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1.
J Am Chem Soc ; 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37870621

RESUMO

mRNA lipid nanoparticle (LNP) technology presents enormous opportunities to prevent and treat various diseases. Here, we developed a novel series of LNPs containing ionizable amino-lipids showing a remarkable array of tunable and pH-sensitive lyotropic liquid crystalline mesophases including the inverse bicontinuous cubic and hexagonal phases characterized by high-throughput synchrotron radiation X-ray scattering. Furthermore, with an interest in developing mRNA therapeutics for lung macrophage targeting, we discovered that there is a strong correlation between the mesophase transition of the LNPs during acidification and the macrophage association/transfection efficiency of mRNAs. The slight molecular structural differences between the SM-102 and ALC-0315 ionizable lipids are linked to the LNP's ability to transform their internal structures from an amorphous state to the inverse micellar, hexagonal, and finally cubic structures during endosomal maturation. SM-102 LNPs showed exceptionally improved transfection efficiency due to their ability to form a cubic structure at a lower pH than the ALC-0315 analogues, which remained within the hexagonal structure, previously attributed to promoting endosomal escape of the ionizable LNPs. Overall, the new knowledge draws our attention to the important role of mesophase transition in endosomal escape, and the novel LNP libraries reported herein have broad prospects for advancing mRNA therapeutics.

2.
BMC Oral Health ; 23(1): 538, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37542215

RESUMO

BACKGROUND: External factors such as the daily use of antimicrobial mouthwashes to maintain oral hygiene and to reduce the microbial activity can contribute to alter the mechanical properties of the elastomeric chains used during orthodontic treatments, causing loss of effectiveness. This systematic review and a meta-analysis assessed the rate of force decay and degradation of the polymeric chains depending on the type of mouthwash. METHODS: A systematic search of the literature were there was an exposure of orthodontic elastomeric chains to certain mouthwashes was conducted in the electronic databases of PubMed, Cochrane Library (CENTRAL), Scopus, EMBASE and Web of Science, as well as grey literature (Opengrey). No limit was placed on publication year and research was done up to June 2022. Based on inclusion/ exclusion criteria, data were extracted by two independent reviewers. For the quantitative analysis, studies were analysed with a mixed-effect (random effect) meta-regression model, with beta coefficients and R [2] values. I [2] index and Q and Egger tests were used to find heterogeneity among studies. RESULTS: A total of 178 potentially eligible studies were identified, of which 14 were eventually included in the qualitative analysis and 14 in the quantitative meta-analysis. The meta-analysis showed that all the mouthwashes were associated with a greater force decay than the control groups. After 7 days (p = 0.005) significant differences were found among the different mouthwashes, with those containing alcohol having significantly higher impact on the force decay than those containing chlorhexidine 0.2%, sodium fluoride or Persica. However, at 24 h (p = 0.200), 14 days (p = 0.076), 21 days (p = 0.120) and 28 days (p = 0.778) no statistically significant differences among the different mouthwashes were found, although those containing alcohol presented a strong tendency. CONCLUSION: Although mouthwashes tend to increase the speed of force decay of elastomeric chains, especially those containing alcohol, clorhexidine 0.2% can be a good alternative due to its low impact on the force decay and its ability to maintain low microbial activity. More in vitro and in vivo studies comparing different manufacturers and other agents should be performed.


Assuntos
Anti-Infecciosos , Antissépticos Bucais , Humanos , Clorexidina/farmacologia , Fluoreto de Sódio , Elasticidade , Etanol , Polímeros
3.
Rev Panam Salud Publica ; 45: e82, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220994

RESUMO

Access to information and intercultural approaches in the field of health are essential for the elimination of inequities in health access and care. Intercultural models such as traditional, complementary, and integrative medicine (TCIM) are an important part of health care in most countries and often contribute to expanding access to primary health care. Despite legal recognition and policies to integrate TCIM into health systems, their contribution to health, well-being, and people-centered care to achieve universal health is still underestimated. This article presents the progress (2017-2020) achieved by the Virtual Health Library specialized in the TCIM (VHL TCIM Americas), an initiative created as a tool to reduce the gaps in the production and access to validated information on TCIM. Through collaborative network work, VHL TCIM Americas contributes to the democratization of health, access to verified scientific data, visibility of non-conventional knowledge, strengthening of research capacities, and exchange of experiences for informed decision-making.


El acceso a la información y los abordajes interculturales en el ámbito de la salud son esenciales para la eliminación de inequidades en el acceso a los servicios de salud y la atención sanitaria. Los modelos interculturales, como las medicinas tradicionales, complementarias e integrativas (MTCI) son una parte importante del cuidado de la salud en la mayoría de los países y frecuentemente contribuyen a ampliar el acceso a la atención primaria de salud. A pesar del reconocimiento legal y de la existencia de políticas para la integración de las MTCI en los sistemas de salud, aún se subestima su contribución a la salud, el bienestar y la atención de la salud centrada en las personas para alcanzar la salud universal. En este artículo se presentan los avances (2017-2020) alcanzados por la Biblioteca Virtual en Salud especializada en las MTCI (BVS MTCI Américas), iniciativa creada como herramienta para disminuir las brechas en la producción y el acceso a la información validada sobre las MTCI. Mediante el trabajo colaborativo en red, la BVS MTCI Américas contribuye a la democratización de la salud, el acceso a datos científicos verificados disponibles, la visibilización de conocimientos no convencionales, el fortalecimiento de capacidades de investigación y el intercambio de experiencias para la toma informada de decisiones.


O acesso à informação e as abordagens interculturais no setor da saúde são essenciais para eliminar as desigualdades no acesso aos serviços de saúde. Os modelos interculturais, como as medicinas tradicionais, complementares e integrativas (MTCI), são uma parte importante da atenção à saúde na maioria dos países e frequentemente contribuem para ampliar o acesso à atenção primária. Apesar do reconhecimento legal e da existência de políticas para a integração das MTCI nos sistemas de saúde, a sua contribuição para a saúde, o bem-estar e a atenção centrada nas pessoas para alcançar a saúde universal ainda é subestimada. Este artigo apresenta o progresso (de 2017 a 2020) alcançado pela Biblioteca Virtual em Saúde especializada em MTCI (BVS MTCI Américas), uma iniciativa criada como ferramenta para reduzir as disparidades na produção e no acesso a informações validadas sobre as MTCI. Realizando um trabalho colaborativo em rede, a BVS MTCI Américas contribui para a democratização da saúde, o acesso a dados científicos verificados, a visibilidade dos conhecimentos não convencionais, o fortalecimento das capacidades de pesquisa e a troca de experiências para a tomada de decisões bem informada.

4.
Medicina (Kaunas) ; 57(7)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34356964

RESUMO

Background and objectives: Although the main objective of any orthodontic treatment is to correct malocclusion, a range of psychosocial and/or esthetic factors drive patients to undergo orthodontic treatment. The aim of the present study was to analyze variations in oral health-related quality of life (OHRQL) levels in patients undergoing orthodontic treatment by means of four types of appliances: fixed buccal metal brackets, fixed buccal esthetic/ceramic brackets, fixed lingual brackets, and clear aligners. Material and Methods: The study sample comprised 120 patients aged 18 to 68 years who attended the Orthodontic department at the Dental Clinic of the University of Valencia. The Index of Orthodontic Treatment Need (IOTN) was used to measure orthodontic treatment need. Each patient completed three different intervals of the 14-item Oral Health Impact Profile (OHIP-14): before treatment (T0); six months after placing the orthodontic appliances (T1) and at the end of orthodontic treatment (T2). Results: All groups suffered a reduction in quality of life from T0 to T1 except the metal bracket group which presented the same level for the functional limitation domain (p = 1.000), the lingual bracket group for the psychological discomfort domain (p = 1.000) and clear aligner group for the physical disability domain (p = 0.118) and psychological disability domain (p = 1.000). Nevertheless, quality of life for most domains was similar in all groups at the end of treatment (T2). Conclusions: Patients underwent a significant reduction in quality of life during treatment in comparison with their pre-treatment condition but showed significant improvements at the end of treatment.


Assuntos
Má Oclusão , Qualidade de Vida , Humanos , Índice de Necessidade de Tratamento Ortodôntico , Má Oclusão/terapia , Aparelhos Ortodônticos , Inquéritos e Questionários
5.
J Chem Inf Model ; 60(12): 6007-6019, 2020 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-33259212

RESUMO

The rise of novel artificial intelligence (AI) methods necessitates their benchmarking against classical machine learning for a typical drug-discovery project. Inhibition of the potassium ion channel, whose alpha subunit is encoded by the human ether-à-go-go-related gene (hERG), leads to a prolonged QT interval of the cardiac action potential and is a significant safety pharmacology target for the development of new medicines. Several computational approaches have been employed to develop prediction models for the assessment of hERG liabilities of small molecules including recent work using deep learning methods. Here, we perform a comprehensive comparison of hERG effect prediction models based on classical approaches (random forests and gradient boosting) and modern AI methods [deep neural networks (DNNs) and recurrent neural networks (RNNs)]. The training set (∼9000 compounds) was compiled by integrating the hERG bioactivity data from the ChEMBL database with experimental data generated from an in-house, high-throughput thallium flux assay. We utilized different molecular descriptors including the latent descriptors, which are real-value continuous vectors derived from chemical autoencoders trained on a large chemical space (>1.5 million compounds). The models were prospectively validated on ∼840 in-house compounds screened in the same thallium flux assay. The best results were obtained with the XGBoost method and RDKit descriptors. The comparison of models based only on latent descriptors revealed that the DNNs performed significantly better than the classical methods. The RNNs that operate on SMILES provided the highest model sensitivity. The best models were merged into a consensus model that offered superior performance compared to reference models from academic and commercial domains. Furthermore, we shed light on the potential of AI methods to exploit the big data in chemistry and generate novel chemical representations useful in predictive modeling and tailoring a new chemical space.


Assuntos
Canais de Potássio Éter-A-Go-Go , Bloqueadores dos Canais de Potássio , Inteligência Artificial , Big Data , Descoberta de Drogas , Humanos , Bloqueadores dos Canais de Potássio/farmacologia
6.
Rev Panam Salud Publica ; 44: e143, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-33196705

RESUMO

Access to information and intercultural approaches in the field of health are essential for the elimination of inequities in health access and care. Intercultural models such as traditional, complementary and integrative medicine (TCIM) are an important part of health care in most countries and often contribute to expanding access to primary health care. Despite legal recognition and policies to integrate TCIM into health systems, their contribution to health, well-being, and people-centered care to achieve universal health is still underestimated. This article presents the progress (2017-2020) achieved by the Virtual Health Library specialized in the TCIM (VHL TCIM Americas), an initiative created as a tool to reduce the gaps in the production and access to validated information on TCIM. Through collaborative network work, the VHL TCIM Americas contributes to the democratization of health, access to verified scientific data, visibility of non-conventional knowledge, strengthening of research capacities, and exchange of experiences for informed decision-making.


O acesso à informação e as abordagens interculturais no setor da saúde são essenciais para eliminar as desigualdades no acesso aos serviços de saúde. Os modelos interculturais, como as medicinas tradicionais, complementares e integrativas (MTCI), são uma parte importante da atenção à saúde na maioria dos países e frequentemente contribuem para ampliar o acesso à atenção primária. Apesar do reconhecimento legal e da existência de políticas para a integração das MTCI nos sistemas de saúde, a sua contribuição para a saúde, o bem-estar e a atenção centrada nas pessoas para alcançar a saúde universal ainda é subestimada. Este artigo apresenta o progresso (de 2017 a 2020) alcançado pela Biblioteca Virtual em Saúde especializada em MTCI (BVS MTCI Américas), uma iniciativa criada como ferramenta para reduzir as disparidades na produção e no acesso a informações validadas sobre as MTCI. Realizando um trabalho colaborativo em rede, a BVS MTCI Américas contribui para a democratização da saúde, o acesso a dados científicos verificados, a visibilidade dos conhecimentos não convencionais, o fortalecimento das capacidades de pesquisa e a troca de experiências para a tomada de decisões bem informada.
.

7.
Mar Drugs ; 17(4)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934741

RESUMO

Vibrio diabolicus A1SM3 strain was isolated from a sediment sample from Manaure Solar Saltern in La Guajira and the produced crude extracts have shown antibacterial activity against methicillin-resistant Staphylococcus aureus and cytotoxic activity against human lung cell line. Thus, the aim of this research was to identify the main compound responsible for the biological activity observed and to systematically study how each carbon and nitrogen source in the growth media, and variation of the salinity, affect its production. For the characterization of the bioactive metabolites, 15 fractions obtained from Vibrio diabolicus A1SM3 crude extract were analyzed by HPLC-MS/MS and their activity was established. The bioactive fractions were dereplicated with Antibase and Marinlit databases, which combined with nuclear magnetic resonance (NMR) spectra and fragmentation by MS/MS, led to the identification of 2,2-di(3-indolyl)-3-indolone (isotrisindoline), an indole-derivative antibiotic, previously isolated from marine organisms. The influence of the variations of the culture media in isotrisindoline production was established by molecular network and MZmine showing that the media containing starch and peptone at 7% NaCl was the best culture media to produce it. Also, polyhydroxybutyrates (PHB) identification was established by MS/MS mainly in casamino acids media, contributing to the first report on PHB production by this strain.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Técnicas Bacteriológicas/métodos , Vibrio/química , Vibrio/metabolismo , Alcaloides/biossíntese , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Organismos Aquáticos/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Misturas Complexas/química , Misturas Complexas/isolamento & purificação , Meios de Cultura , Humanos , Hidroxibutiratos/química , Hidroxibutiratos/farmacologia , Isoindóis/isolamento & purificação , Isoindóis/metabolismo , Modelos Moleculares , Poliésteres/química , Poliésteres/farmacologia , Poli-Hidroxialcanoatos/química , Poli-Hidroxialcanoatos/farmacologia , Proibitinas , Salinidade
8.
J Dairy Sci ; 102(12): 11636-11651, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31548051

RESUMO

The objective of this study was to evaluate expression of a cluster of genes encoding ß-defensin antimicrobial peptides in neutrophils of postpartum cows in relation to prepartum dietary cation-anion difference (DCAD), vitamin D, and postpartum disease. Pregnant dry Holstein cows (28 nulliparous and 51 parous) at 255 d gestation were blocked by parity and randomly assigned to 4 prepartum diets of positive (+130 mEq/kg) or negative (-130 mEq/kg) DCAD and either 3 mg vitamin D3 or 3 mg of 25-hydroxyvitamin D3 per 11 kg of dry matter/d. Treatment diets were fed from 255 d of gestation until calving. Peripheral blood neutrophils of 35 parous cows were collected at 0 and 3 d after calving and stimulated with 0 or 100 ng/mL of lipopolysaccharide (LPS). Furthermore, serum Ca and incidences of postpartum diseases were recorded for all cows. The mRNA transcripts of ß-defensin genes were quantified by real-time PCR, and data were analyzed with a general linear mixed model to test for fixed effects and interactions of day, level of DCAD, source of vitamin D, and incidence of disease. Effects of DCAD and vitamin D on neutrophil oxidative burst and phagocytosis were previously reported but were analyzed for effects of disease in the present study. Transcripts for DEFB1, DEFB3, DEFB4, DEFB5, DEFB7, DEFB10, and lingual antimicrobial peptide (LAP) in neutrophils were upregulated by LPS at 0 d but not at 3 d. Transcripts for DEFB4 and DEFB7 in LPS-stimulated neutrophils were greater in cows fed negative DCAD diets compared with positive DCAD. Source of vitamin D (vitamin D3 vs. 25-hydroxyvitamin D3) did not affect expression of ß-defensins in neutrophils. Cows with postpartum subclinical hypocalcemia (serum Ca <2.0 mM) had decreased DEFB3, DEFB4, DEFB6, DEFB7, DEFB10, and LAP expression in LPS-stimulated neutrophils compared with cows that did not experience subclinical hypocalcemia. Likewise, DEFB4, DEFB6, DEFB7, DEFB10, and LAP in LPS-stimulated neutrophils at 3 d postpartum were positively associated with serum Ca at 0 d postpartum. Transcripts for DEFB7, DEFB10 and LAP also were less abundant in neutrophils from cows with metritis compared with healthy cows. In conclusion, feeding a prepartum negative DCAD to improve postpartum serum Ca resulted in greater neutrophil ß-defensin expression, and greater neutrophil ß-defensin expression was positively associated with postpartum health.


Assuntos
Ração Animal/análise , Ânions/metabolismo , Cátions/metabolismo , Doenças dos Bovinos/metabolismo , Hipocalcemia/veterinária , beta-Defensinas/genética , Animais , Bovinos , Dieta/veterinária , Suplementos Nutricionais/análise , Feminino , Regulação da Expressão Gênica , Humanos , Hipocalcemia/metabolismo , Lactação , Neutrófilos/metabolismo , Paridade , Período Pós-Parto , Gravidez , Distribuição Aleatória , Vitamina D/metabolismo
9.
BMC Microbiol ; 17(1): 230, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29216824

RESUMO

BACKGROUND: Water evaporation in solar salterns creates salinity gradients that promote the adaptation of microbial species to different salinities. This competitive habitat challenges the metabolic capabilities of microorganisms and promotes alterations in their production of secondary metabolites. Thus, solar salterns are a potentially important source of new natural products. In Colombia, the most important and representative solar saltern is located in Manaure (La Guajira) in the north of Colombia. The aim of this study was to develop an alternative screening strategy to select halophilic bacteria as producers of bioactive compounds from mixed microbial cultures rather than individual environmental isolates. Brine and sediment samples from different ponds (across a salinity gradient) were inoculated in seven different culture media to grow bacteria and archaea, allowing for a total of 40 different mixed cultures. An organic extract from each mixed culture was obtained and tested against multidrug resistant pathogens, including Klebsiella pneumoniae, vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus and Bacillus subtilis. In addition, the extracts were tested against two human cancer cell lines, cervical adenocarcinoma (SiHa) and lung carcinoma (A-549). RESULTS: Twenty-four of the forty extracts from mixed cultures obtained from brine and sediment samples from the Manaure solar saltern showed antibacterial activity against Bacillus subtilis. Two extracts, referred to as A1SM3-29 and A1SM3-36, were also active against a methicillin-resistant Staphylococcus aureus, with the latter extract also showing slight cytotoxic activity against the assayed human lung cancer cell line. From this mixed culture, nine isolates were cultivated, and their extracts were tested against the same pathogens, resulting in the identification of a Vibrio sp. strain (A1SM3-36-8) with antimicrobial activity that was similar to that observed for the mixed culture extract. The extract of this strain was subjected to a bioautography assay, and 3 different fractions exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus. Based on the amount obtained for each fraction, F3 was selected to isolate and identify its metabolites. The major compound was identified by NMR and HRMS as 13-cis-docosenamide, an amide that has been previously reported to be an antimicrobial and cytotoxic compound. CONCLUSIONS: Our results shows the utility of our strategy in detecting bioactive molecules in initial mixed cultures by biological assays, resulting in the isolation and characterization of Vibrio sp. A1SM3-36-8, a halophilic strain with great antibacterial and cytotoxic potential.


Assuntos
Bactérias/efeitos dos fármacos , Misturas Complexas/farmacologia , Euryarchaeota/química , Euryarchaeota/isolamento & purificação , Sedimentos Geológicos/microbiologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colômbia , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Microbiologia Ambiental , Humanos , Testes de Sensibilidade Microbiana , Sais , Metabolismo Secundário
10.
Wound Repair Regen ; 24(2): 411-7, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26834030

RESUMO

Aged and adult populations have differences in the structural, biological, and healing properties of skin. Comparative studies of healing under the influence of retinoids in both these populations are very important and, to the best of our knowledge, have not been performed to date. The purpose of this study was to compare the activities of topical tretinoin in aged and adult animal models of wound healing by secondary intention. Male aged rats (24 months old, n = 7) and adult rats (6 months old, n = 8) were used. The rats were assigned to the following groups according to the dates on which wound samples were excised (day 14 or 21 after model creation): treated group, control group, and naive group. Topical application of tretinoin cream was used only on the proximal wound and was applied daily for 7 days. Wound healing areas were measured using metal calipers, and morphological analysis was performed. Slides were stained with Hematoxylin and Eosin, Masson's trichrome, and periodic acid-Schiff stains. Statistical analysis adopted a 5% coefficient for rejection of the null hypothesis. Although aged animals showed skin repair, complete reepithelialization was found on day 21 in some animals of both groups (treated and control). In aged rats, the wound area was significantly smaller in treated wounds than in untreated wounds, resulting in a larger scar area compared with the adult group. When treated wounds were compared, no differences were found between the wound areas in adult and aged rats. As expected, the collagen concentration was higher in normal skin from adult rats than in normal skin from aged animals, but there was no difference when aged skin was treated with tretinoin. These results indicate that tretinoin increases collagen synthesis in aged skin and returns the healing process to a normal state of skin healing.


Assuntos
Ceratolíticos/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/patologia , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Tecido de Granulação/metabolismo , Ceratolíticos/uso terapêutico , Masculino , Ratos , Ratos Wistar , Reepitelização/efeitos dos fármacos , Ferimentos e Lesões/patologia
11.
RNA ; 19(5): 605-12, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23485552

RESUMO

Argonaute proteins are essential components of microRNA (miRNA)- and small interfering (siRNA)-mediated post-transcriptional gene-silencing pathways. In mammals, Argonaute2 (Ago2) is the catalytic center of the RNA-induced silencing complex (RISC) that recognizes and endonucleolytically cleaves messenger RNAs of complementary sequence. Although Ago2 is essential for RISC activity, the mechanisms regulating Argonaute protein expression are largely unknown. Here we report that Ago2 expression is dependent on miRNA abundance and that unloaded Ago2 protein is unstable. We observed a low level of Ago2 protein in Dicer- or DGCR8-deficent mouse embryonic stem cells (ESCs) that could be rescued by reintroduction of the respective cDNAs or by transfection of miRNAs or siRNAs. We found expression of Ago2 protein from a transgene to be similarly regulated, further supporting a post-transcriptional control mechanism. Inhibition of Hsc70/Hsp90 led to decreased Ago2 expression consistent with the reported role of this chaperone complex in RISC assembly. We furthermore found that the degradation of Ago2 was specifically blocked by inhibition of the lysosome, but not the proteasome. Our results illuminate a novel feedback mechanism that post-transcriptionally couples Ago2 protein levels with small RNA abundance with implications for RNA-interference (RNAi) and miRNA function.


Assuntos
Proteínas Argonautas , Inativação Gênica , MicroRNAs , Interferência de RNA , Animais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Carboxipeptidases/metabolismo , Linhagem Celular , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação da Expressão Gênica , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA
12.
RNA ; 19(11): 1583-93, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24049110

RESUMO

Argonaute2 (Ago2) protein and associated microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC) for target messenger RNA cleavage and post-transcriptional gene silencing. Although Ago2 is essential for RISC activity, the mechanism of RISC assembly is not well understood, and factors controlling Ago2 protein expression are largely unknown. A role for the Hsc70/Hsp90 chaperone complex in loading small RNA duplexes into the RISC has been demonstrated in cell extracts, and unloaded Ago2 is unstable and degraded by the lysosome in mammalian cells. Here we identify the co-chaperones Fkbp4 and Fkbp5 as Ago2-associated proteins in mouse embryonic stem cells. Pharmacological inhibition of this interaction using FK506 or siRNA-mediated Fkbp4/5 depletion leads to decreased Ago2 protein levels. We find FK506 treatment inhibits, whereas Fkbp4/5 overexpression promotes, miRNA-mediated stabilization of Ago2 expression. Simultaneous treatment with a lysosome inhibitor revealed the accumulation of unloaded Ago2 complexes in FK506-treated cells. We find that, consistent with unloaded miRNAs being unstable, FK506 treatment also affects miRNA abundance, particularly nascent miRNAs. Our results support a role for Fkbp4/5 in RISC assembly.


Assuntos
Proteínas Argonautas/biossíntese , Complexo de Inativação Induzido por RNA/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Linhagem Celular , Células-Tronco Embrionárias , Proteínas de Choque Térmico HSC70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lisossomos/metabolismo , Camundongos , MicroRNAs/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Tacrolimo/metabolismo , Proteínas de Ligação a Tacrolimo/genética
13.
Drug Discov Today Technol ; 18: 9-17, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26723887

RESUMO

Histone methylation is a prevalent and dynamic chromatin modification, executed by the action of histone methyltransferases (HMTs) and demethylases (HDMs). Aberrant activity of many of these enzymes is associated with human disease, hence, there is a growing interest in identifying corresponding small molecule inhibitors with therapeutic potential. To date, most of the technologies supporting the identification of these inhibitors constitute in vitro biochemical assays which, although robust and sensitive, do not study HMTs and HDMs in their native cellular state nor provide information of inhibitor's cell permeability and toxicity. The evident need for complementary cellular approaches has recently propelled the development of cell-based assays that enable screening of HMT and HDM enzymes in a more relevant environment. Here, we highlight current cellular methodologies for HMT and HDM drug discovery support. We anticipate that implementation of these cell-based assays will positively impact the discovery of pharmacologically potent HMT and HDM inhibitors.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histonas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Bioensaio , Células Cultivadas , Perfilação da Expressão Gênica , Histona Desmetilases/genética , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Humanos , Metilação , Ligação Proteica
16.
Scand J Gastroenterol ; 49(3): 309-16, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24325610

RESUMO

The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and ß-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for ß-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and ß-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and ß-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and ß-catenin). ß-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for ß-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, ß-catenin, and MMP2 expression in animal models of colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Fenótipo , Ratos , Ratos Nus , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , beta Catenina/genética
17.
Sensors (Basel) ; 14(1): 1358-71, 2014 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-24419164

RESUMO

Two new coumarin-based "turn-off" fluorescent probes, (E)-3-((3,4-dihydroxybenzylidene)amino)-7-hydroxy-2H-chromen-2-one (BS1) and (E)-3-((2,4-dihydroxybenzylidene)amino)-7-hydroxy-2H-chromen-2-one (BS2), were synthesized and their detection of copper(II) and iron(III) ions was studied. Results show that both compounds are highly selective for Cu²âº and Fe³âº ions over other metal ions. However, BS2 is detected directly, while detection of BS1 involves a hydrolysis reaction to regenerate 3-amino-7-hydroxycoumarin (3) and 3,4-dihydroxybenzaldehyde, of which 3 is able to react with copper(II) or iron(III) ions. The interaction between the tested compounds and copper or iron ions is associated with a large fluorescence decrease, showing detection limits of ca. 10⁻5 M. Preliminary studies employing epifluorescence microscopy demonstrate that Cu²âº and Fe³âº ions can be imaged in human neuroblastoma SH-SY5Y cells treated with the tested probes.


Assuntos
Cumarínicos/química , Fluorescência , Imagem Molecular/métodos , Linhagem Celular Tumoral , Rastreamento de Células , Cobre/química , Corantes Fluorescentes , Humanos , Peróxido de Hidrogênio , Íons/química , Ferro/química
18.
Heliyon ; 10(6): e27721, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38545197

RESUMO

Objectives: Evaluate the strength degradation of polymeric ligature chains after their immersion in cetylpyridinium chloride-based mouthwashes. Methods: 240 elastomeric samples from four different manufacturers (Rocky Mountain®, Ormco®, Morelli® and Dentaurum®) in two types of configurations (with and without intermodular links) and divided in 3 groups (distilled water, Vitis CPC Protect® and PERIO·AID® 0.05%) at 5 follow-up periods (0-24 h, 7-14 -21 days) were immersed twice a day for 60 s, following the manufacturers' protocols. A universal traction machine was used to perform the measurements and a post hoc multiple comparisons were based on the Bonferroni test and extended to a 3-way ANOVA test (α = 0.05). Results: There was a drop in strength up to 35.9% at 24 h. After a week, the short chains (52%) degraded less than the long ones (57.3%) with significant differences (p < 0.001) and the same pattern was observed until 21 days (p < 0.001). At 24 h, the degradation of the chains exposed in distilled water was 25.8%, in VITIS CPC Protect® 28.6% and in PERIO· AID® 0.05%, 27% with significant differences (p < 0.001). At 21 days, the VITIS CPC Protect® group obtained a much greater loss of strength, being this drop statistically significant (p < 0.001). The chains from Ormco® and RMO® experienced the least loss of force when immersed in the control group or PERIO AID® 0 0.05% (48% and 51%), while Dentaurum's in VITIS CPC Protect® lost more than 75%. Conclusions: The orthodontic elastomeric chains suffer a sharp drop in strength during the first days of treatment. When comparing the mouthwashes, there were statistically significant differences in terms of strength degradation. Clinical significance: Based on the results, some types of chains, such as the ones without intermodular links from Ormco® showed better properties throughout the study. When immersed in PERIO·AID®0.05%, all showed significantly better results over time. Thus, PERIO·AID®0.05% can be recommended as a complementary oral hygiene element in dental treatments when elastomeric chains are used.

19.
J Am Dent Assoc ; 155(10): 845-857, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39207281

RESUMO

BACKGROUND: Social networks have become a widely used and accessible source of health-related information for patients, but this material is not always accurate or appropriate. The purpose of this study was to evaluate the quality of orthodontic information available on 2 of the most popular social media platforms. STUDIES REVIEWED: The authors conducted a systematic search of the literature that analyzed the quality of information regarding orthodontics on social networks and used recognized quality-evaluation methods, such as DISCERN, modified DISCERN, and the Quality Global Scale or the Video Information Quality Index, in the electronic databases of PubMed, Embase, and Scopus and through a manual search of gray literature. RESULTS: The authors identified a total of 534 potentially eligible articles, of which 22 eventually were included in the qualitative analysis. The application of the scales revealed that most of the content was of insufficient quality and lacked scientific rigor, precision, and support from reliable sources. The authors observed marked heterogeneity in the nature of the publications analyzed, with the most recurrent topics being general orthodontic treatment and the use of clear aligners. PRACTICAL IMPLICATIONS: Social media platforms provide low-quality information to patients, which potentially can be harmful. These findings underscore the need to offer alternative ways to resolve patient queries before and during treatment and highlight the importance of promoting informed and responsible education regarding online information on orthodontic treatments.


Assuntos
Ortodontia , Mídias Sociais , Humanos , Informação de Saúde ao Consumidor/normas
20.
Rev Med Inst Mex Seguro Soc ; 62(1): 1-7, 2024 Jan 08.
Artigo em Espanhol | MEDLINE | ID: mdl-39110914

RESUMO

Background: HER-2 positive (+) breast cancer (BC) accounts for 20-25% of BC, it is more aggressive, and it has a lower survival rate. Since the approval of trastuzumab in 1998, other HER-2-targeted therapies such as pertuzumab and trastuzumab emtansine (TDM1) have been introduced, improving patient survival. However, cardiotoxicity is an adverse effect of these treatments. Objective: To estimate the incidence of cardiotoxicity with trastuzumab, trastuzumab/pertuzumab, and TDM1 in women with HER-2 + BC treated over a 6-year period at the Hospital de Clínicas and the Hospital Departamental de Soriano. Material and methods: Observational, descriptive, and retrospective study which included patients with HER-2 + BC treated with trastuzumab, trastuzumab/pertuzumab, or TDM1. Results: 81 patients were included, with a cardiotoxicity incidence of 23.4%. Cardiotoxicity was determined by a > 10% decrease in left ventricular ejection fraction (LVEF) (57.9%) and a LVEF < 50% evident during treatment (42.1%). Only 1 patient presented symptomatic heart failure. 63.1% of those who discontinued treatment due to cardiotoxicity managed to resume it. No relationship was evident between cardiovascular history or the administration regimen and the development of cardiotoxicity. Conclusion: The study showed a cardiotoxicity incidence similar to the international one. Most did not present cardiac toxicity, and if they did, it was asymptomatic and reversible.


Introducción: el cáncer de mama (CM) HER-2 positivo (+) representa el 20-25% de los CM, es más agresivo y tiene menor sobrevida. Desde la aprobación del trastuzumab en 1998, se han introducido otras terapias dirigidas al HER-2 como pertuzumab y trastuzumab emtansina (TDM1), con lo cual ha mejorado la supervivencia de las pacientes. Sin embargo, la cardiotoxicidad representa un efecto adverso de estos tratamientos. Objetivo: estimar la incidencia de cardiotoxicidad con trastuzumab, trastuzumab/pertuzumab y TDM1 en mujeres con CM HER-2 +, tratadas en un periodo de 6 años en el Hospital de Clínicas y el Hospital Departamental de Soriano. Material y métodos: estudio observacional, descriptivo y retrospectivo que incluyó pacientes con CM HER-2 +, tratadas con trastuzumab, trastuzumab/pertuzumab o TDM1. Resultados: se incluyeron 81 pacientes. La incidencia de cardiotoxicidad fue del 23.4%. La cardiotoxicidad se determinó por una disminución > 10% de la fracción de ejección del venticulo izquierdo (FEVI) (57.9%) y por una FEVI < 50%, evidenciada durante el tratamiento (42.1%). Únicamente una paciente presentó insuficiencia cardiaca sintomática. El 63.1% de quienes suspendieron el tratamiento por cardiotoxicidad logró reanudarlo. No se evidenció una relación entre los antecedentes cardiovasculares ni con el esquema de administración y el desarrollo de cardiotoxicidad. Conclusión: el estudio mostró una incidencia de cardiotoxicidad similar a la internacional. La mayoría no tuvo toxicidad cardiaca y si la hubo fue asintomática y reversible.


Assuntos
Ado-Trastuzumab Emtansina , Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Cardiotoxicidade , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Cardiotoxicidade/etiologia , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Adulto , Ado-Trastuzumab Emtansina/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Incidência , Maitansina/análogos & derivados , Maitansina/efeitos adversos
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