin's venom proteins effectively interact with H. pylori proteins Cag A, Cag L, GGT, Cag D, and urease that may be promising proteins in cancer therapy.


Assuntos
Proteínas de Bactérias/química , Proteínas de Peixes/química , Venenos de Peixe/química , Helicobacter pylori/química , Simulação de Acoplamento Molecular , Perciformes , Fatores de Virulência/química , Animais , Humanos , Neoplasias Gástricas
8.
Toxins (Basel) ; 13(12)2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34941715

RESUMO

The majority of the effects observed upon envenomation by scorpaenoid fish species can be reproduced by the cytolysins present in their venoms. Fish cytolysins are multifunctional proteins that elicit lethal, cytolytic, cardiovascular, inflammatory, nociceptive, and neuromuscular activities, representing a novel class of protein toxins. These large proteins (MW 150-320 kDa) are composed by two different subunits, termed α and ß, with about 700 amino acid residues each, being usually active in oligomeric form. There is a high degree of similarity between the primary sequences of cytolysins from different fish species. This suggests these molecules share similar mechanisms of action, which, at least regarding the cytolytic activity, has been proved to involve pore formation. Although the remaining components of fish venoms have interesting biological activities, fish cytolysins stand out because of their multifunctional nature and their ability to reproduce the main events of envenomation on their own. Considerable knowledge about fish cytolysins has been accumulated over the years, although there remains much to be unveiled. In this review, we compiled and compared the current information on the biochemical aspects and pharmacological activities of fish cytolysins, going over their structures, activities, mechanisms of action, and perspectives for the future.


Assuntos
Citotoxinas/análise , Citotoxinas/toxicidade , Venenos de Peixe/análise , Venenos de Peixe/toxicidade , Alimentos Marinhos/análise , Alimentos Marinhos/toxicidade , Toxinas Biológicas/análise , Toxinas Biológicas/toxicidade , Animais , Estrutura Molecular
10.
Toxins (Basel) ; 13(8)2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34437409

RESUMO

Since the first record of the five founder members of the group of Natterin proteins in the venom of the medically significant fish Thalassophryne nattereri, new sequences have been identified in other species. In this work, we performed a detailed screening using available genome databases across a wide range of species to identify sequence members of the Natterin group, sequence similarities, conserved domains, and evolutionary relationships. The high-throughput tools have enabled us to dramatically expand the number of members within this group of proteins, which has a remote origin (around 400 million years ago) and is spread across Eukarya organisms, even in plants and primitive Agnathans jawless fish. Overall, the survey resulted in 331 species presenting Natterin-like proteins, mainly fish, and 859 putative genes. Besides fish, the groups with more species included in our analysis were insects and birds. The number and variety of annotations increased the knowledge of the obtained sequences in detail, such as the conserved motif AGIP in the pore-forming loop involved in the transmembrane barrel insertion, allowing us to classify them as important constituents of the innate immune defense system as effector molecules activating immune cells by interacting with conserved intracellular signaling mechanisms in the hosts.


Assuntos
Venenos de Peixe , Proteínas Citotóxicas Formadoras de Poros , Animais , Venenos de Peixe/química , Venenos de Peixe/genética , Venenos de Peixe/imunologia , Estrutura Molecular , Filogenia , Proteínas Citotóxicas Formadoras de Poros/química , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/imunologia
11.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281170

RESUMO

miRNAs regulate gene expression post-transcriptionally in various processes, e.g., immunity, development, and diseases. Since their experimental analysis is complex, in silico target prediction is important for directing investigations. TnP is a candidate peptide for anti-inflammatory therapy, first discovered in the venom of Thalassophryne nattereri, which led to miRNAs overexpression in LPS-inflamed zebrafish post-treatment. This work aimed to predict miR-21, miR-122, miR-731, and miR-26 targets using overlapped results of DIANA microT-CDS and TargetScanFish software. This study described 513 miRNAs targets using highly specific thresholds. Using Gene Ontology over-representation analysis, we identified their main roles in regulating gene expression, neurogenesis, DNA-binding, transcription regulation, immune system process, and inflammatory response. miRNAs act in post-transcriptional regulation, but we revealed that their targets are strongly related to expression regulation at the transcriptional level, e.g., transcription factors proteins. A few predicted genes participated concomitantly in many biological processes and molecular functions, such as foxo3a, rbpjb, rxrbb, tyrobp, hes6, zic5, smad1, e2f7, and npas4a. Others were particularly involved in innate immunity regulation: il17a/f2, pik3r3b, and nlrc6. Together, these findings not only provide new insights into the miRNAs mode of action but also raise hope for TnP therapy and may direct future experimental investigations.


Assuntos
Anti-Inflamatórios/farmacologia , Venenos de Peixe/farmacologia , Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Peptídeos/farmacologia , Animais , Biologia Computacional/métodos , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Ontologia Genética , Imunidade Inata/genética , Lipopolissacarídeos/farmacologia , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Peixe-Zebra
12.
Asian Pac J Cancer Prev ; 22(7): 2295-2302, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34319055

RESUMO

Background: Glioblastoma is the most common primary malignant tumor of the central nervous system that occurs in the spinal cord or brain. Pseudosynanceia melanostigma is a venomous stonefish in the Persian Gulf, which our knowledge about is little. This study's goal is to investigate the toxicity of stonefish crude venom on mitochondria isolated from U87 cells. Methods: In the first stage, we extracted venom stonefish and then isolated mitochondria have exposed to different concentrations of venom. Finally, mitochondrial toxicity parameters (Succinate dehydrogenase (SDH) activity, Reactive oxygen species (ROS), cytochrome c release, Mitochondrial Membrane Potential (MMP), and mitochondrial swelling) have evaluated. Results: To determine mitochondrial parameters, we used 115, 230, and 460 µg/ml concentrations. The results of our study show that the venom of stonefish selectively increases upstream parameters of apoptosis such as mitochondrial swelling, cytochrome c release, MMP collapse and ROS. Conclusion: This study suggests that Pseudosynanceia melanostigma crude venom has selectively caused toxicity by increasing active mitochondrial oxygen radicals. This venom could potentially be a candidate for the treatment of glioblastoma.


Assuntos
Venenos de Peixe/farmacologia , Peixes Venenosos , Glioblastoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocromos/efeitos dos fármacos , Oceano Índico , Potenciais da Membrana/efeitos dos fármacos , Espécies Reativas de Oxigênio , Succinato Desidrogenase/efeitos dos fármacos
13.
Mar Drugs ; 19(6)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073964

RESUMO

Stonefish are regarded as one of the most venomous fish in the world. Research on stonefish venom has chiefly focused on the in vitro and in vivo neurological, cardiovascular, cytotoxic and nociceptive effects of the venom. The last literature review on stonefish venom was published over a decade ago, and much has changed in the field since. In this review, we have generated a global map of the current distribution of all stonefish (Synanceia) species, presented a table of clinical case reports and provided up-to-date information about the development of polyspecific stonefish antivenom. We have also presented an overview of recent advancements in the biomolecular composition of stonefish venom, including the analysis of transcriptomic and proteomic data from Synanceia horrida venom gland. Moreover, this review highlights the need for further research on the composition and properties of stonefish venom, which may reveal novel molecules for drug discovery, development or other novel physiological uses.


Assuntos
Mordeduras e Picadas/epidemiologia , Mordeduras e Picadas/terapia , Venenos de Peixe/envenenamento , Peixes Venenosos , Animais , Mordeduras e Picadas/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Venenos de Peixe/análise , Venenos de Peixe/química , Peixes Venenosos/fisiologia , Geografia , Humanos , Oceano Índico/epidemiologia , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/etiologia , Doenças Neuromusculares/terapia , Oceano Pacífico/epidemiologia
14.
Toxicol Lett ; 346: 16-22, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33878385

RESUMO

The reef stonefish (Synanceia verrucosa) is a venomous fish which causes excruciatingly painful envenomations. While some research on the pathophysiology and functions of the venom have been conducted, there are still some gaps in the understanding of the venom effects due to the extreme lability of fish venom toxins and the lack of available testing platforms. Here we set out to assess new functions of the venom whilst also attempting to address some unclear pathophysiological effects from previous literature. Utilising a biolayer interferometry assay, our results highlight that the venom binds to the orthosteric site of the α-1 nicotinic acetylcholine receptor as well as the domain IV of voltage-gated Ca2+ (CaV1.2) channel mimotopes. Both these results add some clarity to the previously ambiguous literature. We further assessed the coagulotoxic effects of the venom using thromboelastography and Stago STA-R Max coagulation analyser assays. We reveal that the venom produced anticoagulant activity and significantly delayed time until clot formation of recalcified human plasma which is likely through the degradation of phospholipids. There was a difference between fresh and lyophilised venom activity toward the nicotinic acetylcholine receptor mimotopes and coagulation assays, whilst no difference was observed in the activity toward the domain IV of CaV1.2 mimotopes. This research adds further insights into the neglected area of fish venom whilst also highlighting the extreme labile nature of fish venom toxins.


Assuntos
Venenos de Peixe/toxicidade , Peixes/fisiologia , Receptores Nicotínicos/química , Animais , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Plasma/química , Domínios Proteicos , Tromboelastografia
15.
Cell Biol Int ; 45(8): 1698-1709, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33818831

RESUMO

This study investigates the antioxidant and antidiabetic activity of the WL15 peptide derived from Channa striatus on regulating the antioxidant property in the rat skeletal muscle cell line (L6) and enhancing glucose uptake via glucose metabolism. Increased oxidative stress plays a major role in the development of diabetes and its complications. Strategies are needed to mitigate the oxidative stress that can reduce these pathogenic processes. Our results showed that with treatment with WL15 peptide, the reactive oxygen species significantly decreased in L6 myotubes in a dose-dependent manner, and increased antioxidant enzymes help to prevent the formation of lipid peroxidation in L6 myotubes. The cytotoxicity of WL15 is evaluated in the L6 cells and found to be non-cytotoxic at the tested concentration. Also, for the analysis of glucose uptake activity in L6 cells, the 2-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxy- d -glucose assay was performed in the presence of wortmannin and genistein inhibitors. WL15 demonstrated antidiabetic activities through a dose-dependent increase in glucose uptake (64%) and glycogen storage (7.8 mM). The optimal concentration for the maximum activity was found to be 50 µM. In addition, studies of gene expression in L6 myotubes demonstrated upregulation of antioxidant genes and genes involved in the pathway of insulin signaling. In cell-based assays, WL15 peptide decreased intracellular reactive oxygen species levels and demonstrated insulin mimic activity by enhancing the primary genes involved in the insulin signaling pathway by increased glucose uptake indicating that glucose transporter type 4 (GLUT4) is regulated from the intracellular pool to the plasma membrane.


Assuntos
Cisteína/metabolismo , Venenos de Peixe/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/toxicidade , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Venenos de Peixe/isolamento & purificação , Glucose/administração & dosagem , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Fragmentos de Peptídeos/isolamento & purificação , Ratos
16.
Toxicon ; 194: 63-69, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33631138

RESUMO

Despite comprising over half of the biodiversity of living venomous vertebrates, fish venoms are comparatively understudied. Venom from the lesser weever fish (Echiichthys vipera syn. Trachinus vipera) has received only cursory attention despite containing one of the most potent venom toxins (trachinine). Literature records are further complicated by early studies combining the venom with that of the related greater weever (Trachinus draco). The current study used a chicken chorioallantoic membrane assay to investigate venom bioactivity following the application of measured quantities of crude venom to a major bilateral vein at 1 cm distance from the heart. The venom had a dose-dependent effect on survival rate and exhibited dose-dependent cardiotoxic properties at day six of development. Crude E. vipera triggered tachycardia at doses of 37.58 and 44.88 µg/µL and bradycardia at 77.4 µg/µL. The three highest doses (65.73, 77.4 and 151.24 µg/µL) caused significant mortality. These data also suggested intra-specific variation in E. vipera venom potency. Unlike a number of other piscine venoms, E. vipera venom was not haemorrhagic at the concentrations assayed.


Assuntos
Venenos de Peixe , Perciformes , Viperidae , Animais , Venenos de Peixe/toxicidade , Peixes , Peçonhas , Venenos de Víboras/toxicidade
17.
Mar Drugs ; 20(1)2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-35049882

RESUMO

Animal venoms offer a valuable source of potent new drug leads, but their mechanisms of action are largely unknown. We therefore developed a novel network pharmacology approach based on multi-omics functional data integration to predict how stingray venom disrupts the physiological systems of target animals. We integrated 10 million transcripts from five stingray venom transcriptomes and 848,640 records from three high-content venom bioactivity datasets into a large functional data network. The network featured 216 signaling pathways, 29 of which were shared and targeted by 70 transcripts and 70 bioactivity hits. The network revealed clusters for single envenomation outcomes, such as pain, cardiotoxicity and hemorrhage. We carried out a detailed analysis of the pain cluster representing a primary envenomation symptom, revealing bibrotoxin and cholecystotoxin-like transcripts encoding pain-inducing candidate proteins in stingray venom. The cluster also suggested that such pain-inducing toxins primarily activate the inositol-3-phosphate receptor cascade, inducing intracellular calcium release. We also found strong evidence for synergistic activity among these candidates, with nerve growth factors cooperating with the most abundant translationally-controlled tumor proteins to activate pain signaling pathways. Our network pharmacology approach, here applied to stingray venom, can be used as a template for drug discovery in neglected venomous species.


Assuntos
Venenos de Peixe/farmacologia , Rajidae , Animais , Organismos Aquáticos , Venenos de Peixe/química , Farmacologia em Rede
18.
Toxins (Basel) ; 14(1)2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-35050979

RESUMO

TmC4-47.2 is a toxin with myotoxic activity found in the venom of Thalassophryne maculosa, a venomous fish commonly found in Latin America whose envenomation produces an injury characterized by delayed neutrophil migration, production of major pro-inflammatory cytokines, and necrosis at the wound site, as well as a specific systemic immune response. However, there are few studies on the protein structure and functions associated with it. Here, the toxin was identified from the crude venom by chromatography and protein purification systems. TmC4-47.2 shows high homology with the Nattectin from Thalassophryne nattereri venom, with 6 cysteines and QPD domain for binding to galactose. We confirm its hemagglutinating and microbicide abilities independent of carbohydrate binding, supporting its classification as a nattectin-like lectin. After performing the characterization of TmC4-47.2, we verified its ability to induce an increase in the rolling and adherence of leukocytes in cremaster post-capillary venules dependent on the α5ß1 integrin. Finally, we could observe the inflammatory activity of TmC4-47.2 through the production of IL-6 and eotaxin in the peritoneal cavity with sustained recruitment of eosinophils and neutrophils up to 24 h. Together, our study characterized a nattectin-like protein from T. maculosa, pointing to its role as a molecule involved in the carbohydrate-independent agglutination response and modulation of eosinophilic and neutrophilic inflammation.


Assuntos
Batracoidiformes , Venenos de Peixe/química , Lectinas Tipo C/química , Toxinas Marinhas/química , Sequência de Aminoácidos , Animais , Venenos de Peixe/farmacologia , Toxinas Marinhas/farmacologia
19.
Int Immunopharmacol ; 91: 107287, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33378723

RESUMO

Natterin is an aerolysin-like pore-forming toxin responsible for the toxic effects of the venom of the medically significant fish Thalassophryne nattereri. Using a combination of pharmacologic and genetic loss-of-function approaches we conduct a systematic investigation of the regulatory mechanisms that control Natterin-induced neutrophilic inflammation in the peritonitis model. Our data confirmed the capacity of Natterin to induce a strong and sustained neutrophilic inflammation leading to systemic inflammatory lung infiltration and revealed overlapping regulatory paths in its control. We found that Natterin induced the extracellular release of mature IL-1ß and the sustained production of IL-33 by bronchial epithelial cells. We confirmed the dependence of both ST2/IL-33 and IL-17A/IL-17RA signaling on the local and systemic neutrophils migration, as well as the crucial role of IL-1α, caspase-1 and caspase-11 for neutrophilic inflammation. The inflammation triggered by Natterin was a gasdermin-D-dependent inflammasome process, despite the cells did not die by pyroptosis. Finally, neutrophilic inflammation was mediated by non-canonical NLRP6 and NLRC4 adaptors through ASC interaction, independent of NLRP3. Our data highlight that the inflammatory process dependent on non-canonical inflammasome activation can be a target for pharmacological intervention in accidents by T. nattereri, which does not have adequate specific therapy.


Assuntos
Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Venenos de Peixe/farmacologia , Inflamassomos/metabolismo , Inflamação/imunologia , Interleucina-1beta/metabolismo , Pulmão/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Peritonite/induzido quimicamente , Receptores de Superfície Celular/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 1/genética , Caspases Iniciadoras/genética , Feminino , Inflamassomos/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/enzimologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/enzimologia , Neutrófilos/imunologia , Peritonite/enzimologia , Peritonite/genética , Peritonite/imunologia , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Transdução de Sinais
20.
Toxicon ; 187: 129-135, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32916140

RESUMO

Ocean organisms live in competitive environments that demand the production of poisons and toxins. In some cases, these substances have been used in the pharmaceutical industry for human disease treatments. Most fish poisons generally have potent cytolytic activity, probably through cardiovascular and neuromuscular effects. In the case of marine stingrays, the injuries made by their tail venom apparatus are caused by the mechanical penetration of their sting and a subsequent venom release. This study focused on the evaluation of substances with cytotoxic activity in the epithelium that covers the venom apparatus from the marine stingray Hypanus dipterurus. To demonstrate the above, the hemolytic, proteolytic and cytotoxic capacities of H. dipterurus epithelium substances were determined. Discs impregnated with epithelial extract were used on blood agar plates. The proteolytic activity was analyzed using casein as substrate and for gelatin the liquefaction activity test. To determine the cytotoxicity degree of the extracts, the proliferation and cell viability MTT bioassay was implemented on human cervical carcinoma cells (HeLa). The results showed that no hemolytic or proteolytic activity existed against casein associated with the epithelial extract, but gelatin hydrolysis and cytotoxic activity against the HeLa cell line were observed. This study concludes that the substances found in the epithelium covering the H. dipterurus stingray venom apparatus are a mixture of various proteins, among which, glycosylated anionic proteins represent a potential source of molecules with cytotoxic and hydrolytic activity.


Assuntos
Venenos de Peixe , Rajidae , Animais , Células Epiteliais , Células HeLa , Hemólise , Humanos
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