Programa de Pós-Graduação em Ciências Farmacêuticas
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Master Thesis Investigação fitoquímica e avliação do potencial efetivo antiviral e da toxicidade oral aguda de Scoparia dulcis L. (Vassourinha)(Universidade Federal do Rio Grande do Norte, 2020-09-18) Jales, Francisco Leandro Medeiros de Lucena; Langassner, Silvana Maria Zucolotto; Pedrosa, Matheus de Freitas Fernandes; http://lattes.cnpq.br/2929963416385218; https://orcid.org/0000-0002-2768-0793; http://lattes.cnpq.br/7390416147619446; Araújo, Joselio Maria Galvão de; https://orcid.org/0000-0003-3548-2786; http://lattes.cnpq.br/6430774978643765; Fernandes, Júlia Morais; https://orcid.org/0000-0001-9769-5352; http://lattes.cnpq.br/8060189333626922The species Scoparia dulcis L. (Plantaginaceae), commonly known as broom, is popularly used as a healing, anti-inflammatory and in the treatment of gastrointestinal diseases. The main secondary metabolites described for the speciesare terpenes such as scopadulcic acids A and B, scopadiol, scopadulciol, scopadulinic, scoparic acids A - C, but there are also reports of the presence of flavonoids. The present study aimed to investigate the phytochemical profile and evaluate the antiviral potential and toxicity of the extract of the leaves of S. dulcis. Four hydroethanolic extracts were prepared from the urban area of the city of Natal,and only one extract produced from the collection carried out in the rural area of thecity of Serra CaiadaRN, with variation in the method of extraction and alcohol content: maceration 35%, and 70% and 35% and 70% turbolysis. The extracts wereanalyzed by Thin Layer Chromatography and Liquid Chromatography coupled to a mass spectrometer and the content of total flavonoids and phenols was observed. The extracts obtained from samples from the urban area were subjected to non- clinical in vitro cytotoxicity tests, through the evaluation of cell viability in Vero cells by the MTT assay, and of antiviral activity against Herpes virus type 1 and antiviral activity against the herpes virus type I- (HSV-1) in the tests: virucidal activity, post- infection, concomitant and pretreatment. The acute oral toxicity of the extract obtained by macerating 70% of samples collected from the rural area of Serra Caiada was evaluated in an in vivo model, by oral administration of 2000 mg / kg. 31substances in S. dulcis extracts, mostly flavonoids such as quercetin-derived O- glycosides, in addition to benzyl alcohol, benzoic acid methyl ester, palmitic acid methyl ester, oleic acid methyl ester, phytol acid methyl ester, methyl ester stearic acid, n-tetracosane and five more compounds with a fragmentation profile similar toterpenes have been described for the species. As for the content of total phenols and flavonoids, the extracts that presented the highest content were: turbolysis 70%urban area with 104.18 ± 0.05 for phenols and 64.06 ± 0.05 for flavonoids and maceration 70% rural area, with 98.04 ± 0.03 and 56.75 ± 0.06. There was a cell viability above 80% for all extracts from the urban zone up to a concentration of 250µg / mL, with the exception of the extract obtained by 35% turbolysis, which presented cell viability below 50%. In the studied antiviral models, the extract obtained by turbolysis 70% proved to be the most efficient when compared to the other extracts, since it promoted a significant inhibition of the HSV-1 virus. Regardingthe assessment of acute toxicity in vivo of the extract obtained by maceration 70% (rural sample), no changes were observed in the biochemical, behavioral or hematological parameters that were suggestive of toxicity generated by the extract in the evaluated / tested concentration. Finally, the species showed a potential antiviral effect in vitro and showed no signs of toxicity in vitro and in an acute modelin vivo.Master Thesis Caracterização estrutural de compostos fenólicos de erythrina velutina willd. por espectrometria de massas associada às redes moleculares (molecular networking)(Universidade Federal do Rio Grande do Norte, 2022-01-26) Pinheiro, Francisco Ayrton Senna Domingos; Ferreira, Leandro de Santis; Giordani, Raquel Brandt; https://orcid.org/0000-0002-8408-5886; http://lattes.cnpq.br/6622861873027635; https://orcid.org/0000-0002-5887-4240; http://lattes.cnpq.br/0857551775355388; Jordão, Alessandro Kappel; Bueno, Paula Carolina PiresThe identification, characterization, and study of bioactive compounds can open doors to understanding numerous applications of interest for research. The arboreal species Erythrina velutina Willd., popularly known as “mulungu,” belonging to the Fabaceae family and the Papilionoideae subfamily, is distributed throughout the Brazilian Northeast. Its leaves, seeds, and mainly trunk bark are used in folk medicine in teas to treat sleep disorders and central nervous system (CNS) conditions. Previous works with the species relate its pharmacological, anxiolytic, and sedative properties, mainly to the presence of flavonoids and benzylisoquinoline alkaloids. Given the above, the study proposal aimed to characterize the phenolic compounds present in the leaves and seeds of the species collected in four different locations in the Seridó region of Rio Grande do Norte. Dereplication of the crude ethanol extract of seeds and leaves from different populations occurred with the aid of the GNPS (Global Natural Product Social Molecular Networking) platform, based on mass data and fragmentation patterns obtained by analysis by liquid chromatography coupled with mass spectrometry (LC-MS), which led to the formation of a molecular network that presented clusters attributed to phenolic compounds. A total of 136 compounds were annotated, being 32 flavonoids, two coumarins, two anthocyanins, an aurone, and a chalcone annotated by the platform library. The analysis of unannotated metabolites indicated similarities in the fragmentation pattern related to the aglycones present in the sample with some variations present in the substituents. Principal component analysis (PCA) for the substances noted, and present in samples from different populations of E. velutina made it possible to evidence which compounds allow the differentiation of the studied organs, seeds and leaves. In addition, the PCA analysis for the seed samples allowed to evidence the separation of the samples according to the collection region. Complementary methodologies were also developed and standardized for the analysis of metabolites by gas chromatography, which allowed the identification of different fatty acids such as palmitic, linoleic, oleic and stearic acids present in Erythrina seeds, through the esterification reaction, as well as other substances, such as phytosterols, silylated fatty acids and alkaloids, by silylation reaction with a derivatizing agent BSTFA. Thus, this work contributes to a greater understanding of the profile of phenolic compounds present in E. velutina and standardizing techniques that may contribute to the knowledge of the metabolome of this species in the future.Doctoral Thesis Integração de dados moleculares e químicos para análise da biossíntese de metabólitos especializados em Erythrina velutina Willd(Universidade Federal do Rio Grande do Norte, 2024-03-27) Chacon, Daisy Sotero; Giordani, Raquel Brandt; Fett Neto, Arthur Germano; http://lattes.cnpq.br/5032750980466610; https://orcid.org/0000-0003-1932-2301; http://lattes.cnpq.br/6025915331568147; Aragão, Cicero Flávio Soares; http://orcid.org/0000-0002-3434-2602; http://lattes.cnpq.br/9657118649043311; Fett, Janette Palma; Ferreira, Leandro de Santis; Araújo, Wagner LuizThe study of plants is under increasing transformation due to the availability of molecular and bioinformatics tools to understand metabolism and point out potential sources of new bioactive chemical entities with pharmaceutical interest. In this scenario, Erythrina velutina stands out as a medicinal plant found in the northeast region of Brazil, mainly in the Caatinga biome. This plant has a remarkable ability to produce alkaloids and flavonoids, which are the main secondary metabolites of the genus and are often associated with pharmacological activities, such as modulators of the central nervous system (with antidepressant and anxiolytic effects) and anti-inflammatory action. Although some natural products (NP) have been effective as a source of new drugs, the pharmaceutical industry still faces challenges in the identification and optimized production of these compounds and this has led to a reduction in interest in NP-based drugs. In order to minimize these gaps, this study aims to integrate molecular and chemical data to investigate the biosynthesis of the main metabolites present in E. velutina under three aspects: to evaluate the metabolic production in plants collected in natural habitat (Caatinga) and in cultivated plants submitted to different elicitors (ii); identify reference genes that normalize RT-qPCR tests for the species (ii) and evaluate the expression of target genes responsible for the production of alkaloids and flavonoids with bioactive potential (iii). The study focuses on transcriptome, proteome and metabolome data obtained from samples collected in their natural habitat, in addition to seedling cultivation subjected to environmental stresses (temperature, UV, water stress, salt stress and mechanical damage) and phytohormones (methyljasmonate , salicylic acid, nitric oxide and abscisic acid). As a result, the predominant flavonoids observed were flavones, isoflavones, and flavonols, along with several isoquinoline alkaloids from both dienoids and alkenoids. Transcriptome analysis revealed the presence of enzymes involved in the flavonoid and alkaloid biosynthesis pathways, including those differentially expressed, such as EvCHI, EvIF7GT, EvCHS, EvCOR, EvNMT and EvODM. Among the treatments tested, the most significant accumulation of metabolites occurred in response to NO, MeJA, water stress and heat, while ABA caused the least pronounced effect. For normalization of RT-qPCR assays, EvCSTF64, EvRAB7, EvNLE, EvUPF and EvARP4 were identified as the most stable reference genes, while EvNADH and EvPBL27 exhibited lower stability. These genes serve as reliable reference points to ensure accurate normalization of gene expression data in subsequent analyses. The results pointed to NO as crucial in increasing the expression of CHI and the amounts of isoflavones noted. Drought stress negatively affected early precursors of the Erythrina alkaloid pathway, while MeJA had the opposite effect. Exposure to heat increased alkaloid concentrations. This study will contribute to the understanding of the secondary metabolism of plants in the semi-arid/xeric environmental conditions, characteristic of the Caatinga region. In addition, may help to improve the production of bioactive molecules in the species and to value a plant from the Caatinga of Rio Grande do Norte as a source of compounds with pharmaceutical potential. This research represents the first step towards guiding the management for optimal target metabolite production in E. velutina.Master Thesis Estudo fitoquímico e avaliação do efeito gastroprotetor e anti-inflamatório do extrato do cladódio de Nopalea cochenillifera em modelos animais(Universidade Federal do Rio Grande do Norte, 2021-11-22) Silva, Elaine Cristine Souza da; Langassner, Silvana Maria Zucolotto; Guerra, Gerlane Coelho Bernardo; http://lattes.cnpq.br/5677318431530876; https://orcid.org/0000-0002-2768-0793; http://lattes.cnpq.br/7390416147619446; http://lattes.cnpq.br/9551845574128253; Araújo, Daline Fernandes de Souza; Alves, Jovelina Samara FerreiraNopalea cochenillifera, from the Cactaceae family, is popularly known as “sweet” or “miúda” palm and is widely cultivated in the Northeast region of Brazil. This research aimed to characterize the chromatographic profile and evaluate the gastroprotective and anti-inflammatory effect of the hydroethanolic extract of N. cochenillifera. For this, the cactaceae cladode was collected, cut and dried in an oven, crushed, macerated with ethanol and water, obtaining the hydroethanolic extract, which was lyophilized. The phytochemical study of the hydroethanolic extract was performed by Thin Layer Chromatography (TCD) and High Performance Liquid Chromatography Coupled with Mass Spectrometer (HPLC-ESI-IT). The content of total phenols and flavonoids was evaluated by ultraviolet spectrophotometry. TLC evaluation indicated the presence of phenolic compounds, including flavonoids. Analysis by HPLC-ESI-IT identified the presence of six compounds, with a predominance of caffeic acid hexoside. The content of total phenols and flavonoids in the extract was 67.85% and 46.16%, respectively. In the pharmacological study to evaluate the anti-inflammatory activity, Swiss mice were randomly divided into groups (n=.5) carrageenan (treated with saline), dexamethasone (1 mg/g), N. cochenillifera extract (200; 400 or 600 mg/kg). Myeloperoxidase (MPO) enzyme activity was evaluated as a marker of neutrophil infiltration. For the evaluation of the gastroprotective activity, Rattus norvegicus (Wistar) were used, randomly distributed in groups (n=7) control gastric lesions, healthy group (saline), extract of N. cochenillifera (50, 100 and 200 mg/kg) and ranitidine (50 mg/kg), administered by gavage. The results show that the extract has an antiedematogenic activity, the dose of 600 mg/kg showed the percentage of inhibition of edema of 58.00% ± 6.02 (P< 0.01). The anti-inflammatory activity of the extract could be confirmed by the significant reduction of the enzyme myeloperoxidase (MPO) (P< 0.01). In models induced by ethanol and indomethacin, the extract showed that it prevented the formation of gastric lesions, at a dose of 100 mg/kg, ethanol model (P<0.001); and at doses of 100 mg/kg (P<0.05) and 200 mg/kg (P<0.01), in the indomethacin model. Macroscopic evaluation of the stomachs showed a reduction in the ulceration index, accompanied by a reduction in myeloperoxide (MPO) and malondialdehyde (MDA) activity, preservation of GSH, reduction of gastric levels of pro-inflammatory cytokines (TNF-α and IL-1β), and elevation of IL-10. Histopathological analyzes revealed that the extract prevented the morphological changes induced by ethanol and indomethacin, preserving gastric tissue integrity, and also reduced the inflammatory infiltrate, which was confirmed by the reduction of MPO. In the immunohistochemical analysis, the extract decreased the expression of the COX-2 enzyme and increased the expression of SOD at a dose of 200 mg/kg when induced by indomethacin and ethanol. The pre-treatment with extract of N. cochenillifera did not change the pH, volume or total acidity of gastric juice, but preserved mucus secretion and could have a cytoprotective effect. The results of the present work provide preclinical evidence that the N. cochenillifera extract has gastroprotective and anti-inflammatory activities, which may be related to the richness of phenolic compounds, especially flavonoids.Master Thesis Desenvolvimento de nanoemulsões contendo extrato hidroetanólico das folhas de Kalanchoe laciniata (L.) DC. e avaliação in vitro da atividade antioxidante(Universidade Federal do Rio Grande do Norte, 2020-10-29) Araújo, Samara Vitória Ferreira de; Ferrari, Márcio; ; http://lattes.cnpq.br/5782539548696465; ; http://lattes.cnpq.br/5974296784809880; Damasceno, Gabriel Azevedo de Brito; ; http://lattes.cnpq.br/7785267108600430; Fernandes, Julia Morais; ; http://lattes.cnpq.br/8060189333626922Kalanchoe laciniata (L.) DC. species (Crassulaceae), popularly known as saião, is a small plant that is an easy cultivated plant that has in its chemical constitution metabolites that can be used in products to prevent the signs of skin aging. In cosmetics, the addition of plant active ingredients in nanoemulsified systems has received great prominence, due to the smaller droplet size, sensory and more pleasant physical aspect. Therefore, this work aimed to develop cosmetic nanoemulsions with antioxidant activity to prevent skin aging, using hydroethanolic extract of K. laciniata leaves. For this purpose, a hydroethanolic turboextraction with 50% ethanol (v/v) was carried out using fresh leaves in a 1: 1 ratio (plant:solvent) (w/v). The extract obtained was quantitatively characterized in relation to the concentration of phenolics and total flavonoids. The antioxidant in vitro potential of extract was evaluated using different antioxidant methodologies: 2,2-difenil-1-picrilhidrazil (DPPH) radical scavenging, 2,2′- Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS˖+) radical scavenging, total antioxidant capacity, reducing power, superoxide radicals scavenging, Cu2+ and Fe2+ chelation and hydroxyl radicals scavening. Nanoemulsions were obtained form an experimental design (2³ + 3PC) by low and high energy emulsification methods, characterized by droplet size, polydispersity and zeta potential and then evaluated for their preliminary and accelerated stability under different storage conditions. The extract showed the presence of phenolic compounds, flavonoids and antioxidant activity. A cosmetic nanoemulsion stable for 90 days was obtained by the high energy process, containing 20% of emollient, 5.0% of surfactants, 1% of preservative, 0.5% of the Kalanchoe laciniata hydroethanolic extract, and 73.5% distilled water. Accordingly, we conclude that the extract acted in different stages of the oxidative cascade indicating the antioxidant potential of the hydroethanolic extract of Kalanchoe laciniata as a cosmetic raw material for preventing the signs of skin aging, as well as demonstrating the viability of an innovative nanoemulsified cosmetic product.Doctoral Thesis Avaliação da composição química e do perfil toxicológico e farmacológico dos extratos obtidos do resíduo industrial dos frutos de Passiflora edulis f. flavicarpa O. Deg(Universidade Federal do Rio Grande do Norte, 2020-08-28) Cabral, Bárbara; Langassner, Silvana Maria Zucolotto; Rezende, Adriana Augusto de; ; http://lattes.cnpq.br/4245215108740331; ; http://lattes.cnpq.br/7390416147619446; ; http://lattes.cnpq.br/2236334270659871; Silva Júnior, Edilson Dantas da; ; Ferreira, Leandro de Santis; ; http://lattes.cnpq.br/6622861873027635; Baratto, Leopoldo Clemente; ; http://lattes.cnpq.br/9495378271045592; Espindola, Foued Salmen; ; http://lattes.cnpq.br/0692083522907038Hypertension and Diabetes Mellitus are diseases on the rise in the world and can cause several cardiovascular complications. Several drugs have efficacy in the treatment of these diseases, however, many have adverse effects and limitations of efficacy. The peel of the fruit of P. edulis f. flavicarpa O. Degener (yellow passion fruit), considered a waste from the food industry, is rich in bioactive compounds. Thus, due to the need to search for new treatments for hypertension and diabetes, and in order to stimulate the development of herbal medicines with species native to Brazil, the study aimed to evaluate the phytochemical composition, the toxicity profile and the pharmacological potential of P. edulis peel extracts in non-clinical models of hypertension and diabetes. Methodology was divided into the following parts: i: phytochemical study, assessment of antioxidant activity in vitro and acute oral toxicity ii: non-clinical assessment of antihypertensive activity in an ex vivo model of isolated arteries and in chronic model of spontaneously hypertensive rats; iii acute and chronic non-clinical evaluation of antidiabetic activity in models of type 1 diabetes, induced by streptozotocin. Two extracts were produced (aqueous, prepared by decoction-AFA and hydroethanolic -AFM, obtained by maceration) from the peel flour (dry and crushed peel) of P. edulis. Phytochemical analysis was performerd by CCD, UHPLC/UV-DAD and HPLC-ESI-MSn. In both extracts C-glycosylated flavonoids were identified. Among the identified flavonoids, it was possible to quantify the content of vicenin-2, orientin, isoorientin, vitexin and isovitexin by HPLC-QqQ-MS/MS. The polysaccharide pectin was found only in the AFA extract, through high performance steric exclusion chromatography and NMR, its content was 34.3%. According to the results obtained in acute oral toxicity, extracts were classified in category 5 by GSH (Globally Harmonized Classification System for Chemical Substances and Mixtures) with LD50> 2000mg/kg, since they did not show signs of acute toxicity. The in vitro antioxidant assay showed that the extracts have good antioxidant activity observed by TAC, reducing power and DPPH tests. In the evaluation of the antihypertensive effect, it was verified in an ex vivo model of isolated artery that the AFM extract had the best relaxation profile, when compared to AFA. It effect may be due to the opening of the potassium channels. In addition, the AFM extract at doses 200 and 400 mg/kg, orally, showed a significant hypotensive effect after 28 days of treatment and improved vascular function in the mesenteric artery. This was verified by a decrease in vascular hypercontractility and an increase in the vasorelaxant effect in response to sodium nitroprusside and acetylcholine. There was also a decrease in endothelial dysfunction that can be attributed to the increased bioavailability of nitric oxide. Thus, our hypothesis is that all these effects were able to contribute to the reduction of peripheral vascular resistance, causing a significant hypotensive effect. These results are unprecedented for the pericarp of P. edulis. In addition, there was a decrease in plasma MDA levels in the heart and an increase in glutathione, suggesting a decrease in oxidative stress, as well as an increase in plasma of anti-inflammatory cytokines such as IL-10. In the acute in vivo antidiabetic model, it was observed that the extracts at doses of 400 and 600 mg/kg associated with insulin were able to significantly reduce blood glucose, when compared to diabetic rats that received only insulin, being this effect more significant with AFA treatment. In the chronic antidiabetic model, the treatment with the extracts during 60 days caused a significant reduction in glycemia observed at a dose of 400 mg/kg. In addition, extracts decreased MDA in the liver and MPO in the heart and kidney, suggesting that the extracts may act by reducing oxidative stress and inflammation caused in diabetes. Renal fibrosis was also reduced with chronic treatment. Taken together, toxicological and pharmacological studies proved the safe and the potential effect of P.edulis peel fruit extracts in development new phytoterapics.Master Thesis Planejamento assistido por computador e síntese de potenciais inibidores seletivos de PDE4 baseados em produtos naturais(Universidade Federal do Rio Grande do Norte, 2020-03-26) Lourenço, Estela Mariana Guimarães; Barbosa, Euzébio Guimarães; Lima, Dênis Pires de; ; ; ; Santos, Edson dos Anjos dos; ; Giordani, Raquel Brandt;The development of organic synthesis represents an important advance in the discovery of new drugs, being considered an important step in medicinal chemistry. However, the preparation and optimization of drugs is considered a challenge task. The expenditure and time consuming involved in this process are result, particularly, of the prioritization of the synthesis of new compounds without deeper molecular studies. The use of computer aided-drug design using prototypes is considered an important tool, capable to generate guide the synthesis of new molecules. In addition, the prospection of natural products has a long history in drug discovery and is still a source of unprecedented prototypes. Recently, a glycosylated flavonoid with remarkable selectivity for PDE4B isoform in comparison with PDE4A was isolated. This target can be highlighted as a promising alternative for the treatment of diseases as asthma and chronical obstructive pulmonary disease. Nonetheless, the structure of the flavonoid has some structural challenges that prevent it from being considered a potential drug. The present study aims to design and synthesize new potential selective inhibitors of PDE4 enzyme using the quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside as a prototype. Therefore, a library of selective phosphodiesterase 4B inhibitors was constructed and utilized for the elaboration of a 4D QSAR model and a structureactivity relationship. Molecular dynamics studies and binding free energy calculations were also made to construct hypothesis related to the binding mode of the prototype in the active site of both isoforms. The results demonstrated the importance of polar groups capable to interact with the amino acid residues of M and S pockets. Hydrophobic intermolecular interactions with the phenylalanine present in the Q pocket have been identified as essential, justifying the need of the presence of an aromatic ring or heterocycle in the molecular structure of the inhibitors. The calculated values of binding free energy and the study of protein flexibility allowed the determination of two potential binding modes of the flavonoid in the PDE4A and PDE4B and corroborated with the selectivity observed in vitro. With these informations, analogues that can be obtained by an accessible and versatile synthetic route have been proposed. The compounds have already been obtained from different methodologies that follow the principles of green chemistry. This study may contribute to the obtention of the target compounds and potential new drug prototypes for the treatment of chronic obstructive pulmonary disease and asthma.Master Thesis Avaliação de toxicidade e da atividade anti-inflamatória intestinal do extrato aquoso das folhas de Ipomoea asarifolia (Desc.) Roem. & Schult(Universidade Federal do Rio Grande do Norte, 2020-04-06) Silva, Valéria Costa da; Guerra, Gerlane Coelho Bernardo; Araújo, Aurigena Antunes de; ; ; ; Silva Júnior, Edilson Dantas da; ; Queiroga, Rita de Cássia Ramos do Egypto;Ipomoea asarifolia (Desc.) Roem. & Schult., Popularly known as “salsa” or “salsa brava”, belongs to the family Convolvulaceae. Previous studies with the extract of I. asarifolia and its major compounds, chlorogenic acid, caffeic acid and rutin, have shown excellent antiinflammatory activity. Thus, the objective of this work was to evaluate possible toxic effects of the aqueous extract of the leaves of I. asarifolia (IA), by means of acute and subchronic toxicity tests, as well as to evaluate the preventive effect of the extract in the 2,4- dinitrobenzene sulfonic acid (DNBS)-induced intestinal inflammation. In acute and subchronic toxicity tests, single dose (2000 mg/kg) and serial doses were performed for 28 days (50, 100 and 200 mg/kg) of IA, respectively; in the acute colitis assay, rats pretreated with extract IA (25, 50 and 100 mg/kg) or sulfasalazine 250 mg/kg received intracolonic instillation of DNBS in 50% (v/v) ethanol to evaluate the preventive effect of IA. The hematological, hepatic, renal and central nervous system assessment in toxicity tests did not reveal toxic effects. Whereas in the colitis model, IA showed a protective effect against intestinal inflammation induced by DNBS, with improvement in the disease activity index, in macroscopic intestinal damage and in the colonic weight/length ratio. Pretreatment with the extract promoted downregulation of important molecules involved in intestinal inflammation signaling pathways such as JNK1, NF-κB-p65 and STAT3, while SOCS1 had upregulation. Consequently, IA promoted downregulation of IL-17 and iNOS and reduced levels of IL-1β and TNF-α, pro-inflammatory markers. On the other hand, it significantly increased IL-10, an important anti-inflammatory cytokine. The anti-inflammatory effect of IA was also confirmed by the reduction in colonic MPO activity. In association with these results, there was a significant improvement in oxidative stress with reduced MDA and increased GSH, results that can be attributed to the rich content of phenols and total flavonoids in the extract. Additionally, the IA effect was confirmed in the histological evaluation, demonstrating preservation of the colonic cytoarchitecture, which corroborates with the data referring to upregulation for MUC2, a glycoprotein involved in the integrity of the intestinal barrier. In view of the results presented, conclude that the extract of I. asarifolia has low toxicity and protective activity against intestinal inflammation, revealing the potential for possible adjuvant application in the control of human IBD.Master Thesis Commiphora leptophloeos (Mart.) J.B. Gillett (Burseraceae): estudo fitoquímico, toxicidade e avaliação do potencial antiinflamatório e antimicrobiano(Universidade Federal do Rio Grande do Norte, 2019-03-28) Medeiros, Renato Dantas de; Langassner, Silvana Maria Zucolotto; Silva, Juliana Félix da; Ferreira, Leandro de SantisThe specie Commiphora leptophloeos (Burseraceae) is a native plant from Brazil, belongs to caatinga biome and is known popularly as “imburana-de-espinho” and “imburana-decambão”. The ethnopharmacology studies mention the use of this specie in the treatment of inflammations and infections. In this context, the present study aimed to evaluate the toxicity, anti-inflammatory and antimicrobial activity in non-clinical in vitro and in vivo assays of leaf and stem bark extracts, and to isolate, identify and quantify chemical markers. In the phytochemical study, the hydroethanolic extract was prepared by maceration and the fractionation was performaded by liquid-liquid partition (dichloromethane, ethyl acetateAcOEt and n-buthanol-BuOH fractions). Isolation, structural elucidation and characterization of the extracts were performed by CPC, LC-MS, FIA-ESI-IT-MS/MS and 1H NMR and quantification of the content of markers in the extracts was made by HPLC-DAD and HPLCELSD. The toxicity of both extracts was evaluated by MTT and flow cytometry assays and in vivo by the acute toxicity test. The in vitro anti-inflammatory activity was evaluated using LPS-induced nitric oxide assay and in viv by carrageenan-induced paw edema and oral zymosan induced air pocket models. The antimicrobial activity was measured by the determination of minimum inhibitory concentration (MIC) and virtual screening of the isolated compounds was performed by in silico studies. From leaves extract, 2 flavonoids were isolated by CPC and 16 compounds were characterized by Mass spectrometry such as phenolic acids, glycosylated flavonoids derivatives of quercetin, luteolin and apigenin, and condensed tannins derivatives of catechin. From the stem bark extract, 2 tannins were isolated by CPC and 8 compounds were characterized as phenolic acids and procyanidins. The leaves extract at 200 µg/mL and stem bark extract at concentrations of 1, 10, 100 and 200 µg/mL demonstrated in vitro anti-inflammatory effect in the LPS-induced nitric oxide assay. In the carrageenan-induced paw edema of model, the extracts of leaves and stem bark at the doses of 100, 200 and 400 mg/kg, by oral route, significantly reduced the edema followed by reduction of myeloperoxidase (MPO) and in the zymosan-induced model of pouch-air, at doses tested, significantly reducing (p < 0.001), cell migration, total protein concentration, myeloperoxidase (MPO), and malondialdehyde (MDA) and the proinflammatory cytokine TNF-α and increased the production of the anti-inflammatory cytokine IL-10. In the evaluation of the antimicrobial activity, the extracts of the barks and the AcOET and BuOH fractions at concentrations of 20 to 100 μg/mL demonstrated a fungistatic and bactericidal effect. The in silico study indicated possible ligands of type B dimeric procyanidin and isovitexin related to anti-inflammatory and antimicrobial activity. The results obtained are unprecedent for the specie, justify its use in folk medicine and reveals that extracts of leaves and stem bark have a therapeutic potential for the development of herbal products with antiinflammatory and antimicrobial properties.Master Thesis Kalanchoe brasiliensis Cambess e Kalanchoe pinnata (Lamarck) Persoon: caracterização química, avaliação gastroprotetora e anti-inflamatória tópica(2017-06-30) Araújo, Edilane Rodrigues Dantas de; Guerra, Gerlane Coelho Bernardo; http://lattes.cnpq.br/5677318431530876; http://lattes.cnpq.br/4189208604689711; Ferreira, Leandro de Santis; https://orcid.org/0000-0002-8408-5886; http://lattes.cnpq.br/6622861873027635; Batista, Leônia MariaKalanchoe brasiliensis and Kalanchoe pinnata (Crassulaceae), known as "saião" and "coirama", have wide popular use in the treatment of peptic ulcers and cutaneous inflammations. It is worth mentioning that K. pinnata is present in the National List of Plants of Interest of the Unified Health System - RENISUS (2009). Within this context, the objective of the present study was to characterize the chemical markers in the leaf juices of both species and to evaluate the gastroprotective and topical anti-inflammatory activities. Phytochemical characterization was performed by Thin Layer Chromatography (TLC) and Ultra High Performance Liquid Chromatography coupled to Mass Spectrometer (UHPLC- MS). Gastroprotective activity was evaluated in ethanol and indomethacin induced acute ulcer models, whereas gastric secretion was evaluated in the pylorus ligature model in Wistar rats. Pre-treatment was performed with the juices at the doses of 125, 250 and 500 mg/kg and ranitidine (50 mg/kg) orally. The topical anti-inflammatory activity was evaluated in the carrageenan induced paw edema model and croton oil-induced ear edema in Swiss mice using gel formulations containing the juices at different concentrations (1,25%, 2,5% and 5%) and as the standard drug dexamethasone (1mg/g), all administered topically immediately after induction. The TLC analysis revealed the presence of flavonoid stains in the juices of both species after revelation with the Natural Reagent A, being observed that the two species have different flavonoid profiles. In the analysis by UHPLC-MS the K. brasiliensis leaf juice showed glycosylated flavonoids derived mainly from patuletin, while that of K. pinnata presented glycosylated flavonoids derived mainly from quercetin. The pre-treatment with the K. brasiliensis leaf juice at doses of 125 mg/kg (P<0,01), 250 mg/kg and 500 mg/kg (P<0,001) and K. pinnata at doses of 125 mg/kg (P<0,01), 250 mg/kg and 500 mg/kg (P<0,001) significantly reduced the lesions compared to the positive control in the ethanol induction model. In the indomethacin induction model, the K. brasiliensis leaf juice showed significant results at doses of 250 mg/kg (P<0,05) and 500 mg/kg (P<0,01) and K. pinnata at doses of 250 and 500 mg/kg (P<0,001). Reduction of lesions was accompanied by an increase in total glutathione content and reduction of malondialdehyde levels. In addition, levels of myeloperoxidase, IL-1β and TNF-α were reduced. Cytoprotective effect was also observed in histological evaluation with H&E and maintenance of mucus production with PAS, as well as reduction of iNOS and NF-κB p65 expression and increased expression of ZO-1 by immunohistochemistry. Leaf juices from both species did not change the acidity, pH and volume of the gastric juice. In the ear edema model, the formulations containing the three concentrations of the K. brasiliensis leaf juice significantly reduced the edema when compared to the placebo group (1,25% P<0,05, 2,5% P<0,01 and 5% P<0,01). However, only the formulation containing the juice of the K. pinnata leaf juice at 5% concentration showed a significant result (P<0,01). In the paw edema model, the formulations containing the K. brasiliensis leaf juice at concentrations of 1,25 and 2,5% significantly reduced (P<0,05) the edema in the time 4 h. The formulation at 5% concentration significantly reduced edema at 1 h (P <0,001), 2 h, 3 h and 4 h (P <0,01). Regarding the formulations containing the K. pinnata leaf juice, the concentration of 1,25% significantly reduced the edema in the time 1 h (P<0,01) and 2 h (P<0,05), in the concentration of 5% significantly reduced in time 1 h (P<0,05). The decrease in edema was followed by reduction of miloperoxidase. It was concluded that the juices of both species presented gastroprotective and topical anti-inflammatory activity in vivo models, results that justify the popular use of the species.