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Quantification of One Prenylated Flavanone from Eysenhardtia platycarpa and Four Derivatives in Ex Vivo Human Skin Permeation Samples Applying a Validated HPLC Method

Prenylated flavanones are polyphenols that have diverse biological properties. The present paper focuses on a HPLC method validation for the quantification of prenylated flavanones (2S)-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1Benzopyran-4-one 1 and derivatives (2S)-5,7-bis(acetyloxy)-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one A; (2S)-5-hydroxy-7-methoxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one B; (8S)-5-hydroxy-2,2-dimethyl-8-phenyl-3,4,7,8-tetrahydro-2H,6H-Benzo[1,2-b:5,4-bˈ]dipyran-6-one C; and (8S)-5-hydroxy-2,2-dimethyl-8-phenyl-7,8-dihydro-2H,6H-Benzo[1,2-b:5,4-bˈ]dipyran-6-one D applied in biopharmaceutic studies. The linear relationships are proven with significant correlation coefficients (R2 ˃ 0.999) in the range of 1.56 to 200 μg/mL with low limits of detection and quantification, on average of 0.4 μg/mL and 1.2 μg/mL, respectively. The validation method used in this work is highly accurate and precise, with values lower than 15%. The relative standard deviation values of repeatability of the instrumental system are demonstrated with less than 0.6% for all studied flavanones. Therefore, the applicability method of the quantification of the prenylated flavanones was established using the permeation of human skin in the Franz cell system. During the method previously described, there was no interference observed from human skin components in ex vivo permeation studies

Ex Vivo and In Vivo Anti-inflammatory Evaluations of Modulated Flavanones Solutions

Abstract: Interest has developed in natural molecules due to their clinically proven effects on skin deseases. Flavanones display several biological activities, and recently have been the focus of studies due to their anti-inflammatory effect. To improve their pharmacological profile four flavanones (A, B, C and D), were synthesized by structural modification of one natural flavanone 1 (semi-systematic name: (2S)-5,7-dihydroxy-6-prenylflavanone) extracted from Eysenhardtia platycarpa. The hydroalcoholic flavanone solutions (FS) were assayed to investigated their anti-inflammatory effect on two in vivo cutaneous inflammation models. Materials and methods: the topical anti-inflammatory effect of FS were evaluated against models of 12-O-tetradecanoylphorbol acetate (TPA) induced mouse ear edema and arachidonic acid (AA) in rat ear edema. Results: The vinylogous cyclized derivative (flavanone D) caused edema inhibition in the TPA- induced models with an inhibition of 96.27 ± 1.93 %; equally effective and potent in inhibiting the mouse ear edema as Indometacine had been. In addition, the AA-induced increase in ear thickness was reduced the most by the topical application of modulated ether (flavanone B). Conclusions: The in vivo and histology results suggest that flavanones B and D are effective as a topical anti-inflammatory agents in inflammatory processes. Thus, this new compounds represents a promising agent for the management of skin diseases with an inflammatory component

In Vitro Approaches to Explore the Anticancer Potential of One Natural Flavanone and Four Derivatives Loaded in Biopolymeric Nanoparticles for Application in Topical Delivery Treatments

The increasing number of skin cancer cases worldwide and the adverse side effects of current treatments have led to the search for new anticancer agents. In this present work, the anticancer potential of the natural flavanone 1, extracted from Eysenhardtia platycarpa, and four flavanone derivatives 1a-d obtained by different reactions from 1 was investigated by an in silico study and through cytotoxicity assays in melanoma (M21), cervical cancer (HeLa) cell lines and in a non-tumor cell line (HEK-293). The free compounds and compounds loaded in biopolymeric nanoparticles (PLGA NPs 1, 1a-d) were assayed. A structure-activity study (SAR) was performed to establish the main physicochemical characteristics that most contribute to cytotoxicity. Finally, ex vivo permeation studies were performed to assess the suitability of the flavanones for topical administration. Results revealed that most of the studied flavanones and their respective PLGA NPs inhibited cell growth depending on the concentration; 1b should be highlighted. The descriptors of the energetic factor were those that played a more important role in cellular activity. PLGA NPs demonstrated their ability to penetrate (Qp of 17.84-118.29 micrograms) and be retained (Qr of 0.01-1.44 g/gskin/cm2) in the skin and to exert their action for longer. The results of the study suggest that flavanones could offer many opportunities as a future anticancer topical adjuvant treatment

Cytotoxic evaluation of (2S)-5,7-dihydroxy-6-prenylflavanone derivatives loaded PLGA nanoparticles against MiaPaCa-2 cells

The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2S)-5,7-dihydroxy-6-prenylflavanone (semi-systematic name), also called (2S)-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one (CAS Name registered) (1) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a, 1b, 1c and 1d. These compounds 1, 1a, 1b, 1c, and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1, 1a, 1b, 1c, and 1d and encapsulated in polymeric NPs (NPs1, NPs1a, NPs1b, NPs1c and NPs1d) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs1a and NPs1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a. Based on these results, NPs1a were proposed as promising anticancer agent candidates

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels

Purpose: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed. Methods: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. Results: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. Conclusions: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect

PLGA Nanoparticles Containing Natural Flavanones for Ocular Inflammation

Flavanones are natural compounds that display anti-inflammatory activity. The aimof this work was to prepare PLGA nanoparticles (NPs) containing natural flavanones I ((2S)-5,7-dihydroxy-6-methyl-8-(3-methyl-2-buten-1-il)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one) andII (2S)-5,7-dihydroxy-2-(40-methoxyphenyl)-6-methyl-8-(3-methyl-2-buten-1-yl)-2,3-dihydro-4H-1-Benzopyran-4-one) (NP I and NP II, respectively) so as to evaluate their potential for topical antiinflammatoryocular therapy. An in silico study was carried out using the Molinspiration® and PASSOnline web platforms before evaluating the in vitro release study and the ex vivo porcine corneaand sclera permeation. The HPLC analytical method was also established and validated. Finally, thein vitro anti-inflammatory efficacy of NPs was studied in the HCE-2 model. The flavanones I and IIcould be released following a kinetic hyperbolic model. Neither of the two NPs was able to permeatethrough the tissues. NP I and NP II were found to be respectful of any changes in the tissues’morphology, as evidenced by histological studies. In HCE-2 cells, NP I and NP II were not cytotoxicat concentrations up to 25 M. NP I showed higher anti-inflammatory activity than NP II, being ableto significantly reduce IL-8 production in LPS-treated HCE-2 cells. In summary, ocular treatmentwith NP I and NP II could be used as a promising therapy for the inhibition of ocular inflammation

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Mejora de la calidad educativa en la Escuela de Técnicos Laboratoristas

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/6652

Cytotoxic Evaluation of (2S)-5,7-Dihydroxy-6-prenylflavanone Derivatives Loaded PLGA Nanoparticles against MiaPaCa-2 Cells

The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2S)-5,7-dihydroxy-6-prenylflavanone (semi-systematic name), also called (2S)-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one (CAS Name registered) (1) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a, 1b, 1c and 1d. These compounds 1, 1a, 1b, 1c, and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1, 1a, 1b, 1c, and 1d and encapsulated in polymeric NPs (NPs1, NPs1a, NPs1b, NPs1c and NPs1d) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs1a and NPs1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a. Based on these results, NPs1a were proposed as promising anticancer agent candidates