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2.
Toxicon ; 127: 22-36, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28063838

RESUMO

Phospholipases A2 (PLA2s) constitute a class of extensively studied toxins, isolated from snake venoms. Basic PLA2 isoforms mediate various toxicological effects, while the acidic isoforms generally have higher enzymatic activities, but do not promote evident toxic effects. The functions of these acidic isoforms in snake venoms are still not completely understood and more studies are needed to characterize the biological functions and diversification of acidic toxins in order to justify their abundant presence in these secretions. Recently, Lomonte and collaborators demonstrated, in a proteomic and toxicological study, high concentrations of PLA2s in the venom of Agkistrodon piscivorus leucostoma. We have, herein, purified and characterized an acidic PLA2 from this snake venom, denominated AplTx-I, in order to better understand its biochemical and structural characteristics, as well as its biological effects. AplTx-I was purified using two chromatographic steps, in association with enzymatic and biological assays. The acidic toxin was found to be one of the most abundant proteins in the venom of A. p. leucostoma; the protein was monomeric with a molecular mass of 13,885.8 Da, as identified by mass spectrometry ESI-TOF and electrophoresis. The toxin has similar primary and tridimensional structures to those of other acidic PLA2s, a theoretical and experimental isoelectric point of ≈5.12, and a calcium-dependent enzyme activity of 25.8985 nM/min/mg, with maximum values at 37 °C and pH 8.0. Despite its high enzymatic activity on synthetic substrate, AplTx-I did not induce high or significant myotoxic, coagulant, anticoagulant, edema, neuromuscular toxicity in mouse phrenic nerve-diaphragm preparations or antibacterial activities. Interestingly, AplTx-I triggered a high and selective neuromuscular toxicity in chick biventer cervicis preparations. These findings are relevant to provide a deeper understanding of the pharmacology, role and diversification of acidic phospholipase A2 isoforms in snake venoms.


Assuntos
Agkistrodon , Venenos de Crotalídeos/toxicidade , Fosfolipases A2/toxicidade , Animais , Galinhas , Venenos de Crotalídeos/química , Camundongos , Peso Molecular , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Fosfolipases A2/química , Nervo Frênico/efeitos dos fármacos , Nervo Frênico/fisiologia , Isoformas de Proteínas , Ratos Wistar
3.
Curr Med Chem ; 24(30): 3254-3282, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27804880

RESUMO

Snake venoms are natural sources of biologically active molecules that are able to act selectively and specifically on different cellular targets, modulating physiological functions. Thus, these mixtures, composed mainly of proteins and peptides, provide ample and challenging opportunities and a diversified molecular architecture to design and develop tools and agents of scientific and therapeutic interest. Among these components, peptides and small proteins play diverse roles in numerous physiological processes, exerting a wide range of pharmacological activities, such as antimicrobial, antihypertensive, analgesic, antitumor, analgesic, among others. The pharmaceutical and cosmetic industries have recognized the huge potential of these privileged frameworks and believe them to be a promising alternative to contemporary drugs. A number of natural or synthetic peptides from snake venoms have already found preclinical or clinical applications for the treatment of pain, hypertension, cardiovascular diseases and aging skin. A well-known example is captopril, whose natural peptide precursor was isolated from Bothrops jararaca snake venom, which is a peptide-based drug that inhibits the angiotensin-converting enzyme, producing an anti-hypertensive effect. The present review looks at the main peptides (natriuretic peptides, bradykinin-potentiating peptides and sarafotoxins) and low mass proteins (crotamine, disintegrins and three-Finger toxins) from snake venoms, as well as synthetic peptides inspired by them, describing their biochemical, structural and physiological features, as well as their applications as research tools and therapeutic agents.


Assuntos
Peptídeos/química , Venenos de Serpentes/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Bothrops/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Peptídeos/isolamento & purificação , Peptídeos/uso terapêutico , Peptidomiméticos/química , Peptidomiméticos/uso terapêutico , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/isolamento & purificação , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/tratamento farmacológico
4.
Toxicon ; 117: 1-12, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26996495

RESUMO

Commonly, phospholipases A2 (PLA2s) play key roles in the pathogenesis of the local tissue damage characteristic of crotaline and viperine snake envenomations. Crotalus oreganus lutosus snake venom has not been extensively studied; therefore, the characterization of its components represents a valuable biotechnological tool for studying pathophysiological processes of envenoming and for gaining a deeper understanding of its biological effects. In this study, for the first time, a basic PLA2 myotoxin, ColTx-I, was purified from C. o. lutosus through two chromatographic steps. ColTx-I is monomeric with calculated molecular mass weight (Mw) of 14,145 Da and a primary structure closely related to basic PLA2s from viperid venoms. The pure enzyme has a specific activity of 15.87 ± 0.65 nmol/min/mg at optimal conditions (pH 8.0 and 37 °C). ColTx-I activity was found to be dependent on Ca(2+), as its substitution by other ionic species as well as the addition of chelating agents significantly reduced its phospholipase activity. In vivo, ColTx-I triggered dose-dependent inflammatory responses, measured using the paw edema model, with an increase in IL-6 levels, systemic and local myotoxicity, characterized by elevated plasma creatine kinase activity. ColTx-I induced a complex series of degenerative events associated with edema, inflammatory infiltrate and skeletal muscle necrosis. These biochemical and functional results suggest that ColTx-I, a myotoxic and inflammatory mediator, plays a relevant role in C. o. lutosus envenomation. Thus, detailed studies on its mechanism of action, such as evaluating the synergism between ColTx-I and other venom components may reveal targets for the development of more specific and effective therapies.


Assuntos
Venenos de Crotalídeos/química , Crotalus , Fosfolipases A2/toxicidade , Proteínas de Répteis/toxicidade , Animais , Camundongos , Fosfolipases A2/química , Fosfolipases A2/isolamento & purificação , Filogenia , Proteínas de Répteis/química , Proteínas de Répteis/isolamento & purificação , Alinhamento de Sequência , Análise de Sequência de Proteína
5.
Biomed Res Int ; 2013: 153045, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24171158

RESUMO

Ophidian envenomation is an important health problem in Brazil and other South American countries. In folk medicine, especially in developing countries, several vegetal species are employed for the treatment of snakebites in communities that lack prompt access to serum therapy. However, the identification and characterization of the effects of several new plants or their isolated compounds, which are able to inhibit the activities of snake venom, are extremely important and such studies are imperative. Snake venom contains several organic and inorganic compounds; phospholipases A2 (PLA2s) are one of the principal toxic components of venom. PLA2s display a wide variety of pharmacological activities, such as neurotoxicity, myotoxicity, cardiotoxicity, anticoagulant, hemorrhagic, and edema-inducing effects. PLA2 inhibition is of pharmacological and therapeutic interests as these enzymes are involved in several inflammatory diseases. This review describes the results of several studies of plant extracts and their isolated active principles, when used against crude snake venoms or their toxic fractions. Isolated inhibitors, such as steroids, terpenoids, and phenolic compounds, are able to inhibit PLA2s from different snake venoms. The design of specific inhibitors of PLA2s might help in the development of new pharmaceutical drugs, more specific antivenom, or even as alternative approaches for treating snakebites.


Assuntos
Produtos Biológicos/isolamento & purificação , Inibidores de Fosfolipase A2/isolamento & purificação , Plantas/química , Venenos de Serpentes/química , Animais , Produtos Biológicos/química , Brasil , Inibidores de Fosfolipase A2/química
6.
Int Endod J ; 42(9): 785-93, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19548934

RESUMO

AIM: To assess the physicochemical properties and the surface morphology of AH Plus, Epiphany, and Epiphany SE root canal sealers. METHODOLOGY: Five samples of each material were employed for each test according to ANSI/ADA specification 57. The samples were assigned to four groups: (i) AH Plus; (ii) Epiphany; (iii) Epiphany + Thinning Resin; (iv) Epiphany SE. The distilled water used during the solubility test was submitted to spectrometry to verify the release of calcium ions. The morphologies of the external surface and the cross-section of the samples were analysed by means of a scanning electron microscope (SEM). Statistical analysis was performed by using One-Way ANOVA and post hoc Tukey-Kramer tests with the null hypothesis set as 5%. RESULTS: Setting time, flow and radiopacity results were in accordance with ANSI/ADA requirements whereas the dimensional change of all sealers and solubility of Epiphany did not fulfil ANSI/ADA protocols. AH Plus and Epiphany SE were similar in terms of flow, radiopacity, solubility and dimensional change. The spectrometry test revealed significant calcium ion release from Epiphany with and without the thinning resin. SEM analysis revealed essentially a homogeneous surface with compact layer and some rough areas. CONCLUSIONS: Setting time, flow, and radiopacity tests conformed to ANSI/ADA standardization. The dimensional change in all groups and the solubility of Epiphany were greater than values considered acceptable, with higher amounts of calcium ion release. Epiphany SE revealed more organized, compacted, and homogeneous polymers in a reduced resin matrix when compared with the other groups.


Assuntos
Resinas Epóxi/química , Metacrilatos/química , Materiais Restauradores do Canal Radicular/química , Análise de Variância , Fenômenos Químicos , Análise do Estresse Dentário , Combinação de Medicamentos , Cura Luminosa de Adesivos Dentários , Teste de Materiais , Radiografia Dentária , Solubilidade , Estatísticas não Paramétricas
7.
Pediatr Blood Cancer ; 43(2): 115-9, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15236276

RESUMO

BACKGROUND: The p53 tumor suppressor gene is affected in a wide range of human cancers, including hematological malignancies. This gene encodes a nuclear phosphoprotein p53, which plays a key role in cell cycle arrest, induction of apoptosis, and DNA repair. Mutations of the p53 gene often lead to the accumulation of the mutated protein in the nucleus of neoplastic cells. However, p53 protein expression is frequently detected in non-Hodgkin lymphomas (NHL) without any correlation with p53 mutations. This discordance suggests the existence of other mechanisms to stabilize the p53 protein, including binding of p53 protein to viral proteins. p53 protein has been shown to bind to proteins encoded by the Epstein-Barr virus (EBV). PROCEDURE: The aim of this study was to analyze p53 expression in childhood B-NHL and correlate its expression in the absence of p53 mutations with EBV in order to investigate a possible involvement of EBV in p53 stabilization. DESIGNS AND METHODS: Tumor specimens from 35 children with B-NHL were analyzed by immunohistochemistry (IHC) with the DO7 monoclonal antibody, which recognizes an epitope at N-terminus of p53 protein and reacts with wild type and mutant proteins. To detect p53 mutations, PCR/SSCP and sequencing were performed. EBV status was determinated using a specific PCR technique. RESULTS: The overall frequency of p53 immunostaining positivity was 45% (16 of 35). p53 mutations were detected in nine patients (25.6%). p53 immunoreactivity was observed in all cases with mutations. Additionally, we identified 7 p53 positive cases among 26 tumors without mutations. EBV DNA was detected in 24 of 35 cases. Four patients with p53 expression dissociated from mutation were EBV positive. No statistically significant association was found between p53 expression and EBV cases despite the exclusion of those patients in which p53 expression was related with p53 mutations (P = 0.28 and 0.54, respectively). CONCLUSIONS: Our results suggested that in childhood B-NHL, the expression of p53 dissociated from mutations could not be related to EBV infection. Further studies with larger patient sets will be necessary to determinate if EBV-encoded protein may play a role for nuclear accumulation of p53 protein.


Assuntos
Infecções por Vírus Epstein-Barr/fisiopatologia , Linfoma de Células B/metabolismo , Linfoma de Células B/virologia , Proteína Supressora de Tumor p53/metabolismo , Brasil/epidemiologia , Pré-Escolar , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Genes p53/genética , Humanos , Imuno-Histoquímica , Linfoma de Células B/genética , Masculino , Mutação
8.
Sao Paulo Med J ; 119(6): 212-5, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11723536

RESUMO

CONTEXT: Mutations or deletions in the tumor-suppressor gene p53 are among the commonest genetic changes found in human neoplasms including breast, lung and bowel cancers. In hematological malignancies, p53 is most often mutated in Burkitt's lymphoma, with p53 mutations present in 30 to 40% of tumor samples and in 70% of cell lines. OBJECTIVE: To analyze the p53 gene alterations in child patients with B non-Hodgkin's lymphoma. DESIGN: Descriptive study. SETTING: Tertiary oncology care center. PARTICIPANTS: The study investigated 12 patients with childhood B non-Hodgkin's lymphoma (Burkitt's lymphoma). Screening for p53 mutations was done by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of exon 5 to 8/9 of the gene. RESULTS: Abnormal polymerase chain reaction-single strand conformational polymorphism migration pattern was observed in 4 patients (33.3%), one on exon 6 and three on exon 7. Positive cases included 2 patients who died from disease. CONCLUSION: These preliminary results suggest that p53 mutations are quite frequent in children with Burkitt's lymphoma and may play a role in lymphoma genesis or disease progression.


Assuntos
Linfoma de Burkitt/genética , Genes p53/genética , Mutação , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples
9.
Braz J Med Biol Res ; 26(12): 1279-89, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8136729

RESUMO

1. Helicobacter pylori status and the histology of the antral and oxyntic mucosa were evaluated in 25 patients with duodenal ulcer treated with a triple schedule of furazolidone, metronidazole and amoxicillin, and in 16 patients treated only with cimetidine. 2. Before treatment, H. pylori was detected in all patients. One month after treatment with the antimicrobial agents, H. pylori was not found in 18 (72.0%) of 25 patients treated with the triple schedule. In the patients treated with cimetidine (N = 16) the H. pylori tests continued to be positive after treatment. 3. Inflammatory activity and intensity of gastritis were significantly reduced in patients treated with the antimicrobial agents but not in cimetidine-treated patients. Three patients who had negative cultures and improvement of gastritis 1 month after treatment became H. pylori positive again within 2 months, with concomitant reappearance of gastritis. 4. This study provides additional evidence that histological gastritis observed in H. pylori-positive patients with duodenal ulcer is due to the presence of the microorganism.


Assuntos
Quimioterapia Combinada/uso terapêutico , Úlcera Duodenal/patologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Adulto , Amoxicilina/uso terapêutico , Úlcera Duodenal/microbiologia , Feminino , Furazolidona/uso terapêutico , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Fatores de Tempo
10.
Braz. j. med. biol. res ; 26(12): 1279-89, Dec. 1993. ilus, tab
Artigo em Inglês | LILACS | ID: lil-148833

RESUMO

1. Helicobacter pylori status and the histology of the antral and oxyntic mucosa were evaluated in 25 patients with duodenal ulcer treated with a triple schedule of furazolidone, metronidazole and amoxicillin, and in 16 patients treated only with cimetidine. 2. Before treatment, H. pylori was detected in all patients. One month after treatment with the antimicrobial agents, H. pylori was not found in 18 (72.0 per cent ) of 25 patients treated with the triple schedule. In the patients treated with cimetidine (N = 16) the H. pylori tests continued to be positive after treatment. 3. Inflammatory activity and intensity of gastritis were significantly reduced in patients treated with the antimicrobial agents but not in cimetidine-treated patients. Three patients who had negative cultures and improvement of gastritis 1 month after treatment became H. pylori positive again within 2 months, with concomitant reappearance of gastritis. 4. This study provides additional evidence that histological gastritis observed in H. pylori-positive patients with duodenal ulcer is due to the presence of the microorganism


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Quimioterapia Combinada/uso terapêutico , Helicobacter pylori/isolamento & purificação , Infecções por Helicobacter/tratamento farmacológico , Mucosa Gástrica/patologia , Úlcera Duodenal/patologia , Amoxicilina/uso terapêutico , Furazolidona/uso terapêutico , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Metronidazol/uso terapêutico , Mucosa Gástrica/microbiologia , Fatores de Tempo , Úlcera Duodenal/microbiologia
11.
Scand J Gastroenterol ; 28(10): 858-64, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7903471

RESUMO

The density of antral gastrin (G)- and somatostatin (D)-immunoreactive cells and the contents of antral gastrin and somatostatin were investigated in endoscopic antral biopsy specimens from patients with duodenal ulcer before and after eradication of Helicobacter pylori. After H. pylori eradication both antral somatostatin concentration (p = 0.0002) and antral D-cell density (p = 0.01) increased significantly. Conversely, although the number of G-cells was unchanged, antral (p = 0.0002) and serum (p = 0.001) gastrin contents decreased significantly. The number of oxyntic D-cells did not change significantly. These results strongly suggest that the hypergastrinaemia observed in H. pylori-positive patients may be due to a deficiency in antral somatostatin, which normally inhibits the synthesis and release of gastrin.


Assuntos
Úlcera Duodenal/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Gastrite/metabolismo , Infecções por Helicobacter , Helicobacter pylori , Antro Pilórico/metabolismo , Somatostatina/metabolismo , Adulto , Biópsia , Contagem de Células , Doença Crônica , Úlcera Duodenal/diagnóstico , Úlcera Duodenal/tratamento farmacológico , Úlcera Duodenal/microbiologia , Feminino , Mucosa Gástrica/patologia , Gastrite/diagnóstico , Gastrite/tratamento farmacológico , Gastrite/microbiologia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Antro Pilórico/patologia , Fatores de Tempo
12.
Am J Gastroenterol ; 88(8): 1228-32, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8338090

RESUMO

The histamine concentration of the oxyntic mucosa was determined in Helicobacter pylori-positive patients with duodenal ulcer before and after antimicrobial therapy and in H. pylori-negative subjects. Determination of serum gastrin was also performed in duodenal ulcer patients before and after H. pylori eradication. The histamine content of the oxyntic mucosa was lower in patients with duodenal ulcer than in H. pylori-negative subjects, but it increased after H. pylori eradication. Conversely, in patients in whom therapy failed to eradicate the microorganism, the histamine content remained unchanged. Serum gastrin levels fell after microorganism eradication, and the percentage of this fall was correlated with the percentage of increase in gastric histamine. In conclusion, our findings suggest that abnormalities of histamine store present in duodenal ulcer patients might be a feature of H. pylori infection.


Assuntos
Úlcera Duodenal/microbiologia , Mucosa Gástrica/química , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Histamina/análise , Adulto , Amoxicilina/uso terapêutico , Quimioterapia Combinada/uso terapêutico , Úlcera Duodenal/metabolismo , Feminino , Furazolidona/uso terapêutico , Gastrinas/sangue , Infecções por Helicobacter/metabolismo , Humanos , Masculino , Metronidazol/uso terapêutico , Fatores de Tempo
13.
Braz J Med Biol Res ; 26(7): 699-702, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8268818

RESUMO

The sensitivity and specificity of the preformed urease test and of carbolfuchsin-stained smears for the diagnosis of the presence of Helicobacter pylori in gastric mucosa were evaluated before and after antimicrobial treatment. The results obtained by culture were used as the reference point. We studied 41 patients with endoscopically diagnosed duodenal ulcer. Twenty-five of these were treated with furazolidone (100 mg t.i.d.), amoxicillin (500 mg t.i.d.) and metronidazole (250 mg t.i.d.) for 5 days and then with only furazolidone (100 mg t.i.d.) for an additional 25 days. The 16 control patients were treated with cimetidine (800 mg, 4 times a day). The sensitivity of the urease test and of direct smear examination was 100% before treatment and 84.6% and 92.3%, respectively, after treatment. We conclude that the urease test and carbolfuchsin-stained smears, which are highly sensitive for H. pylori diagnosis, present reduced sensitivity when they are employed for the follow-up of patients treated with antimicrobials.


Assuntos
Ensaios Enzimáticos Clínicos , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Antro Pilórico/microbiologia , Urease/análise , Adulto , Úlcera Duodenal/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Fatores de Tempo
14.
Braz. j. med. biol. res ; 26(7): 699-702, Jul. 1993. tab
Artigo em Inglês | LILACS | ID: lil-148724

RESUMO

The sensitivity and specificity of the preformed urease test and of carbolfuchsin-stained smears for the diagnosis of the presence of Helicobacter pylori in gastric mucosa were evaluated before and after antimicrobial treatment. The results obtained by culture were used as the reference point. We studied 41 patients with endoscopically diagnosed duodenal ulcer. Twenty-five of these were treated with furazolidone (100 mg t.i.d.), amoxicillin (500 mg t.i.d.) and metronidazole (250 mg t.i.d.) for 5 days and then with only furazolidone (100 mg t.i.d.) for an additional 25 days. The 16 control patients were treated with cimetidine (800 mg, 4 times a day). The sensitivity of the urease test and of direct smear examination was 100 per cent before treatment and 84.6 per cent and 92.3 per cent , respectively, after treatment. We conclude that the urease test and carbolfuchsin-stained smears, which are highly sensitive for H. pylori diagnosis, present reduced sensitivity when they are employed for the follow-up of patients treated with antimicrobials


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antro Pilórico/microbiologia , Ensaios Enzimáticos Clínicos , Infecções por Helicobacter , Helicobacter pylori/isolamento & purificação , Urease/análise , Mucosa Gástrica/microbiologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Fatores de Tempo , Úlcera Duodenal/microbiologia
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