New Evidence on BPA's Role in Adipose Tissue Development of Proinflammatory Processes and Its Relationship with Obesity.

Bisphenol A (BPA) is a xenobiotic with endocrine disruptor properties which interacts with various receptors, eliciting a cellular response. In the plastic industry, BPA is widely used in the production of polycarbonate and epoxy-phenolic resins to provide elastic properties. It can be found in the lining of canned foods, certain plastic containers, thermal printing papers, composite dental fillings, and medical devices, among other things. Therefore, it is a compound that, directly or indirectly, is in daily contact with the human organism. BPA is postulated to be a factor responsible for the global epidemic of obesity and non-communicable chronic diseases, belonging to the obesogenic and diabetogenic group of compounds. Hence, this endocrine disruptor may be responsible for the development of metabolic disorders, promoting in fat cells an increase in proinflammatory pathways and upregulating the expression and release of certain cytokines, such as IL6, IL1ß, and TNFα. These, in turn, at a systemic and local level, are associated with a chronic low-grade inflammatory state, which allows the perpetuation of the typical physiological complications of obesity.

Improving Lurasidone Hydrochloride's Solubility and Stability by Higher-Order Complex Formation with Hydroxypropyl-ß-cyclodextrin.

The biopharmaceutical classification system groups low-solubility drugs into two groups: II and IV, with high and low permeability, respectively. Most of the new drugs developed for common pathologies present solubility issues. This is the case of lurasidone hydrochloride-a drug used for the treatment of schizophrenia and bipolar depression. Likewise, the stability problems of some drugs limit the possibility of preparing them in liquid pharmaceutical forms where hydrolysis and oxidation reactions can be favored. Lurasidone hydrochloride presents the isoindole-1,3-dione ring, which is highly susceptible to alkaline hydrolysis, and the benzisothiazole ring, which is susceptible to a lesser extent to oxidation. Herein, we propose to study the increase in the solubility and stability of lurasidone hydrochloride by the formation of higher-order inclusion complexes with hydroxypropyl-ß-cyclodextrin. Several stoichiometric relationships were studied at between 0.5 and 3 hydroxypropyl-ß-cyclodextrin molecules per drug molecule. The obtained products were characterized, and their solubility and stability were assessed. According to the obtained results, the formation of inclusion complexes dramatically increased the solubility of the drug, and this increased with the increase in the inclusion ratio. This was associated with the loss of crystalline state of the drug, which was in an amorphous state according to infrared spectroscopy, calorimetry, and X-ray analysis. This was also correlated with the stabilization of lurasidone by the cyclodextrin inhibiting its recrystallization. Phase solubility,1H-NMR, and docking computational characterization suggested that the main stoichiometric ratio was 1:1; however, we cannot rule out a 1:2 ratio, where a second cyclodextrin molecule could bind through the isoindole-1,3-dione ring, improving its stability as well. Finally, we can conclude that the formation of higher-order inclusion complexes of lurasidone with hydroxypropyl-ß-cyclodextrin is a successful strategy to increase the solubility and stability of the drug.

Specialized Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis.

Cardiovascular disease (CVD) is a global public health issue due to its high morbidity, mortality, and economic impact. The implementation of innovative therapeutic alternatives for CVD is urgently required. Specialized proresolving lipid mediators (SPMs) are bioactive compounds derived from ω-3 and ω-6 fatty acids, integrated into four families: Lipoxins, Resolvins, Protectins, and Maresins. SPMs have generated interest in recent years due to their ability to promote the resolution of inflammation associated with the pathogeneses of numerous illnesses, particularly CVD. Several preclinical studies in animal models have evidenced their ability to decrease the progression of atherosclerosis, intimal hyperplasia, and reperfusion injury via diverse mechanisms. Large-scale clinical trials are required to determine the effects of SPMs in humans. This review integrates the currently available knowledge of the therapeutic impact of SPMs in CVD from preclinical and clinical studies, along with the implicated molecular pathways. In vitro results have been promising, and as such, SPMs could soon represent a new therapeutic alternative for CVD.

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity.

Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, understanding the biological regulation of adipose tissue is of fundamental relevance. Connexin, a protein that forms intercellular membrane channels of gap junctions and unopposed hemichannels, plays a key role in adipogenesis and in the maintenance of adipose tissue homeostasis. The expression and function of Connexin 43 (Cx43) during the different stages of the adipogenesis are differentially regulated. Moreover, it has been shown that cell-cell communication decreases dramatically upon differentiation into adipocytes. Furthermore, inhibition of Cx43 degradation or constitutive overexpression of Cx43 blocks adipocyte differentiation. In the first events of adipogenesis, the connexin is highly phosphorylated, which is likely associated with enhanced Gap Junction (GJ) communication. In an intermediate state of adipocyte differentiation, Cx43 phosphorylation decreases, as it is displaced from the membrane and degraded through the proteasome; thus, Cx43 total protein is reduced. Cx is involved in cardiac disease as well as in obesity-related cardiovascular diseases. Different studies suggest that obesity together with a high-fat diet are related to the production of remodeling factors associated with expression and distribution of Cx43 in the atrium.

Specialized Pro-Resolving Lipid Mediators: The Future of Chronic Pain Therapy?

Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.

Adipogenesis Regulation and Endocrine Disruptors: Emerging Insights in Obesity.

Endocrine disruptors (EDs) are defined as environmental pollutants capable of interfering with the functioning of the hormonal system. They are environmentally distributed as synthetic fertilizers, electronic waste, and several food additives that are part of the food chain. They can be considered as obesogenic compounds since they have the capacity to influence cellular events related to adipose tissue, altering lipid metabolism and adipogenesis processes. This review will present the latest scientific evidence of different EDs such as persistent organic pollutants (POPs), heavy metals, "nonpersistent" phenolic compounds, triclosan, polybrominated diphenyl ethers (PBDEs), and smoke-derived compounds (benzo -alpha-pyrene) and their influence on the differentiation processes towards adipocytes in both in vitro and in vivo models.

[Eating behavior and its association with nutritional status and physical activity in a general Chilean population]. / Comportamiento hacia los alimentos y su asociación con el estado nutricional y la actividad física en una población general chilena.

INTRODUCTION: obesity has become a chronic disease whose etiology can be based on an imbalance between the contribution and energy expenditure of the individual, where the behavior against food consumption and physical activity play an important role as determinants in this energy balance. METHODS: in the present study, behavior in relation to food consumption and physical activity and its association with nutritional status in a general Chilean population was analyzed. It was a cross-sectional study in 629 people, belonging to the university community of the Andres Bello University. The subjects answered online surveys about sociodemographic, anthropometric, attitude to food consumption (TFEQ) and physical activity (GPAQ). RESULTS: the factorial structure of the TFEQ questionnaire in Spanish showed two factors: the "cognitive restriction" factor and the "disinhibition versus food" factor. With regard to nutritional status, it was found that 39.4% of the population had malnutrition due to excess. In relation to physical activity, half of the subjects performed less than 36 minutes of exercise per day. Individuals with uninhibited behavior towards food presented less practice of total physical activity. Additionally, subjects with low BMI and with greater age were more likely to present a restrictive behavior towards food. CONCLUSION: in the TFEQ questionnaire, two factors were found that explain the variation of behavior in relation to food consumption, which were associated with BMI and with physical activity in the study population.

INTRODUCCIÓN: la obesidad se ha transformado en una enfermedad crónica cuya etiología puede basarse en un desequilibrio entre el aporte y el gasto energético del individuo. Por lo tanto, el comportamiento frente al consumo de alimentos y la actividad física juegan un papel importante como determinantes clave en el resultado del balance energético. MÉTODOS: en el presente estudio se analizó la conducta frente al consumo de alimentos y la actividad física y su asociación con el estado nutricional en una población general chilena. Fue un estudio de corte transversal en 629 personas, pertenecientes a la comunidad universitaria de la Universidad Andres Bello. Los sujetos contestaron encuestas en línea acerca de antecedentes sociodemográficos, antropométricos, actitud frente al consumo de alimentos (TFEQ) y actividad física (GPAQ). RESULTADOS: la estructura factorial del cuestionario TFEQ en español mostró dos factores: el factor de ­restricción cognitiva­ y el factor de ­desinhibición frente a los alimentos­. Con relación al estado nutricional, se encontró que un 39,4% de la población presentó malnutrición por exceso. En cuanto a la actividad física, la mitad de los sujetos realizaban menos de 36 minutos de ejercicio al día. Los individuos con una conducta desinhibida frente a los alimentos presentaron menor práctica de actividad física total. Adicionalmente, sujetos con índice de masa corporal (IMC) bajo y con mayor edad tuvieron mayor probabilidad de presentar una conducta restrictiva frente a los alimentos. CONCLUSIÓN: en el cuestionario TFEQ se encontraron dos factores que explican la variación de la conducta frente al consumo de alimentos, los cuales se asociaron con IMC y con actividad física en la población de estudio.

Comportamiento hacia los alimentos y su asociación con el estado nutricional y la actividad física en una población general chilena / Eating behavior and its association with nutritional status and physical activity in a general Chilean population

Introducción: la obesidad se ha transformado en una enfermedad crónica cuya etiología puede basarse en un desequilibrio entre el aporte y el gasto energético del individuo. Por lo tanto, el comportamiento frente al consumo de alimentos y la actividad física juegan un papel importante como determinantes clave en el resultado del balance energético. Métodos: en el presente estudio se analizó la conducta frente al consumo de alimentos y la actividad física y su asociación con el estado nutricional en una población general chilena. Fue un estudio de corte transversal en 629 personas, pertenecientes a la comunidad universitaria de la Universidad Andres Bello. Los sujetos contestaron encuestas en línea acerca de antecedentes sociodemográficos, antropométricos, actitud frente al consumo de alimentos (TFEQ) y actividad física (GPAQ). Resultados: la estructura factorial del cuestionario TFEQ en español mostró dos factores: el factor de -restricción cognitiva- y el factor de -desinhibición frente a los alimentos-. Con relación al estado nutricional, se encontró que un 39,4% de la población presentó malnutrición por exceso. En cuanto a la actividad física, la mitad de los sujetos realizaban menos de 36 minutos de ejercicio al día. Los individuos con una conducta desinhibida frente a los alimentos presentaron menor práctica de actividad física total. Adicionalmente, sujetos con índice de masa corporal (IMC) bajo y con mayor edad tuvieron mayor probabilidad de presentar una conducta restrictiva frente a los alimentos. Conclusión: en el cuestionario TFEQ se encontraron dos factores que explican la variación de la conducta frente al consumo de alimentos, los cuales se asociaron con IMC y con actividad física en la población de estudio

Introduction: obesity has become a chronic disease whose etiology can be based on an imbalance between the contribution and energy expenditure of the individual, where the behavior against food consumption and physical activity play an important role as determinants in this energy balance. Methods: in the present study, behavior in relation to food consumption and physical activity and its association with nutritional status in a general Chilean population was analyzed. It was a cross-sectional study in 629 people, belonging to the university community of the Andres Bello University. The subjects answered online surveys about sociodemographic, anthropometric, attitude to food consumption (TFEQ) and physical activity (GPAQ). Results: the factorial structure of the TFEQ questionnaire in Spanish showed two factors: the "cognitive restriction" factor and the "disinhibition versus food" factor. With regard to nutritional status, it was found that 39.4% of the population had malnutrition due to excess. In relation to physical activity, half of the subjects performed less than 36 minutes of exercise per day. Individuals with uninhibited behavior towards food presented less practice of total physical activity. Additionally, subjects with low BMI and with greater age were more likely to present a restrictive behavior towards food. Conclusion: in the TFEQ questionnaire, two factors were found that explain the variation of behavior in relation to food consumption, which were associated with BMI and with physical activity in the study population

Alpha-1-adrenoceptor subtype selective regulation of connexin 43 expression in rat cardiomyocytes.

Connexin43 (Cx43) is the predominant intercellular gap junction protein in the heart providing intercellular communication for the cell-to-cell transfer of electrical activation. In a previous study, we could show that alpha-adrenoceptor stimulation can affect Cx43 expression and function. We now wanted to elucidate which alpha1-adrenoceptor subtype might be involved. Cultured neonatal rat cardiomyocytes were exposed to various concentrations of phenylephrine (0.1-1,000 nM) for 24 h (n=6). Thereafter, cells were harvested, and after lysis, Cx43 content was determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot. Results were normalised to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Finally, we determined the effect of this treatment on intercellular gap junction conductivity using dual whole-cell voltage clamp. Similarly, we tested the effect of an additional treatment with either 10 nM prazosin or, to assess the subtypes, 10 nM of the alpha(1A)-antagonist RS17053 (n=6), 500 nM of the alpha(1B)-antagonist AH1111OA (n=6), or 50 nM of the alpha(1D)-antagonist BMY7378 (n = 6). Moreover, we incubated the cells for 24 h with the alpha(1A)-adrenoceptor agonist A61603 (10 nM). Phenylephrine led to enhanced Cx43 expression with a pEC50 8.00+/-0.06. The other cardiac connexins, Cx40 and Cx45, as well as GAPDH were not affected. This increase in Cx43 expression resulted in enhanced gap-junction conductance (44+/-4 nS vs 26+/-4 nS). As expected, the increased Cx43 expression could be antagonized by prazosin. Moreover, it was nearly completely inhibited by BMY7378 but was not significantly affected by RS17053. AH1111OA led to a moderate but incomplete inhibition. In contrast, beta-actin expression was also up-regulated by phenylephrine but was inhibited by prazosin or RS17053, while it was not affected by BMY7378 or AH1111OA. About 24 h exposure to the alpha(1A)-adrenoceptor agonist A61603 led to a twofold increase in beta-actin but did not affect Cx43. The low pEC50 value of about 1 nM for noradrenaline reported in our earlier study fits well to the hypothesis of an effect mediated predominantly via alpha(1D)-adrenoceptors, which is further supported by the finding of a nearly complete antagonisation of the phenylephrine effect by BMY7378. Thus, we conclude that cardiac Cx43 expression seems to be regulated via alpha(1)-adrenoceptors predominantly by subtype alpha(1D)-adrenoceptors, while other proteins like beta-actin seem to be regulated via alpha(1A)-adrenoceptors.