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1.
Arch Microbiol ; 204(1): 27, 2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34921623

RESUMO

Induratia spp. fungi have been poorly evaluated for their non-volatile secondary metabolites. In the present work, we evaluated the effects of non-volatile secondary metabolites released into the culture medium by Induratia spp. upon toxic alterations induced by Bothrops spp. venoms. B. atrox venom phospholipase was inhibited by Induratia spp. around 12 and 16%. The extracts of the two strains inhibited 12-25% of the hemolysis induced by B.moojeni venom. Thrombolysis was inhibited by 30-60% by the compounds present in both extracts. The coagulation induced by B. moojeni venom was prolonged by 26-41 s by the action of the extracts of I. coffeana. The fungal extracts did not exert any cytotoxic effect, nor did they induce any alteration in the other evaluated substrates show the potential use of non-volatile metabolites produced by the fungi evaluated as enzyme modulators, especially for proteases with a fundamental role in human hemostasis.


Assuntos
Endopeptidases , Hemostasia , Peptídeo Hidrolases , Xylariales/química , Animais , Bothrops , Morte Celular , Humanos , Venenos de Serpentes
2.
Int J Biol Macromol ; 192: 1040-1057, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34656540

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent responsible for the Coronavirus Disease-2019 (COVID-19) pandemic, has infected over 185 million individuals across 200 countries since December 2019 resulting in 4.0 million deaths. While COVID-19 is primarily associated with respiratory illnesses, an increasing number of clinical reports indicate that severely ill patients often develop thrombotic complications that are associated with increased mortality. As a consequence, treatment strategies that target COVID-associated thrombosis are of utmost clinical importance. An array of pharmacologically active compounds from natural products exhibit effects on blood coagulation pathways, and have generated interest for their potential therapeutic applications towards thrombotic diseases. In particular, a number of snake venom compounds exhibit high specificity on different blood coagulation factors and represent excellent tools that could be utilized to treat thrombosis. The aim of this review is to provide a brief summary of the current understanding of COVID-19 associated thrombosis, and highlight several snake venom compounds that could be utilized as antithrombotic agents to target this disease.


Assuntos
COVID-19/sangue , Fibrinolíticos/farmacologia , Venenos de Serpentes/farmacologia , Trombose/tratamento farmacológico , Trombose/virologia , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/patologia , Humanos , Pandemias , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade
3.
Protein J ; 40(6): 799-841, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34499333

RESUMO

As expected, several new variants of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) emerged and have been detected around the world throughout this Coronavirus Disease of 2019 (COVID-19) pandemic. Currently, there is no specific developed drug against COVID-19 and the challenge of developing effective antiviral strategies based on natural agents with different mechanisms of action becomes an urgent need and requires identification of genetic differences among variants. Such data is used to improve therapeutics to combat SARS-CoV-2 variants. Nature is known to offer many biotherapeutics from animal venoms, algae and plant that have been historically used in traditional medicine. Among these bioresources, snake venom displays many bioactivities of interest such as antiviral, antiplatelet, antithrombotic, anti-inflammatory, antimicrobial and antitumoral. COVID-19 is a viral respiratory sickness due to SARS-CoV-2 which induces thrombotic disorders due to cytokine storm, platelet hyperactivation and endothelial dysfunction. This review aims to: (1) present an overview on the infection, the developed thrombo-inflammatory responses and mechanisms of induced thrombosis of COVID-19 compared to other similar pathogenesis; (2) underline the role of natural compounds such as anticoagulant, antiplatelet and thrombolytic agents; (3) investigate the management of coagulopathy related to COVID-19 and provide insight on therapeutic such as venom compounds. We also summarize the updated advances on antiviral proteins and peptides derived from snake venoms that could weaken coagulopathy characterizing COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Peptídeos/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Venenos de Serpentes/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Humanos , Pandemias , Peptídeos/química , SARS-CoV-2/patogenicidade , Venenos de Serpentes/química
4.
J Proteomics ; 249: 104379, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34534714

RESUMO

We report the first proteomics analyses of the venoms of two poorly studied snakes, the Manabi hognosed pitviper Porthidium arcosae endemic to the western coastal province of Manabí (Ecuador), and the Costa Rican hognosed pitviper P. volcanicum with distribution restricted to South Pacific Costa Rica and western Panamá. These venom proteomes share a conserved compositional pattern reported in four other congeneric species within the clade of South American Porthidium species, P. nasutum, P. lansbergii, P. ophryomegas, and P. porrasi. The paraspecific immunorecognition profile of antivenoms produced in Costa Rica (ICP polyvalent), Perú (Instituto Nacional de Salud) and Brazil (soro antibotrópico pentavalente, SAB, from Instituto Butantan) against the venom of P. arcosae was investigated through a third-generation antivenomics approach. The maximal venom-binding capacities of the investigated antivenoms were 97.1 mg, 21.8 mg, and 25.7 mg of P. arcosae venom proteins per gram of SAB, ICP, and INS-PERU antibody molecules, respectively, which translate into 28.4 mg, 13.1 mg, and 15.2 mg of total venom proteins bound per vial of SAB, ICP, and INS-PERU AV. The antivenomics results suggest that 21.8%, 7.8% and 6.1% of the SAB, ICP, and INS-PERU antibody molecules recognized P. arcosae venom toxins. The SAB antivenom neutralized P. arcosae venom's lethality in mice with an ED50 of 31.3 mgV/g SAB AV. This preclinical neutralization paraspecificity points to Brazilian SAB as a promising candidate for the treatment of envenomings by Ecuadorian P. arcosae. BIOLOGICAL SIGNIFICANCE: Assessing the preclinical efficacy profile of antivenoms against homologous and heterologous medically relevant snake venoms represents an important goal towards defining the biogeographic range of their clinical utility. This is particularly relevant in regions, such as Mesoamerica, where a small number of pharmaceutical companies produce antivenoms against the venoms of a small number of species of maximum medical relevance among the local rich herpetofauna, leaving a wide range of snakes of secondary medical relevance, but also causing life-threatening human envenomings without nominal clinical coverage. This work is part of a larger project aiming at mapping the immunological characteristics of antivenoms generated in Latin American countries towards venoms of such poorly studied snakes of the local and neighboring countries' herpetofauna. Here we report the proteomics characterization of the Manabi hognosed pitviper Porthidium arcosae endemic to the western coastal province of Manabí (Ecuador), and the Costa Rican hognosed pitviper P. volcanicum with distribution restricted to southwestern Costa Rica, the antivenomics assessment of three bothropoid commercial antivenoms produced in Costa Rica, Perú, and Brazil against the venom components of P. arcosae, and the in vivo capacity of the Brazilian soro antibotrópico pentavalente (SAB) from Instituto Butantan to neutralize the murine lethality of P. arcosae venom. The preclinical paraspecific ED50 of 31.3 mg of P. arcosae venom per gram of antivenom points to Brazilian SAB as a promising candidate for the treatment of envenomings by the Manabi hognosed pitviper P. arcosae.


Assuntos
Venenos de Crotalídeos , Crotalinae , Animais , Antivenenos , Camundongos , Proteoma , Proteômica , Venenos de Serpentes
5.
Toxicon ; 202: 46-52, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34516995

RESUMO

Acute kidney injury pathogenesis in envenoming by snakes is multifactorial and involves immunologic reactions, hemodynamic disturbances, and direct nephrotoxicity. Sildenafil (SFC), a phosphodiesterase 5 inhibitor, has been reported to protect against pathological kidney changes. OBJECTIVE: This study aimed to investigate the protective effect of sildenafil against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity. METHODS: Kidneys from Wistar rats (n = 6, weighing 260-300 g) were isolated and divided into four groups: (1) perfused with a modified Krebs-Henseleit solution (MKHS) containing 6 g% of bovine serum albumin; (2) administered 3 µg/mL SFC; (3) perfused with 3 µg/mL BaV; and (4) administered SFC + BaV, both at 3 µg/mL. Subsequently, the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl-, respectively) were evaluated. The cyclic guanosine monophosphate (cGMP) levels were analyzed in the perfusate, and the kidneys were removed to perform oxidative stress and histopathological analyses. RESULTS: All renal parameters evaluated were reduced with BaV. In the SFC + BaV group, SFC restored PP to normal values and promoted a significant increase in %TNa+ and %TCl-. cGMP levels were increased in the SFC + BaV group. The oxidative stress biomarkers, malondialdehyde (MDA) and glutathione (GSH), were reduced by BaV. In the SFC + BaV group, a decrease in MDA without an increase in GSH was observed. These findings were confirmed by histological analysis, which showed improvement mainly in tubulis. CONCLUSION: Our data suggest the involvement of phosphodiesterase-5 and cGMP in BaV-induced nephrotoxicity since its effects were attenuated by the administration of SFC.


Assuntos
Bothrops , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Rim , Inibidores da Fosfodiesterase 5/uso terapêutico , Ratos , Ratos Wistar , Citrato de Sildenafila/uso terapêutico , Venenos de Serpentes/toxicidade
6.
Anal Chem ; 93(42): 14025-14030, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34528790

RESUMO

The identification and discrimination of snake venom are highly desired for timely clinical treatment. However, the complex components in snake venom make it a great challenge to achieve rapid and accurate identification. Inspired by the organism's taste sensing system, a fluorescent sensor array that could differentiate snake venoms was fabricated. The interaction of snake venoms with different fluorescent dyes in the sensor array gave rich information, based on which efficient detection of complex snake venom was achieved. The main six proteins of snake venom in the same concentration, different concentrations, and their mixtures were identified with 100% accuracy. Furthermore, seven snake venoms belonging to different snake families were discriminated in PBS buffer and human plasma. Interferents of bovine serum albumin (BSA), thrombin, and transferrin (TRF) demonstrated the practicability of the fluorescent sensor array. This strategy of a multiresponse sensor array provides an effective method for accurate and rapid venom toxicology analysis, benefiting early and timely clinical diagnosis and treatment.


Assuntos
Venenos de Serpentes , Serpentes , Animais , Humanos , Venenos de Serpentes/toxicidade
7.
Acta Trop ; 224: 106119, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34481791

RESUMO

In South America there are three snake genera with predominantly neurotoxic venoms: Crotalus, Micrurus and Hydrophis, which include nine species/subspecies, 97 species and a single marine species, respectively. Although accidents with neurotoxic venoms are less frequent than those with anticoagulant, cytotoxic or necrotic venoms (e.g. from Bothrops), they are of major public health importance. Venoms from genus Crotalus have been extensively studied, while data on the venoms from the other two genera are very limited, especially for Hydrophis. The venoms of North and South American Crotalus species show biochemical and physiopathological differences. The former species cause bothrops-like envenomation symptoms, while the latter mainly have neurotoxic and myotoxic effects, leading to respiratory paralysis and, occasionally, renal failure by myoglobinuria and death, often with no local lesions. Micrurus and Hydrophis also cause neurotoxic envenomations. Many studies have isolated, identified and characterized new enzymes and toxins, thus expanding the knowledge of snake venom composition. The present review summarizes the currently available information on neurotoxic venoms from South American snakes, with a focus on protein composition and toxicological properties. It also includes some comments concerning potential medical applications of elapid and crotalic toxins.


Assuntos
Bothrops , Crotalus , Animais , Elapidae , Venenos de Serpentes/toxicidade , América do Sul
8.
Toxicon ; 201: 105-114, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34425141

RESUMO

Snake venoms are substances mostly composed by proteins and peptides with high biological activity. Local and systemic effects culminate in clinical manifestations induced by these substances. Pain is the most uncomfortable condition, but it has not been well investigated. This review discusses Bothrops snakebite-induced nociception, highlighting molecules involved in the mediation of this process and perspectives in treatment of pain induced by Bothrops snake venoms (B. alternatus, B. asper, B. atrox, B. insularis, B. jararaca, B. pirajai, B. jararacussu, B. lanceolatus, B. leucurus, B. mattogrossensis, B. moojeni). We highlight, the understanding of the nociceptive signaling, especially in snakebite, enables more efficient treatment approaches. Finally, future perspectives for pain treatment concerning snakebite patients are discussed.


Assuntos
Bothrops , Venenos de Crotalídeos , Mordeduras de Serpentes , Animais , Venenos de Crotalídeos/toxicidade , Humanos , Nociceptividade , Dor/induzido quimicamente , Dor/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/toxicidade
9.
Photochem Photobiol Sci ; 20(8): 1069-1085, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34341968

RESUMO

The purpose of this study was to assess the topic use of Sebastiania hispida extract and low-level gallium-arsenide laser irradiation (GaAs, 904 nm) to reduce the local myonecrosis and edema of Bothrops moojeni snake venom-injected gastrocnemius. Wistar rats receiving intramuscular venom injection (VBm) were compared with saline control (S) and envenomed rats receiving local exposure to plant extract (VExt) or laser irradiation (VL). The phytochemistry and thin-layer chromatography of S. hispida extract indicated the presence of phenolic compounds like gallic acid and flavonoids including quercetin. Gastrocnemius of VExt and VL groups had a significant reduction of edema and creatine kinase (CK) activities and a greater Myogenin (MyoG) expression compared to VBm group, with the plant extract efficacy better than laser exposure. Reduction of edema and serum CK activities reflects a lessening of muscle damage, whereas the increase of MyoG indicates myoblast differentiation and acceleration of muscle repair. The S. hispida richness in phenolic compounds and flavonoids, such as the light modulatory ability to triggering a multitude of cell signalings likely underlie the positive outcomes. Our findings suggest both treatments as potential auxiliary tools to be explored in clinical trials in combination with anti-venom therapy after Bothropic snakebites.


Assuntos
Antivenenos/farmacologia , Terapia com Luz de Baixa Intensidade , Mordeduras de Serpentes/radioterapia , Venenos de Serpentes/toxicidade , Animais , Antivenenos/uso terapêutico , Ratos , Ratos Wistar
10.
Toxicon ; 201: 9-20, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34391787

RESUMO

Various proteins are involved in fish venom toxicity, but limited information is available regarding their structure and mode of action. Here, we analyzed RNA transcripts in the dorsal spine of the devil stinger Inimicus japonicus using next-generation sequencing (NGS), and identified two putative protein toxins, a natterin-like protein (Ij-natterin) and a phospholipase A2 (Ij-PLA2), as well as a previously reported stonustoxin-like protein. The deduced amino acid sequence of Ij-natterin suggested that it acts as a pore-forming toxin through the cooperation of the N-terminal lectin-like domain and the C-terminal pore-forming domain. Ij-PLA2 showed significant homology with secreted Ca2+-dependent PLA2s from snake venom and mammals (sPLA2-I/II). The recombinant Ij-PLA2 protein exhibited PLA2 activity in the absence of Ca2+, in contrast to canonical sPLA2-I/II. Comparison of the amino acid sequences of Ij-PLA2 with the other sPLA2-I/II suggests that the C-terminal extended peptide region of Ij-PLA2 is involved in its Ca2+-independent activity.


Assuntos
Venenos de Serpentes , Toxinas Biológicas , Sequência de Aminoácidos , Animais , Clonagem Molecular , Fosfolipases A2/genética
11.
PLoS Negl Trop Dis ; 15(8): e0009659, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407084

RESUMO

BACKGROUND: Snakebite is a neglected tropical disease that causes high global rates of mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Antivenoms are the mainstay therapeutic for treating the toxic effects of snakebite, but despite saving thousands of lives annually, these therapies are associated with limited cross-snake species efficacy due to venom variation, which ultimately restricts their therapeutic utility to particular geographical regions. METHODOLOGY/PRINCIPAL FINDINGS: In this study we explored the feasibility of generating globally effective pathology-specific antivenoms to counteract the haemotoxic signs of snakebite envenoming. Two different immunogen mixtures, consisting of seven and twelve haemotoxic venoms sourced from geographically diverse and/or medically important snakes, were used to raise ovine polyclonal antibodies, prior to characterisation of their immunological binding characteristics and in vitro neutralisation profiles against each of the venoms. Despite variability of the immunogen mixtures, both experimental antivenoms exhibited broadly comparable in vitro venom binding and neutralisation profiles against the individual venom immunogens in immunological and functional assays. However, in vivo assessments using a murine preclinical model of antivenom efficacy revealed substantial differences in venom neutralisation. The experimental antivenom generated from the seven venom immunogen mixture outperformed the comparator, by providing protective effects against venom lethality caused by seven of the eight geographically diverse venoms tested, including three distinct venoms that were not used as immunogens to generate this antivenom. These findings suggest that a core set of venom immunogens may be sufficient to stimulate antibodies capable of broadly neutralising a geographically diverse array of haemotoxic snake venoms, and that adding additional venom immunogens may impact negatively on the dose efficacy of the resulting antivenom. CONCLUSIONS/SIGNIFICANCE: Although selection of appropriate immunogens that encapsulate venom toxin diversity without diluting antivenom potency remains challenging and further optimisation is required, the findings from this pilot study suggest that the generation of pathology-specific antivenoms with global utility is likely to feasible, thereby highlighting their promise as future modular treatments for the world's tropical snakebite victims.


Assuntos
Antivenenos/imunologia , Antivenenos/farmacologia , Venenos de Serpentes/imunologia , Venenos de Serpentes/toxicidade , Animais , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Reações Cruzadas , Modelos Animais de Doenças , Hemorragia/tratamento farmacológico , Masculino , Camundongos , Projetos Piloto , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/imunologia
12.
PLoS Negl Trop Dis ; 15(8): e0009711, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34449762

RESUMO

A mathematical model is designed to assess the impact of some interventional strategies for curtailing the burden of snakebite envenoming in a community. The model is fitted with real data set. Numerical simulations have shown that public health awareness of the susceptible individuals on snakebite preventive measures could reduce the number of envenoming and prevent deaths and disabilities in the population. The simulations further revealed that if at least fifty percent of snakebite envenoming patients receive early treatment with antivenom a substantial number of deaths will be averted. Furthermore, it is shown using optimal control that combining public health awareness and antivenom treatment averts the highest number of snakebite induced deaths and disability adjusted life years in the study area. To choose the best strategy amidst limited resources in the study area, cost effectiveness analysis in terms of incremental cost effectiveness ratio is performed. It has been established that the control efforts of combining public health awareness of the susceptible individuals and antivenom treatment for victims of snakebite envenoming is the most cost effective strategy. Approximately the sum of US$72,548 is needed to avert 117 deaths or 2,739 disability adjusted life years that are recorded within 21 months in the study area. Thus, the combination of these two control strategies is recommended.


Assuntos
Mordeduras de Serpentes/prevenção & controle , Venenos de Serpentes/toxicidade , Humanos , Modelos Teóricos , Nigéria/epidemiologia , Saúde Pública , Mordeduras de Serpentes/epidemiologia
13.
Acta Trop ; 223: 106113, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34450060

RESUMO

Bothriechis schlegelii is a venomous snake found in Central and South America, mainly sighted in regions devoted to agriculture. However, in Colombia, little is known about its contribution to the total envenoming cases. Furthermore, there are no reports of the biochemical and functional activities of venoms from the southwest populations, and the differences respecting other populations are unknown. This study analyzed the protein profiles of venom samples obtained from three specimens originating from this region of Colombia using electrophoresis and chromatography. The lethality, edema-induction, hemorrhagic, defibrinating, coagulant, and indirect hemolytic activities were also evaluated. As a result, venoms were composed of proteins with a wide range of molecular weights, most of them below <37 kDa, with differences between male and female electrophoretic and chromatographic profiles. These variations were also observed in the evaluation of venom functional activities such as pro-coagulant, indirect hemolytic, and edema-inducing activities, whereas neither hemorrhagic nor defibrinating activities were detected. These results are also different considering reports with venom samples from other geographical locations, restating the existence of high intraspecific variability in B. schlegelii venoms, which could have relevant pathophysiological and therapeutic implications.


Assuntos
Crotalinae , Venenos de Serpentes/química , Animais , Colômbia , Feminino , Masculino , Proteoma
14.
Proc Biol Sci ; 288(1956): 20211391, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34375553

RESUMO

Snake fangs are an iconic exemplar of a complex adaptation, but despite striking developmental and morphological similarities, they probably evolved independently in several lineages of venomous snakes. How snakes could, uniquely among vertebrates, repeatedly evolve their complex venom delivery apparatus is an intriguing question. Here we shed light on the repeated evolution of snake venom fangs using histology, high-resolution computed tomography (microCT) and biomechanical modelling. Our examination of venomous and non-venomous species reveals that most snakes have dentine infoldings at the bases of their teeth, known as plicidentine, and that in venomous species, one of these infoldings was repurposed to form a longitudinal groove for venom delivery. Like plicidentine, venom grooves originate from infoldings of the developing dental epithelium prior to the formation of the tooth hard tissues. Derivation of the venom groove from a large plicidentine fold that develops early in tooth ontogeny reveals how snake venom fangs could originate repeatedly through the co-option of a pre-existing dental feature even without close association to a venom duct. We also show that, contrary to previous assumptions, dentine infoldings do not improve compression or bending resistance of snake teeth during biting; plicidentine may instead have a role in tooth attachment.


Assuntos
Mordeduras e Picadas , Dente , Animais , Epitélio , Venenos de Serpentes , Serpentes
15.
Chem Biol Interact ; 346: 109581, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302801

RESUMO

Bothrops asper is one of the most important snake species in Central America, mainly because of its medical importance in countries like Ecuador, Panama and Costa Rica, where this species causes a high number of snakebite accidents. Several basic phospholipases A2 (PLA2s) have been previously characterized from B. asper venom, but few studies have been carried out with its acidic isoforms. In addition, since snake venom is a rich source of bioactive substances, it is necessary to investigate the biotechnological potential of its components. In this context, this study aimed to carry out the biochemical characterization of PLA2 isoforms isolated from B. asper venom and to evaluate the antiparasitic potential of these toxins. The venom and key fractions were subjected to different chromatographic steps, obtaining nine PLA2s, four acidic ones (BaspAc-I, BaspAc-II, BaspAc-III and BaspAc-IV) and five basic ones (BaspB-I, BaspB-II, BaspB-III, BaspB-IV and BaspB-V). The isoelectric points of the acidic PLA2s were also determined, which presented values ranging between 4.5 and 5. The findings indicated the isolation of five unpublished isoforms, four Asp49-PLA, corresponding to the group of acidic isoforms, and one Lys49-PLA2-like. Acidic PLA2s catalyzed the degradation of all substrates evaluated; however, for the basic PLA2s, there was a preference for phosphatidylglycerol and phosphatidic acid. The antiparasitic potential of the toxins was evaluated, and the acidic PLA2s demonstrated action against the epimastigote forms of T. cruzi and promastigote forms of L. infantum, while the basic PLA2s BaspB-II and BaspB-IV showed activity against P. falciparum. The results indicated an increase of up to 10 times in antiplasmodial activity, when the Asp49-PLA2 and Lys49-PLA2 were associated with one another, denoting synergistic action between these PLA2 isoforms. These findings correspond to the first report of synergistic antiplasmodial action for svPLA2s, demonstrating that these molecules may be important targets in the search for new antiparasitic agents.


Assuntos
Antiprotozoários/farmacologia , Fosfolipases A2/química , Plasmodium falciparum/efeitos dos fármacos , Venenos de Serpentes/metabolismo , Sequência de Aminoácidos , Animais , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Bothrops/metabolismo , Sinergismo Farmacológico , Ponto Isoelétrico , Leishmania infantum/efeitos dos fármacos , Panamá , Testes de Sensibilidade Parasitária , Fosfolipases A2/isolamento & purificação , Fosfolipases A2/farmacologia , Isoformas de Proteínas/química , Isoformas de Proteínas/isolamento & purificação , Isoformas de Proteínas/farmacologia , Alinhamento de Sequência
16.
Acta Trop ; 222: 106047, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273312

RESUMO

The systemic effects generated by Porthidium lansbergii lansbergii envenoming, a species found in the northern region of Colombia, is poorly known. The present study aimed to analyze for the first time the mice's behavior, the histological alterations, and changes in biochemical markers levels resulting from the intraperitoneal injection of an LD50 of P. lansbergii lansbergii snake venom on mice. The envenoming mice displayed hypodynamic condition, clonic head movements, accompanied by bradypnea and thoracoabdominal imbalance. After 7 h of envenoming, the mice showed an ecchymotic region at the injection site, including bleeding in the pleural, liver, and kidney capsules. The effect on the brain revealed a micro-hemorrhage in the sensorimotor cortex with substantial loss of neurons. The venom caused dilated blood vessels in lung tissue, with endothelial necrosis associated with alveolar rupture. The liver showed parenchyma alteration with many extravasated erythrocytes. The kidneys exhibited renal tubules necrosis and a statistically significant increase in creatinine concentration. ALP and ALT's enzymatic activities remained constant at 7 h after envenoming but increased at 12 h. AST and LDH were significantly increased at 7 h but decreased to the near baseline 12 h after venom administration. Massive hemorrhages could trigger a hypovolemic shock, which could lead to death after several h without treatment. Knowledge of P. lansbergii lansbergii snake bites' injuries is essential to make the appropriate diagnostic in human envenoming cases by this snake.


Assuntos
Crotalinae , Mordeduras de Serpentes , Venenos de Serpentes/toxicidade , Animais , Hemorragia/induzido quimicamente , Dose Letal Mediana , Camundongos , Mordeduras de Serpentes/patologia
17.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199017

RESUMO

Venoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the pharmacological potential of crude Pseudocerastes and Eristicophis snake venoms in haematological disorders and cancer treatment. We assessed their antithrombotic potential using fibrinogen thromboelastography, fibrinogen gels with and without protease inhibitors, and colourimetric fibrinolysis assays. These assays indicated that the anticoagulant properties of the venoms are likely induced by the hydrolysis of phospholipids and by selective fibrinogenolysis. Furthermore, while most fibrinogenolysis occurred by the direct activity of snake venom metalloproteases and serine proteases, modest evidence indicated that fibrinogenolytic activity may also be mediated by selective venom phospholipases and an inhibitory venom-derived serine protease. We also found that the Pseudocerastes venoms significantly reduced the viability of human melanoma (MM96L) cells by more than 80%, while it had almost no effect on the healthy neonatal foreskin fibroblasts (NFF) as determined by viability assays. The bioactive properties of these venoms suggest that they contain a number of toxins suitable for downstream pharmacological development as candidates for antithrombotic or anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Fibrinolíticos/farmacologia , Venenos de Serpentes/farmacologia , Venenos de Víboras/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibrinólise/efeitos dos fármacos , Humanos , Inibidores de Serino Proteinase/farmacologia
18.
Int J Biol Macromol ; 185: 494-512, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197854

RESUMO

Snakebite envenoming is the cause of an ongoing health crisis in several regions of the world, particularly in tropical and neotropical countries. This scenario creates an urgent necessity for new practical solutions to address the limitations of current therapies. The current study investigated the isolation, phytochemical characterization, and myotoxicity inhibition mechanism of gallic acid (GA), a myotoxin inhibitor obtained from Anacardium humile. The identification and isolation of GA was achieved by employing analytical chromatographic separation, which exhibited a compound with retention time and nuclear magnetic resonance spectra compatible with GA's commercial standard and data from the literature. GA alone was able to inhibit the myotoxic activity induced by the crude venom of Bothrops jararacussu and its two main myotoxins, BthTX-I and BthTX-II. Circular dichroism (CD), fluorescence spectroscopy (FS), dynamic light scattering (DLS), and interaction studies by molecular docking suggested that GA forms a complex with BthTX-I and II. Surface plasmon resonance (SPR) kinetics assays showed that GA has a high affinity for BthTX-I with a KD of 9.146 × 10-7 M. Taken together, the two-state reaction mode of GA binding to BthTX-I, and CD, FS and DLS assays, suggest that GA is able to induce oligomerization and secondary structure changes for BthTX-I and -II. GA and other tannins have been shown to be effective inhibitors of snake venoms' toxic effects, and herein we demonstrated GA's ability to bind to and inhibit a snake venom PLA2, thus proposing a new mechanism of PLA2 inhibition, and presenting more evidence of GA's potential as an antivenom compound.


Assuntos
Anacardium/química , Ácido Gálico/farmacologia , Miotoxicidade/tratamento farmacológico , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2/metabolismo , Venenos de Serpentes/enzimologia , Animais , Modelos Animais de Doenças , Ácido Gálico/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Miotoxicidade/enzimologia , Miotoxicidade/etiologia , Inibidores de Fosfolipase A2/química , Fosfolipases A2/química , Caules de Planta/química , Proteínas de Répteis/química , Proteínas de Répteis/metabolismo , Ressonância de Plasmônio de Superfície
19.
Int J Biol Macromol ; 185: 240-250, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34118288

RESUMO

Given the magnitude of the global snakebite crisis, strategies to ensure the quality of antivenom, as well as the availability and sustainability of its supply are under development by several research groups. Recombinant DNA technology has allowed the engineering of monoclonal antibodies and recombinant fragments as alternatives to conventional antivenoms. Besides having higher therapeutic efficacy, with broad neutralization capacity against local and systemic toxicity, novel antivenoms need to be safe and cost-effective. Due to the biological and physical chemical properties of camelid single-domain antibodies, with high volume of distribution to distal tissue, their modular format, and their versatility, their biotechnological application has grown considerably in recent decades. This article presents the most up-to-date developments concerning camelid single-domain-based antibodies against major toxins from snake venoms, the main venomous animals responsible for reported envenoming cases and related human deaths. A brief discussion on the composition, challenges, and perspectives of antivenoms is presented, as well as the road ahead for next-generation antivenoms based on single-domain antibodies.


Assuntos
Anticorpos de Domínio Único/farmacologia , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/antagonistas & inibidores , Animais , Camelídeos Americanos , Humanos , Modelos Moleculares , Engenharia de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/genética , Mordeduras de Serpentes/imunologia , Distribuição Tecidual
20.
Nano Lett ; 21(13): 5663-5670, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34181420

RESUMO

A biomimetic of endogenous tissue inhibitors of metalloproteinases (TIMPs) was engineered by introducing three binding elements to a synthetic tetrapolymer. We evaluated the contribution of composition, size, and shape of the TIMP-mimicking polymers to the inhibition of BaP1, a P-I class snake venom metalloproteinase (SVMP). Inhibition was achieved when the size of the linear polymer (LP) was comparable to or greater than that of the enzyme, indicating the efficacy requires binding to a significant portion of the enzyme surface in the vicinity of the active site. The efficacy of a low cross-linked polymer hydrogel nanoparticle (NP) of substantially greater molecular weight was comparable to that of the LPs despite differences in size and shape, an important finding for in vivo applications. The abiotic TIMP was effective against two classes of SVMPs in whole snake venom. The results can serve as a design principle for biomimetic polymer inhibitors of enzymes.


Assuntos
Biomimética , Polímeros , Inibidores Teciduais de Metaloproteinases , Domínio Catalítico , Venenos de Serpentes
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