ABSTRACT
Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.
Subject(s)
Anti-Obesity Agents , Bridged Bicyclo Compounds, Heterocyclic , GABAergic Neurons , Obesity , Animals , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Rats , Mice , Anti-Obesity Agents/pharmacology , Male , Obesity/drug therapy , Obesity/metabolism , Feeding Behavior/drug effects , Hypothalamic Area, Lateral/drug effects , Hypothalamic Area, Lateral/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Mice, Transgenic , Weight Loss/drug effects , Rats, Sprague-DawleyABSTRACT
Introducción: El termino maloclusión hace referencia a la deficiencia en el alineamiento de los dientes y en la forma en que los dientes superiores e inferiores encajan entre sí. La mayoría de las personas tienen algún grado de maloclusión, aunque normalmente no es lo suficientemente grave para requerir tratamiento obligatorio, aunque los pacientes lo requieran por una percepción de estética dental. La aplicación de índices estandarizados permite establecer correctamente la planificación de actividades de prevención y el tratamiento oportuno. Objetivo: Determinar el grado de maloclusiones y la necesidad de tratamiento de ortodoncia en pacientes con dentición mixta. Metodología: Estudio observación al descriptivo de corte transversal en el que se aplicó el índice de estética dental (DAI)utilizando los registros clínicos y fotográficos de pacientes atendidos en la Clínica de Ortodoncia de la Facultad de Odontología de la Universidad del Pacífico en el año 2018. Para el análisis de los datos según estadística descriptiva se utilizó el programa informático Microsoft Excel®. Resultado: El grado de maloclusión más frecuente fue la maloclusión menor, observada en el 45% de los pacientes, seguida por la maloclusión manifiesta en el 42% de los casos. El 55% de los pacientes, según el DAI, tenían indicación de tratamiento de ortodoncia, el 42% en forma electiva, en el 10% un tratamiento altamente deseable y el 3% con indicación de tratamiento obligatorio. Conclusión: La mayoría delos pacientes tenía algún grado de maloclusión con la consiguiente indicación de tratamiento de ortodoncia, los que no tenían indicación de tratamiento según el DAI presentaron afectación en al menos una característica oclusal relacionada a la percepción de estética dental.
Introduction: The term malocclusion refers to a deficiency in the alignment of the teeth and the way the upperand lower teeth fit together. Most people have some degree of malocclusion, although it isusually not severe enough to require mandatory treatment, although patients require itfor perceived dental esthetics. The application of standardized indexes makesit possible to correctly establish the planning of prevention activities and timely treatment. Objective:To determine the degree of malocclusion and the need for orthodontic treatmentin patients with mixed dentition. Methodology:Descriptiveobservational cross-sectional study in which the dental esthetic index (DAI) was applied using the clinical and photographic recordsof patients seen in the Orthodontic Clinic of the Schoolof Dentistry of the Universidad del Pacífico in 2018. For the analysis of thedata according to descriptive statistics, Microsoft Excel® software was used. Result:The most frequent degree of malocclusion was minor malocclusion, observed in 45% ofthe patients, followed by manifest malocclusion in 42% of the cases. According to theDAI, 55% of the patients had an indication for orthodontic treatment, 42% electively, 10% with highly desirable treatment and 3% with an indication for mandatorytreatment. Conclusion:Most of the patients had some degree of malocclusion withthe consequent indication for orthodontic treatment; those who did not havean indication for treatmentaccording to theDAIpresented affectation in at least one occlusal characteristic related tothe perception of dental esthetics.
Subject(s)
Humans , Male , Female , Malocclusion , Orthodontics , Dentition, Mixed , Esthetics, DentalABSTRACT
Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation than normoxic cells. However, the effects of 2-methoxyestradiol (2-ME), an anti-angiogenic, antiproliferative and pro-apoptotic drug, on hypoxic lung cancer cells are unknown. The aim of the present study was to compare the effects of 2-ME on cell growth, apoptosis, hypoxia-inducible factor 1α (HIF-1α) and HIF-2α gene and protein expression in A549 cells under normoxic and hypoxic conditions. To establish the optimal 2-ME concentration with which to carry out the apoptosis assay and to examine mRNA and protein expression of HIFs, cell growth analysis was carried out through N-hexa-methylpararosaniline staining assays in A549 cell cultures treated with one of five different 2-ME concentrations at different times under normoxic or hypoxic growth conditions. The 2-ME concentration of 10 mM at 72 h was selected to perform all further experiments. Apoptotic cells were analyzed by flow cytometry. Western blotting was used to determine HIF-1α and HIF-2α protein expression in total cell extracts. Cellular localization of HIF-1α and HIF-2α was assessed by immunocytochemistry. HIF-1α and HIF-2α gene expression was determined by real-time PCR. A significant increase in the percentage of apoptosis was observed when cells were treated with 2-ME under a normoxic but not under hypoxic conditions (p=0.006). HIF-1α and HIF-2α protein expression levels were significantly decreased in cells cultured under hypoxic conditions and treated with 2-ME (p<0.001). Furthermore, 2-ME decreased the HIF-1α and HIF-2α nuclear staining in cells cultured under hypoxia. The HIF-1α and HIF-2α mRNA levels were significantly lower when cells were exposed to 2-ME under normoxia and hypoxia. Our results suggest that 2-ME could have beneficial results when used with conventional chemotherapy in an attempt to lower the invasive and metastatic processes during cancer development due to its effects on the gene expression and protein synthesis of HIFs.
