Publications by authors named "José R Almeida"

19 Publications

  • Page 1 of 1

Dissection of phospholipases A reveals multifaceted peptides targeting cancer cells, Leishmania and bacteria.

Bioorg Chem 2021 May 31;114:105041. Epub 2021 May 31.

Biomolecules Discovery Group, Universidad Regional Amazónica Ikiam, Km 7 Via Muyuna, Tena, Napo, Ecuador. Electronic address:

Cationic peptides bio-inspired by natural toxins have been recognized as an efficient strategy for the treatment of different health problems. Due to the specific interaction with substrates from biological membranes, snake venom phospholipases (PLAs) represent valuable scaffolds for the research and development of short peptides targeting parasites, bacteria, and cancer cells. Considering this, we evaluated the in vitro therapeutic potential of three biomimetic peptides (pCergo, pBmTxJ and pBmje) based on three different amino acid sequences from Asp49 PLAs. First, short amino acid sequences (12-17 in length) derived from these membranolytic toxins were selected using a combination of bioinformatics tools, including AntiCP, AMPA, PepDraw, ToxinPred, and HemoPI. The peptide, from each polypeptide sequence, with the greatest average antimicrobial index, no toxicity, and no hemolysis predicted was synthesized, purified, and characterized. According to in vitro assays performed, pBmje showed moderate cytotoxicity specifically against MCF-7 (breast cancer cells) with an EC of 464.85 µM, whereas pBmTxJ showed an antimicrobial effect against Staphylococcus aureus (ATCC 25923) with an MIC of 37.5 µM, and pCergo against E. coli (ATCC 25922) with an MIC of 75 µM. In addition, pCergo showed antileishmanial activity with an EC of 93.69 µM and 110.40 µM against promastigotes of Leishmania braziliensis and L. amazonensis, respectively. Altogether, these results confirmed the versatility of PLA-derived synthetic peptides, highlighting the relevance of the use of these membrane-interacting toxins as specific archetypes for drug design focused on public health problems.
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http://dx.doi.org/10.1016/j.bioorg.2021.105041DOI Listing
May 2021

Peptides to Tackle Leishmaniasis: Current Status and Future Directions.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

Biomolecules Discovery Group, Universidad Regional Amazónica Ikiam, Tena 150150, Ecuador.

Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources-amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others-or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of amino acid residues carried out in the peptide sequence, and their implications in the development of antileishmanial candidates for clinical trials. Our bibliographic research highlights that the action of leishmanicidal peptides has been evaluated mainly using in vitro assays, with a special emphasis on the promastigote stage. In light of these findings, and considering the advances in the successful application of peptides in leishmaniasis chemotherapy, possible approaches and future directions are discussed here.
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http://dx.doi.org/10.3390/ijms22094400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122823PMC
April 2021

Structural, enzymatic and pharmacological profiles of AplTX-II - A basic sPLA (D49) isolated from the Agkistrodon piscivorus leucostoma snake venom.

Int J Biol Macromol 2021 Apr 30;175:572-585. Epub 2021 Jan 30.

LAQV/Requimte, University of Porto, Rua do Campo Alegre s/n, Porto, Portugal; Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, Porto, Portugal; Faculty of Chemical Sciences, University of Cuenca, Cuenca, Azuay, Ecuador. Electronic address:

A basic sPLA (D49) from the venom of snake Agkistrodon piscivorus leucostoma (AplTX-II) was isolated, purified and characterized. We determined the enzymatic and pharmacological profiles of this toxin. AplTX-II was isolated with a high level of purity through reverse phase chromatography and molecular exclusion. The enzyme showed pI 9.48 and molecular weight of 14,003 Da. The enzymatic activity of the AplTX-II depended on Ca pH and temperature. The comparison of the primary structure with other sPLAs revealed that AplTX-II presented all the structural reasons expected for a basic sPLAs. Additionally, we have resolved its structure with the docked synthetic substrate NOBA (4-nitro-3-octanoyloxy benzoic acid) by homology modeling, and performed MD simulations with explicit solvent. Structural similarities were found between the enzyme's modeled structure and other snake sPLA X-Ray structures, available in the PDB database. NOBA and active-site water molecules spontaneously adopted stable positions and established interactions in full agreement with the reaction mechanism, proposed for the physiological substrate, suggesting that NOBA hydrolysis is an excellent model to study phospholipid hydrolysis.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.187DOI Listing
April 2021

Bothrops atrox from Ecuadorian Amazon: Initial analyses of venoms from individuals.

Toxicon 2021 Apr 24;193:63-72. Epub 2021 Jan 24.

Biomolecules Discovery Group, Universidad Regional Amazónica Ikiam, Km 7 Via Muyuna, Tena, Napo, Ecuador. Electronic address:

Bothrops atrox is the most clinically relevant snake species within the Amazon region, which includes Ecuadorian territories. It comprises a large distribution, which could contribute to the genetic and venomic variation identified in the species. The high variability and protein isoform diversity of its venom are of medical interest, since it can influence the clinical manifestations caused by envenomation and its treatment. However, in Ecuador there is insufficient information on the diversity of venomic phenotypes, even of relevant species such as B. atrox. Here, we characterized the biochemical and toxicological profiles of the venom of six B. atrox individuals from the Ecuadorian Amazon. Differences in catalytic activities of toxins, elution profiles in liquid chromatography, electrophoretic patterns, and toxic effects among the analyzed samples were identified. Nonetheless, in the preclinical testing of antivenom, two samples from Mera (Pastaza) required a higher dose to achieve total neutralization of lethality and hemorrhage. Taken together, these data highlight the importance of analyzing individual venoms in studies focused on the outcomes of envenoming.
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http://dx.doi.org/10.1016/j.toxicon.2021.01.007DOI Listing
April 2021

Cruzioseptins, antibacterial peptides from Cruziohyla calcarifer skin, as promising leishmanicidal agents.

Pathog Dis 2020 09;78(6)

Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brasil. CEP 13083-862.

Screenings of natural products have significantly contributed to the discovery of novel leishmanicidal agents. In this study, three known cruzioseptins-antibacterial peptides from Cruziohyla calcarifer skin-were synthesized and evaluated against promastigotes and amastigotes stages of Leishmania (L.) amazonensis and L. (V.) braziliensis. EC50 ranged from 9.17 to 74.82 μM, being cruzioseptin-1 the most active and selective compound, with selectivity index > 10 for both promastigotes and amastigotes of L. (V.) braziliensis. In vitro infections incubated with cruzioseptins at 50 μM showed up to ∼86% reduction in the amastigote number. Cruzioseptins were able to destabilize the parasite's cell membrane, allowing the incorporation of a DNA-fluorescent dye. Our data also demonstrated that hydrophobicity and charge appear to be advantageous features for enhancing parasiticidal activity. Antimicrobial cruzioseptins are suitable candidates and alternative molecules that deserve further in vivo investigation focusing on the development of novel antileishmanial therapies.
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http://dx.doi.org/10.1093/femspd/ftaa053DOI Listing
September 2020

Assessing the stability of historical and desiccated snake venoms from a medically important Ecuadorian collection.

Comp Biochem Physiol C Toxicol Pharmacol 2020 Apr 3;230:108702. Epub 2020 Jan 3.

Facultad de Ciencias Química, Universidad de Cuenca, Cuenca, Azuay, Ecuador; Centro de Innovación de la Salud - EUS/EP, Cuenca, Azuay, Ecuador.

Bothrops asper and Bothrops atrox are important venomous snakes from Ecuador responsible for the most of ophidic accidents, which in the past were treated with a national polyvant antivenom. For years, the venom pools were collected and stored at room temperature in a laboratory. Taking into account the controversial ability of desiccated samples to retain their biological effects and enzymatic activities, we investigated the biochemical and toxicological properties of venoms after years of storage. The proteomic profiles of historical venoms analyzed by high-performance liquid chromatography and electrophoresis are very similar. The fresh batches of venom were more lethal than those stored for years, just as the initial and current LD values of these samples changed. Significant differences were showed in the myotoxic and hemorrhagic activity of some venom pools, while no significant statistical differences were found for the edema activity. The enzymatic assays revealed a variation in proteolytic activity on azocasein and phospholipase A activity, and low differences were reported for thrombin-like serine protease activity. The maintenance of the proteomic profile and certain toxicological activities convert this venom library in a valuable source for research purposes. Nonetheless, the significative reduction of toxicological activities, such as hemorrhagic activity not feasible using these samples for the antivenom production.
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http://dx.doi.org/10.1016/j.cbpc.2020.108702DOI Listing
April 2020

Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents.

Comp Biochem Physiol C Toxicol Pharmacol 2019 Dec 24;226:108612. Epub 2019 Aug 24.

Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil. Electronic address:

Phospholipase A toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications.
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http://dx.doi.org/10.1016/j.cbpc.2019.108612DOI Listing
December 2019

Harnessing snake venom phospholipases A to novel approaches for overcoming antibiotic resistance.

Drug Dev Res 2019 02 26;80(1):68-85. Epub 2018 Sep 26.

Facultad de Ciencias Química, Universidad de Cuenca - Cuenca/Azuay - Ecuador.

The emergence of antibiotic resistance drives an essential race against time to reveal new molecular structures capable of addressing this alarming global health problem. Snake venoms are natural catalogs of multifunctional toxins and privileged frameworks, which serve as potential templates for the inspiration of novel treatment strategies for combating antibiotic resistant bacteria. Phospholipases A (PLA s) are one of the main classes of antibacterial biomolecules, with recognized therapeutic value, found in these valuable secretions. Recently, a number of biomimetic oligopeptides based on small fragments of primary structure from PLA toxins has emerged as a meaningful opportunity to overcome multidrug-resistant clinical isolates. Thus, this review will highlight the biochemical and structural properties of antibacterial PLA s and peptides thereof, as well as their possible molecular mechanisms of action and key roles in development of effective therapeutic strategies. Chemical strategies possibly useful to convert antibacterial peptides from PLA s to efficient drugs will be equally addressed.
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http://dx.doi.org/10.1002/ddr.21456DOI Listing
February 2019

Snake Venom, A Natural Library of New Potential Therapeutic Molecules: Challenges and Current Perspectives.

Curr Pharm Biotechnol 2018 ;19(4):308-335

Centro de Estudos de Biomoleculas Aplicadas a Saude, CEBio, Fiocruz Rondonia, FIOCRUZ e Universidade Federal de Rondonia, UNIR, Porto Velho-RO, Brazil.

Background: Research involving snake venom has gradually surpassed the simple discovery of new molecules using purification and structural characterization processes, and extended to the identification of their molecular targets and the evaluation of their therapeutic potential. Nevertheless, this only became possible due to constant progress in experimental biology and protein purification approaches.

Objective: This review aims to discuss the main components of snake venoms that have been investigated for biotechnological purposes, and to discover how these promising biomolecules were obtained with the satisfactory degree of purity that have enabled such studies. Advances in purification technologies of various snake venom molecules have allowed for important discoveries of proteins and peptides with different biomedical and biotechnological applications.

Result And Conclusion: It is believed that significant experimental and computational advances will arise in similar proportions in the coming years that will allow researchers to map the molecular regions responsible for their pharmacological actions, their respective mechanisms of action and their cell targets.
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http://dx.doi.org/10.2174/1389201019666180620111025DOI Listing
October 2018

In vitro effects of Crotalus atrox snake venom on chick and mouse neuromuscular preparations.

Comp Biochem Physiol C Toxicol Pharmacol 2018 Jul 28;209:37-45. Epub 2018 Mar 28.

Ikiam - Universidad Regional Amazónica, Km 7 Via Muyuna, Tena, Napo, Ecuador. Electronic address:

The neuromuscular effect of venoms is not a major clinical manifestation shared between rattlesnakes native to the Americas, which showed two different venom phenotypes. Taking into account this dichotomy, nerve muscle preparations from mice and chicks were used to investigate the ability of Crotalus atrox venom to induce in vitro neurotoxicity and myotoxicity. Unlike crotalic venoms of South America, low concentrations of C. atrox venom did not result in significant effects on mouse neuromuscular preparations. The venom was more active on avian nerve-muscle, showing reduction of twitch heights after 120 min of incubation with 10, 30 and 100 μg/mL of venom with diminished responses to agonists and KCl. Histological analysis highlighted that C. atrox was myotoxic in both species of experimental animals; as evidenced by degenerative events, including edematous cells, delta lesions, hypercontracted fibers and muscle necrosis, which can lead to neurotoxic action. These results provide key insights into the myotoxicity and low neurotoxicity of C. atrox in two animal models, corroborating with previous genomic and proteomic findings and would be useful for a deeper understanding of venom evolution in snakes belonging to the genus Crotalus.
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http://dx.doi.org/10.1016/j.cbpc.2018.03.008DOI Listing
July 2018

A novel synthetic peptide inspired on Lys49 phospholipase A from Crotalus oreganus abyssus snake venom active against multidrug-resistant clinical isolates.

Eur J Med Chem 2018 Apr 21;149:248-256. Epub 2018 Feb 21.

Ikiam - Universidad Regional Amazónica, Km 7 Via Muyuna, Tena, Napo, Ecuador.

Currently, the evolving and complex mechanisms of bacterial resistance to conventional antibiotics are increasing, while alternative medicines are drying up, which urges the need to discover novel agents able to kill antibiotic-resistant bacteria. Lys49 phospholipase As (PLAs) from snake venoms are multifunctional toxins able to induce a huge variety of therapeutic effects and consequently serve as templates for new drug leads. Hence, the present study was aimed at the synthesis of oligopeptides mimicking regions of the antibacterial Lys49 PLA toxin (CoaTx-II), recently isolated from Crotalus oreganus abyssus snake venom, to identify small peptides able to reproduce the therapeutic action of the toxin. Five peptides, representing major regions of interest within CoaTx-II, were synthesized and screened for their antibacterial properties. The 13-mer peptide pC-CoaTxII, corresponding to residues 115-129 of CoaTx-II, was able to reproduce the promising bactericidal effect of the toxin against multi-resistant clinical isolates. Peptide pC-CoaTxII is mainly composed by positively charged and hydrophobic amino acids, a typical trait in most antimicrobial peptides, and presented no defined secondary structure in aqueous environment. The physicochemical properties of pC-CoaTxII are favorable towards a strong interaction with anionic lipid membranes as those in bacteria. Additional in silico studies suggest formation of a water channel across the membrane upon peptide insertion, eventually leading to bacterial cell disruption and death. Overall, our findings confirm the valuable potential of snake venom toxins towards design and synthesis of novel antimicrobials, thus representing key insights towards development of alternative efficient antimicrobials to fight bacterial resistance to current antibiotics.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.055DOI Listing
April 2018

Anti-platelet aggregation activity of two novel acidic Asp49-phospholipases A from Bothrops brazili snake venom.

Int J Biol Macromol 2018 Feb 23;107(Pt A):1014-1022. Epub 2017 Sep 23.

Centro de Estudos de Biomoléculas Aplicadas à Saúde, CEBio, Fundação Oswaldo Cruz, FIOCRUZ, unidade Fiocruz Rondônia e Departamento de Medicina, Núcleo de Saúde, Universidade Federal de Rondônia, UNIR, Porto Velho, RO, Brazil; Centro Universitário São Lucas, UNISL, Porto Velho, RO, Brazil. Electronic address:

Phospholipases A (PLAs) are important enzymes present in snake venoms and are related to a wide spectrum of pharmacological effects, however the toxic potential and therapeutic effects of acidic isoforms have not been fully explored and understood. Due to this, the present study describes the isolation and biochemical characterization of two new acidic Asp49-PLAs from Bothrops brazili snake venom, named Braziliase-I and Braziliase-II. The venom was fractionated in three chromatographic steps: ion exchange, hydrophobic interaction and reversed phase. The isoelectric point (pI) of the isolated PLAs was determined by two-dimensional electrophoresis, and 5.2 and 5.3 pIs for Braziliase-I and II were observed, respectively. The molecular mass was determined with values ​​of 13,894 and 13,869Da for Braziliase-I and II, respectively. Amino acid sequence by Edman degradation and mass spectrometry completed 87% and 74% of the sequences, respectively for Braziliase-I and II. Molecular modeling of isolated PLAs using acid PLABthA-I-PLA from B. jararacussu template showed high quality. Both acidic PLAs showed no significant myotoxic activity, however they induced significant oedematogenic activity. Braziliase-I and II (100μg/mL) showed 31.5% and 33.2% of cytotoxicity on Trypanosoma cruzi and 26.2% and 19.2% on Leishmania infantum, respectively. Braziliase-I and II (10μg) inhibited 96.98% and 87.98% of platelet aggregation induced by ADP and 66.94% and 49% induced by collagen, respectively. The acidic PLAs biochemical and structural characterization can lead to a better understanding of its pharmacological effects and functional roles in snakebites pathophysiology, as well as its possible biotechnological applications as research probes and drug leads.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.09.069DOI Listing
February 2018

The Efficacy of Humanized Antibody against the Antigen, gp70, in Promoting Phagocytosis and Reducing Disease Burden.

Front Microbiol 2017 3;8:345. Epub 2017 Mar 3.

Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo São Paulo, Brazil.

Sporotrichosis is a subcutaneous mycosis distributed worldwide and is frequently reported in countries with tropical climates, as Latin America countries. We previously demonstrated that mice with sporotrichosis produce specific antibodies against a 70-kDa fungal protein, indicating that specific antibodies against this molecule may help to control the sporotrichosis. IgG1 monoclonal antibody was generated, and called mAbP6E7, in mice against a 70-kDa glycoprotein (gp70) of . The mAbP6E7 showed prophylactic and therapeutic activity against sporotrichosis. However, this antibody has a murine origin, and this can generate an immune response when administered to humans, precluding its use for a prolonged time. For its possible use in the treatment of human sporotrichosis, we humanized the mAbP6E7 by genetic engineering. Once expressed, the humanized antibodies had good stability and were able to bind to the 70-kDa cell wall antigens of and . The humanized P6E7 were able to opsonize yeasts, thus increasing the phagocytic index in human monocyte-derived macrophages. The treatment with humanized P6E7 decreased fungal burden . These data suggest that humanized P6E7 may have a therapeutic role in sporotrichosis.
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http://dx.doi.org/10.3389/fmicb.2017.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334357PMC
March 2017

Open or Laparoscopic Treatment: Differences and Outcomes.

J Clin Gastroenterol 2016 10;50 Suppl 1:S74-6

Departments of *Surgery †Internal Medicine, School of Medicine, Universidade Federal de Goias, Goias ‡Department of Internal Medicine, School of Medicine, Universidade Federal de Pernambuco, Recife, Brazil.

Surgical treatment of diverticulitis is still characterized by high morbidity and mortality. Surgical approach evolved from the early 20th century with 3-stage laparotomy to colon resection with primary anastomosis. In the last 2 decades, laparoscopic colectomy has been applied to elective and emergency setting of diverticular disease. Recently, laparoscopic lavage and drainage has been used to treat purulent peritonitis. All those modalities of treatment have been discussed and pointed pros and cons.
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http://dx.doi.org/10.1097/MCG.0000000000000649DOI Listing
October 2016

Isolation, structural and functional characterization of a new Lys49 phospholipase A2 homologue from Bothrops neuwiedi urutu with bactericidal potential.

Toxicon 2016 Jun 27;115:13-21. Epub 2016 Feb 27.

Centro de Estudos de Biomoléculas Aplicadas à Saúde, CEBio, Fundação Oswaldo Cruz, FIOCRUZ, Fiocruz Rondônia, and Departamento de Medicina, Universidade Federal de Rondônia, UNIR, Porto Velho-RO, Brazil; Programa de Pós-Graduação em Biodiversidade e Biotecnologia da Rede BIONORTE, Brazil.

Snake venom is a complex mixture of active compounds consisting of 80-90% proteins and peptides that exhibit a variety of biological actions that are not completely clarified or identified. Of these, phospholipase A2 is one of the molecules that has shown great biotechnological potential. The objectives of this study were to isolate, biochemically and biologically characterize a Lys49 phospholipase A2 homologue from the venom of Bothrops neuwiedi urutu. The protein was purified after two chromatographic steps, anion exchange and reverse phase. The purity and relative molecular mass were assessed by SDS-PAGE, observing a molecular weight typical of PLA2s, subsequently confirmed by mass spectrometry obtaining a mass of 13,733 Da. As for phospholipase activity, the PLA2 proved to be enzymatically inactive. The analyses by Edman degradation and sequencing of the peptide fragments allowed for the identification of 108 amino acid residues; this sequence showed high identity with other phospholipases A2 from Bothrops snake venoms, and identified this molecule as a novel PLA2 isoform from B. neuwiedi urutu venom, called BnuTX-I. In murine models, both BnuTX-I as well as the venom induced edema and myotoxic responses. The cytotoxic effect of BnuTX-I in murine macrophages was observed at concentrations above 12 μg/mL. BnuTX-I also presented antimicrobial activity against gram-positive and negative bacterial strains, having the greatest inhibitory effect on Pseudomonas aeruginosa. The results allowed for the identification of a new myotoxin isoform with PLA2 structure with promising biotechnological applications.
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http://dx.doi.org/10.1016/j.toxicon.2016.02.021DOI Listing
June 2016

Giant high-pressure pulmonary artery aneurysm in an elderly patient with chronic obstructive pulmonary disease.

Rev Port Cardiol 2016 Mar 24;35(3):183.e1-6. Epub 2016 Feb 24.

Serviço de Cardiologia, ULSM - Hospital Pedro Hispano, Matosinhos, Portugal.

The authors report the case of a 74-year-old man, with a history of chronic obstructive pulmonary disease (COPD), GOLD grade 3, stable for the past two decades, who was admitted to our center with severe right heart failure. The chest radiograph showed moderate heart enlargement mainly of the right atrium and pulmonary artery, similar to previous chest radiographs in the previous 20 years. The transthoracic echocardiogram showed a pulmonary artery aneurysm (PAA), dilatation of the right chambers with pulmonary artery systolic pressure of 52 mmHg, and preserved right ventricular systolic function. A thoracic computed tomography scan confirmed the presence of a giant PAA 72 mm in diameter. The patient was started on high-dose diuretics, with significant clinical improvement. After optimization of medical therapy right heart catheterization was carried out with the patient in optimal clinical condition, which revealed mild precapillary pulmonary hypertension with a mean pulmonary artery pressure of 26 mmHg. On the basis of the clinical and imaging findings a stable, giant, high-pressure, PAA was diagnosed secondary to pulmonary hypertension induced by COPD, with a 20-year follow-up without need for surgical repair, which helped in our decision to maintain medical surveillance. The recent onset of heart failure is explained by the unfavorable evolution of COPD. This case may change the attitude expressed in previous studies favoring the choice of an invasive approach to treat giant high-pressure PAAs, instead supporting the maintenance of medical treatment.
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http://dx.doi.org/10.1016/j.repc.2015.06.014DOI Listing
March 2016

The A61G EGF polymorphism is associated with development of extraaxial nervous system tumors but not with overall survival.

Cancer Genet Cytogenet 2010 Apr;198(1):15-21

Oncogenetics Laboratory, Department of Medical Genetics, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil.

Epidermal growth factor can activate several signaling pathways, leading to proliferation, differentiation, and tumorigenesis of epithelial tissues by binding with its receptor. The EGF protein is involved in nervous system development, and polymorphisms in the EGF gene on chromosome band 4q25 are associated with brain cancers. The purpose of this study was to investigate the association between the single-nucleotide polymorphism of EGF+61G/A and extraaxial brain tumors in a population of the southeast of Brazil. We analyzed the genotype distribution of this polymorphism in 90 patients and 100 healthy subjects, using the polymerase chain reaction-restriction fragment length polymorphism technique. Comparison of genotype distribution revealed a significant difference between patients and control subjects (P < 0.001). The variant genotypes of A/G and G/G were associated with a significant increase of the risk of tumor development, compared with the homozygote A/A (P < 0.0001). When the analyses were stratified, we observed that the genotype G/G was more frequent in female patients (P=0.021). The same genotype was observed more frequently in patients with low-grade tumors (P=0.001). Overall survival rates did not show statistically significant differences. Our data suggest that the EGF A61G polymorphism can be associated with susceptibility to development of these tumors.
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http://dx.doi.org/10.1016/j.cancergencyto.2009.11.013DOI Listing
April 2010

Association study of an epidermal growth factor gene functional polymorphism with the risk and prognosis of gliomas in Brazil.

Int J Biol Markers 2009 Oct-Dec;24(4):277-81

Department of Biomedicine, Federal University of Piaui, Parnaiba, Brazil.

Epidermal growth factor (EGF) plays an important role in cancer. A functional single nucleotide polymorphism (SNP) in the 5'-untranslated region of the EGF gene (+61 A>G) may influence its expression and contribute to cancer predisposition and aggressiveness. Aiming to investigate the role of EGF +61 A>G in the susceptibility to glioma and its prognosis, we performed a case-control study with 165 patients and 200 healthy controls from Brazil. Comparisons of genotype distributions and allele frequencies did not reveal any significant differences between the groups. The mean overall survival was 9.2 months for A/A, 8.2 months for A/G, and 7.7 months for G/G. When survival curves were plotted we found that the +61G allele is associated with poor overall survival (p=0.023) but not with disease-free survival (p=0.527). Our data suggest that, although there is no association between the EGF +61 A>G genotype and glioma susceptibility, this SNP is associated with shorter overall survival of glioma patients in the Brazilian population. Nevertheless, future studies utilizing a larger series are essential for a definitive conclusion.
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http://dx.doi.org/10.5301/jbm.2009.5517DOI Listing
March 2010

WRN Cys1367Arg SNP is not associated with risk and prognosis of gliomas in Southeast Brazil.

J Neurooncol 2008 Dec 1;90(3):253-8. Epub 2008 Aug 1.

Human Genetics Laboratory, Federal University of Piauí, Av. São Sebastião 2819, 64202-020 Parnaíba, PI, Brazil.

Werner syndrome (WS) is a premature aging disorder characterized by early onset of symptoms related to normal aging and by a high predisposition to various types of cancer, including gliomas. WS is caused by inherited recessive mutations in the WRN gene, which encodes a helicase considered a caretaker of the genome. Aiming to study the role of WRN Cys1367Arg in glioma susceptibility and oncologic prognosis of patients, we investigated the genotype distribution of this single nucleotide polymorphism in 94 glioma patients and 100 healthy subjects. Comparisons of genotype distributions and allele frequencies did not reveal any significant difference between the groups. Overall and disease-free survival rates were calculated, but no statistically significant difference was observed. Our data suggest that WRN Cys1367Arg SNP is not involved either in susceptibility to developing gliomas or in patient survival, at least in the Brazilian population.
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http://dx.doi.org/10.1007/s11060-008-9664-8DOI Listing
December 2008
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