RESUMO
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.
Assuntos
Disruptores Endócrinos , Humanos , Disruptores Endócrinos/toxicidade , Obesidade , Adipogenia , Adipócitos , Compostos Benzidrílicos/toxicidade , Tecido AdiposoRESUMO
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.
RESUMO
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.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Ácidos Graxos Ômega-3 , Animais , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismoRESUMO
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.
Assuntos
Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Comunicação Celular , Conexina 43/metabolismo , Junções Comunicantes/metabolismo , Obesidade/metabolismo , Animais , HumanosRESUMO
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.
Assuntos
Dor Crônica/metabolismo , Dor Crônica/terapia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Mediadores da Inflamação/metabolismo , Manejo da Dor , Animais , HumanosRESUMO
Diabetic retinopathy (DR) is one of the main causes of vision loss in the working age population. It is characterized by a progressive deterioration of the retinal microvasculature, caused by long-term metabolic alterations inherent to diabetes, leading to a progressive loss of retinal integrity and function. The mammalian retina presents an orderly layered structure that executes initial but complex visual processing and analysis. Gap junction channels (GJC) forming electrical synapses are present in each retinal layer and contribute to the communication between different cell types. In addition, connexin hemichannels (HCs) have emerged as relevant players that influence diverse physiological and pathological processes in the retina. This article highlights the impact of diabetic conditions on GJC and HCs physiology and their involvement in DR pathogenesis. Microvascular damage and concomitant loss of endothelial cells and pericytes are related to alterations in gap junction intercellular communication (GJIC) and decreased connexin 43 (Cx43) expression. On the other hand, it has been shown that the expression and activity of HCs are upregulated in DR, becoming a key element in the establishment of proinflammatory conditions that emerge during hyperglycemia. Hence, novel connexin HCs blockers or drugs to enhance GJIC are promising tools for the development of pharmacological interventions for diabetic retinopathy, and initial in vitro and in vivo studies have shown favorable results in this regard.
Assuntos
Conexinas/metabolismo , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Suscetibilidade a Doenças , Junções Comunicantes/metabolismo , Animais , Conexinas/genética , Retinopatia Diabética/patologia , Junções Comunicantes/genética , Expressão Gênica , Humanos , Neuroglia/metabolismo , Retina/metabolismo , Retina/patologiaRESUMO
Bovine mastitis (BM) is the most prevalent bacterial infection in the livestock sector, affecting the dairy industry greatly. The prevention and treatment of this disease is mainly made via antibiotics, but the increasing antimicrobial resistance of pathogens has affected the efficiency of conventional drugs. Pseudomonas sp. is one of the pathogens involved in this infection. The therapeutic rate of cure for this environmental mastitis-causing pathogen is practically zero, regardless of treatment. Biofilm formation has been one of the main virulence mechanisms of Pseudomonas hence presenting resistance to antibiotic therapy. We have manufactured chitosan nanoparticles (NQo) with tripolyphosphate (TPP) using ionotropic gelation. These NQo were confronted against a Pseudomonas sp. strain isolated from milk samples of cows diagnosed with BM, to evaluate their antimicrobial and antibiofilm capacity. The NQo showed great antibacterial effect in the minimum inhibitory concentrations (MIC), minimum bactericidal concentration (MBC) and disk diffusion assays. Using sub lethal concentrations, NQo were tested for inhibition of biofilm formation. The results show that the nanoparticles exhibited biofilm inhibition and were capable of eradicate pre-existing mature biofilm. These findings indicate that the NQo could act as a potential alternative to antibiotic treatment of BM.
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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.
Assuntos
Adipogenia/fisiologia , Disruptores Endócrinos/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Benzoatos/metabolismo , Poluentes Ambientais/metabolismo , Éteres Difenil Halogenados/metabolismo , Humanos , Metabolismo dos Lipídeos , Fenóis/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Pirenos/metabolismo , Fatores de Transcrição , Triclosan/metabolismoRESUMO
A simple and straightforward technique for coating microplate wells with molecularly imprinted polymer nanoparticles (nanoMIPs) to develop assays similar to the enzyme-linked immunosorbent (ELISA) assay to determine and quantify florfenicol (FF) in real food samples such as liquid milk and salmon muscle is presented here. The nanoMIPs were synthesized by a solid-phase approach with an immobilized FF (template) and characterized using dynamic light scattering, a SPR-2 biosensor system and transmission electron microscopy. Immobilization of nanoMIPs was conducted by preparing a homogenous solution of FF-nanoMIPs in water mixed with polyvinyl alcohol (PVA) 0.2% (w/v) in each well of a microplate. The detection of florfenicol was achieved in competitive binding experiments with a horseradish peroxidase-florfenicol (FF-HRP) conjugate. The assay made it possible to measure FF in buffer and in real samples (liquid milk and salmon muscle) within the range of 60-80 and 90-100 ng/mL, respectively. The immobilized nanoMIPs were stored for six weeks at room temperature and at 5 °C. The results indicate good signal recovery for all FF concentrations in spiked milk samples, without any detrimental effects to their binding properties. The high affinity of nanoMIPs and the lack of a requirement for cold chain logistics make them an attractive alternative to traditional antibodies used in ELISA.
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Oral diabetes-specific nutritional supplements (ONS-D) induce favourable postprandial responses in subjects with type 2 diabetes (DM2), but they have not been correlated yet with incretin release and subjective appetite (SA). This randomised, double-blind, cross-over study compared postprandial effects of ONS-D with isomaltulose and sucromalt versus standard formula (ET) on glycaemic index (GI), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and SA in 16 individuals with DM2. After overnight fasting, subjects consumed a portion of supplements containing 25 g of carbohydrates or reference food. Blood samples were collected at baseline and at 30, 60, 90, 120, 150 and 180 min; and SA sensations were assessed by a visual analogue scale on separate days. Glycaemic index values were low for ONS-D and intermediate for ET (p < 0.001). The insulin area under the curve (AUC0-180 min) (p < 0.02) and GIP AUC (p < 0.02) were lower after ONS-D and higher GLP-1 AUC when compared with ET (p < 0.05). Subjective appetite AUC was greater after ET than ONS-D (p < 0.05). Interactions between hormones, hunger, fullness and GI were found, but not within the ratings of SA; isomaltulose and sucromalt may have influenced these factors.