Programa de Pós-Graduação em Ciências Farmacêuticas
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Master Thesis Avaliação das atividades anti-inflamatória, cicatrizante e antiofídica de um gel contendo extrato hidroetanólico das folhas de Jatropha mollissima (Pohl) Baill(Universidade Federal do Rio Grande do Norte, 2019-03-29) Passos, Júlia Gabriela Ramos; Pedrosa, Matheus de Freitas Fernandes; Silva, Juliana Félix da; https://orcid.org/0000-0003-3131-9025; http://lattes.cnpq.br/7927574480239375; http://lattes.cnpq.br/2929963416385218; http://lattes.cnpq.br/1969453327313987; Guerra, Gerlane Coelho Bernardo; http://lattes.cnpq.br/5677318431530876; Luna, Karla Patrícia de OliveiraAccidents caused by snakes are considered a major public health problem in several regions of the world. Bothrops are responsible for the vast majority of ophidic accidents in Brazil. It is known that, currently, the only specific treatment available for the bite of these snakes is the bothropic antivenom, but it has some limitations, such as not combat local effects effectively, difficult access in some regions, and high cost. Plants of the genus Jatropha (Euphorbiaceae) are often indicated by traditional medicine, in some regions of Brazil, to reverse the damage caused by snake bites and also with anti-inflammatory function. In this view, the objective of this work was to evaluate the anti-inflammatory, healing and antiophidic potential against the venom of the snake Bothrops jararaca of the hydroethanolic extract of the leaves of Jatropha mollissima (Pohl) Baill. incorporated into a formulation developed for topical application. Tests were performed to evaluate the topical anti-inflammatory activity of this species in carrageenan-induced paw edema and ear edema induced by single application (acute inflammation) or multiple applications (chronic inflammation) of chroton oil. Tests were also performed to evaluate the healing activity of the formulation, while the skin irritation test was conducted to analyze safety during topical use of the formulations developed. It was possible to observe that the gel had anti-inflammatory action in acute inflammation models induced by carrageenan, and in acute and chronic inflammation models by chroton oil. chroton oil. It was also observed that the gel has cicatrizant activity, since it significantly decreased the size of the wound in relation to the placebo group. The gel did not cause skin irritation in mice, proving to be safe for topical use. The efficacy of the gel containing the hydroethanolic extract of the leaves of J. mollissima alone and in association with the commercial polyvalent antibothropic-crotalic commercial antivenom in relation to its antiophidic potential against the local effects of B. jararaca envenoming were evaluated in the paw edema and muscle hemorrhagic models and it was seen that the venom-induced edematogenic and hemorrhagic activities were inhibited, both by the gel alone and by the association with the antiophidic antivenom, since these treatments reduced edema (the gel treatment containing the extract in association with the antiophidic antivenom had an inhibition of approximately 90% after four hours of the envenoming), in addition to significantly reducing the concentration of hemoglobin in the evaluated tissues, consequently having a significant anti-hemorrhagic potential. In conclusion, the results show that the gel containing the hydroethanolic extract of the leaves of J. mollissima shows potential anti-inflammatory, healing and antiophidic activity, acting on the local effects of the bite, suggesting that this formulation of topical use has an important antiophidic potential as a complementary alternative to the treatment of local effects caused by bothropic envenoming, besides acting as healing potential and topical antiinflammatory for the treatment of various skin diseases.Doctoral Thesis Análise fitoquímica e avaliação da atividade antiescorpiônica e antiofídica do suco dos frutos de Hancornia speciosa Gomes (Apocynacea)(Universidade Federal do Rio Grande do Norte, 2019-08-30) Yamashita, Fabiana de Oliveira; Pedrosa, Matheus de Freitas Fernandes; Langassner, Silvana Maria Zucolotto; 0000-0002-2768-0793; http://lattes.cnpq.br/7390416147619446; http://lattes.cnpq.br/2929963416385218; http://lattes.cnpq.br/1583697337809267; Queiroz, Giselle Pidde; Ferreira, Leandro de Santis; http://lattes.cnpq.br/6622861873027635; Ururahy, Marcela Abbott Galvão; http://lattes.cnpq.br/8016222352823817; Araújo, Nathalia Kelly de; http://lattes.cnpq.br/3502393944021960Accidents with venomous animals, mainly snakes and scorpions, are considered a serious public health problem. In Brazil, ophidian accidents are mainly provoked by snakes of the genus Bothrops, and those with scorpions, by the species Tityus serrulatus. The conventional treatment is the use of antivenom serotherapy, which in addition to presenting some limitations, such as difficult access in some regions and high cost, is only able to neutralize the poison toxins, being inefficient in inhibiting the endogenous reactions triggered by their presence. In this context, the aim of this paper was to perform a phytochemical analysis of the fruit juice of Hancornia speciosa and its ability to inhibit the effects of the venom of the scorpion Tityus serrulatus and the snake Bothrops jararaca. The phytochemical analysis was performed using high performance liquid chromatography MS/MS. The antiscorpionic activity of the juice was evaluated using the animal model of acute pulmonary edema induced by the scorpion venom T serrulatus. For this, Swiss mice received venom subcutaneously and were treated orally with juice at doses of 100 and 200 mg / kg, using pre- and post-treatment protocols. Two hours after venom administration, the animals were euthanized to collect lungs, kidneys and blood. The following analyzes were performed with the lungs: cytokine quantification, evans blue concentration, myeloperoxidase enzyme (MPO) dosage and relative lung weight percentage; with the kidneys, nitrite dosage and lipid peroxidation; and with blood, hematological and biochemical parameters were evaluated. Regarding botropic venom, the ability of the juice to inhibit its local effects was evaluated in the models of paw edema, hemorrhage, myotoxicity and dermonecrosis. For this, Swiss mice of both sexes were used. In all models the juice was administered orally at doses of 100 and 200 mg / kg and was administered shortly after the botropic venom (post-treatment protocol). Through HPLC-DAD-MS / MS analyzes 13 compounds were identified, the major ones identified as L-bornesitol, quinic acid, chlorogenic acid and rutin. Observations regarding the inhibition of antiscorpionic effects demonstrated that Hancornia speciosa juice was able to significantly decrease some important parameters such as cytokine production, myeloperoxidase activity, evans blue concentration in lung tissue, lipid peroxidation and nitrite. Regarding the botropic effects, the juice was able to significantly reduce the dermonecrotic lesion, the edematogenic activity, the hemorrhagic activity and the concentrations of the creatine kinase and lactate dehydrogenase enzymes. From the results, it can be concluded that Hancornia speciosa Gomes juice has great potential to be used as adjuvant in the treatment of scorpion and botropic poisonings.Doctoral Thesis Potencial da espécie vegetal Jatropha molissima (Pohl) Baill. contra os efeitos tóxicos da serpente Bothrops jararaca e do escorpião Tityus serrulatus(2019-06-27) Gomes, Jacyra Antunes dos Santos; Pedrosa, Matheus de Freitas Fernandes; ; ; Freitas, Janaina Cristiana de Oliveira Crispim; ; Machado, Paula Renata Lima; ; Soares, Luiz Alberto Lira; ; Lima, Maira Conceição Jerônimo de Souza;Accidents caused by venomous animals are a serious public health problem. In Brazil, most accidents are associated with snakes of the genus Bothrops and the scorpion of the genus Tityus. Currently, the main available treatment is the antivenom serum therapy, which has some limitations, such as inability to neutralize local effects, risks of immunological reactions, high cost and difficult access in some regions. In this context, the search for new complementary alternatives to treat venomous animals is relevant. Jatropha mollissima (Pohl) Baill., (Euphorbiaceae), a medicinal plant popularly known in Brazil as "pinhão bravo" is very used in folk medicine as antiophidic and antiinflammatory. Given the relevance of systemic effects of B. jararaca venom and T. serrulatus venom envenoming, the aim of the present work was evaluate the inhibitory efficacy of aqueous extract from leaves of J. mollissima upon systemic effects induced by these venoms. The effect of oral treatment with aqeous extract upon hematological, hemostatic, biochemical alterations and oxidative stress in response to B. jararaca vemom injection was evaluated in mice; and pulmonary edema, biochemical alterations and oxidative stress produced in response to T. serrulatus venom. Extract reduced significantly the effect of venom upon fibrinogen, platelets and activated partial thromboplastin time (APTT), indicating the action of extract upon hemostatic effects of B. jararaca venom. The extract also inhibited B. jararaca venom effects on leukocyte blood series, which indicates benefitial effects upon inflammatory processes. The extract was also able to reduce significantly the renal, hepatic, muscular and pancreatic toxicity of B. jararaca venom, by reverting the effects upon serum levels of urea, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and amylase. The extract inhibited the hepatic and renal oxidative stress of B. jararaca venom, indicating a possible antioxidant action. In addition, pulmonary edema induced by T. serrulatus venom was inhibited significantly by extract. Myeloperoxidase and IL-6 and IL-1β cytokines were reduced in the presence of extract, indicating benefitial effects upon inflammatory processes. The extract was also able to reduce significantly the renal, hepatic, muscular and pancreatic toxicity of T. serrulatus venom, by reverting the effects upon serum levels LDH, creatine kinase (CK), urea, creatinine, AST and amylase suggesting an inhibition of hepatic, renal and pancreatic damage. The extract inhibited the hepatic and renal oxidative stress of T. serrulatus venom, indicating a possible antioxidant action. In vitro, J. mollissima was able to inhibit hemolysis and cytotoxicity against MDCK cells, indicating that the absence of toxicity and, finally, the extract showed antioxidant activity in different models. Thus, it is concluded that the extract of J. mollissima posseses compounds able of decresae systemic alterations induced by B. jararaca and T. serrulatus, indicating the potentiality of this vegetal species as a source of bioactive molecules against bothropic and scorpionic venoms.Master Thesis Nanopartículas poliméricas biodegradáveis de poli (ácido láctico-co-glicólico) funcionalizadas para incorporação de peçonha de Bothrops jararaca(2018-03-08) Silva, Emanuell dos Santos; Silva Júnior, Arnóbio Antonio da; Pedrosa, Matheus de Freitas Fernandes; ; ; ; Tambourgi, Denise Vilarinho; ; Egito, Eryvaldo Sócrates Tabosa do;Snake-envenoming represents a worldwide public health issue. The search for new immunoadjuvants and vaccines expands the therapeutics alternatives and improves antivenoms sera. Nanotechnology is associated to antivenom serum improvement once venom-loaded nanoparticles modulate the protein release and activating immune response to produce specific antibodies. Polymeric nanoparticles are colloidal dispersions with particle size between 1-1000 nm which have been used as drug delivery systems for bioactive macromolecules. The aim of this study is obtain and characterize biodegradable cationic nanoparticles to proteins loading. The sub 200 nm poly (lactic-co-glycolic acid) (PLGA) nanoparticles were produced and functionalized with hyper-branched polyethylenimine (PEI) using the nanoprecipitation technique. The parameters assessed by dynamic light scattering, zeta potential measurements and morphology were monitored to establish a suitable formulation. Small-sized (100– 200 nm) and spherical particles with protein association efficiency of about 100% were reached. The high protein loading efficiency, electrophoresis and zeta potential results demonstrated that Bothrops jararaca venom were adsorbed on particle surface, which remained as a stable colloidal dispersion (over 6 weeks). A slow release protein profile was observed admitting the release kinetics by parabolic diffusion. The in vivo studies showed immunoadjuvant ability of the nanoparticles, similar to that found to aluminum hydroxide. Thus, the cationic nanoparticles as carrier to bioactive molecules was successfully developed and demonstrated to promising immunoadjuvant and a novel nanocarrier for protein or nucleic acids release.Master Thesis Avaliação do efeito citotóxico e apoptótico induzido pela ação dos venenos do gênero Bothrops e Tityus em linhagens de carcinoma cervical transformadas por papilomavírus humano(2015-05-29) Silva, Emanuelly Bernardes de Oliveira da; Freitas, Janaina Cristiana de Oliveira Crispim; Farias, Kleber Juvenal Silva; ; ; ; Andrade Neto, Valter Ferreira de; ; Mendonça, Tarsia Giabardo Silva;Among the types of cancer incidents in Brazil, cervical cancer is the fourth most common type among women, with more than 99.7% of cases associated with infection by human papillomaviruses (HPV) types 16 and 18 mainly. The limited of malignant tumors to conventional chemotherapy response led to the development of new pharmacological strategies based on knowledge of new therapeutic targets. Considering the diversity of scorpions and snakes of Brazilian fauna, these poisonous animals have a pharmacological potential in their venom, being of great interest in the new drugs research and development from raw or fractions poison. Thus, faced with these poisons opens an expectation in the search for new compounds with therapeutic action in the treatment of cancer. The objective of this study was to evaluate the cytotoxic effect and apoptosis of the poisons of the scorpion Tityus serrulatus (TSR), Bothrops jararaca (BJ) and Bothrops erythromelas (BE) in cervical carcinoma cell lines SiHa and HeLa, tranform by the respective HPV 16 and 18. In relation to cell viability by MTT method was obtained challenged cytotoxicity in tumor cell lines with the poisons of snakes BJ and BE compared to the TSR poisons. Similarly, the process of cell death was greater when challenged with BJ and BE. Therefore, Bothrops poisons showed a cytotoxic and apoptotic action on the lines studied, dose-dependent and time-response manner. This study suggests for the first time, a cytotoxic and apoptotic role of poisons of snakes B. jararaca and B. erythromelas in cervical carcinoma cell lines.Master Thesis Atividade antiofídica do decocto das folhas de jatropha gossypiifolia l. frente o veneno de bothrops jararaca(Universidade Federal do Rio Grande do Norte, 2014-02-25) Silva, Juliana Felix da; Pedrosa, Matheus de Freitas Fernandes; Langassner, Silvana Maria Zucolotto; ; http://lattes.cnpq.br/7390416147619446; ; http://lattes.cnpq.br/2929963416385218; ; http://lattes.cnpq.br/7927574480239375; Gavioli, Elaine Cristina; ; http://lattes.cnpq.br/1759328747578795; Melo, Paulo de Assis; ; http://lattes.cnpq.br/6954875796234519Antiophidic activity from decoct of Jatropha gossypiifolia L. leaves against Bothrops jararaca venom. Snakebites are a serious worldwide public health problem. In Latin America, about 90 % of accidents are attributed to snakes from Bothrops genus. Currently, the main available treatment is the antivenom serum therapy, which has some disadvantages such as inability to neutralize local effects, risk of immunological reactions, high cost and difficult access in some regions. In this context, the search for alternative therapies to treat snakebites is relevant. Jatropha gossypiifolia L., a medicinal plant popularly known in Brazil as “pinhão-roxo”, is very used in folk medicine as antiophidic. So, the aim of this study is to evaluate the antiophidic properties of this species against enzymatic and biological activities from Bothrops jararaca snake venom. The aqueous leaf extract of J. gossypiifolia was prepared by decoction. The inhibition studies were performed in vitro, by pre-incubation of a fixed amount of venom with different amounts of extract from J. gossypiifolia for 60 min at 37 °C, and in vivo, through oral or intraperitoneal treatment of animals, in different doses, 60 min before venom injection. The proteolytic activity upon azocasein was efficiently inhibited, indicating inhibitory action upon metalloproteinases (SVMPs) and/or serine proteases (SVSPs). The extract inhibited the fibrinogenolytic activity, which was also confirmed by zymography, where it was possible to observe that the extract preferentially inhibits fibrinogenolytic enzymes of 26 and 28 kDa. The coagulant activity upon fibrinogen and plasma were significantly inhibited, suggesting an inhibitory action upon thrombin-like enzymes (SVTLEs), as well as upon clotting factor activators toxins. The extract prolonged the activated partial thromboplastin time (aPTT), suggesting an inhibitory action toward not only to SVTLEs, but also against endogenous thrombin. The defibrinogenating activity in vivo was efficiently inhibited by the extract on oral route, confirming the previous results. The local hemorrhagic activity was also significantly inhibited by oral route, indicating an inhibitory action upon SVMPs. The phospholipase activity in vitro was not inhibited. Nevertheless, the edematogenic and myotoxic activities were efficiently inhibited, by oral and intraperitoneal route, which may indicate an inhibitory effect of the extract upon Lys49 phospholipase (PLA2) and/ or SVMPs, or also an anti-inflammatory action against endogenous chemical mediators. Regarding the possible action mechanism, was observed that the extract did not presented proteolytic activity, however, presented protein precipitating action. In addition, the extract showed significant antioxidant activity in different models, which could justify, at least partially, the antiophidic activity presented. The metal chelating action presented by extract could be correlated with SVMPs inhibition, once these enzymes are metal-dependent. The phytochemical analysis revealed the presence of sugars, alkaloids, flavonoids, tannins, terpenes and/or steroids and proteins, from which the flavonoids could be pointed as major compounds, based on chromatographic profile obtained by thin layer chromatography (TLC). In conclusion, the results demonstrate that the J. gossypiifolia leaves decoct present potential antiophidic activity, including action upon snakebite local effects, suggesting that this species may be used as a new source of bioactive molecules against bothropic venom.