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A series of three Ni(II)-POCOP complexes para-functionalized with an acetoxyl fragment were synthesized. All complexes (2 a-c) were fully characterized through standard analytical techniques. The molecular structure of complex 2 b was unambiguously determined by single-crystal X-ray diffraction, revealing that the metal center is situated in a slightly distorted square-planar environment. Additionally, the acetoxy fragment at the para-position of the phenyl ring was found to be present. The inâ vitro cytotoxic activity of all complexes was assessed on six human cancer cell lines. Notably, complex 2 b exhibited selective activity against K-562 (chronic myelogenous leukemia) and MCF-7 (mammary adenocarcinoma) with IC50 values of 7.32±0.60â µM and 14.36±0.02â µM, respectively. Furthermore, this compound showed negligible activity on the healthy cell line COS-7, highlighting the potential therapeutic application of 2 b. The cytotoxic evaluations were further complemented with molecular docking calculations to explore the potential biological targets of complex 2 b, revealing interactions with cluster differentiation protein 1a (CD1â A, PDB: 1xz0) for K-562 and with the progesterone receptor for MCF-7.
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Antineoplásicos , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Níquel , Animais , Humanos , Acetilação , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Relação Dose-Resposta a Droga , Estrutura Molecular , Níquel/química , Níquel/farmacologia , Relação Estrutura-Atividade , Receptores de Progesterona/química , Receptores de Progesterona/metabolismoRESUMO
This paper presents a semi-automated, scalable, and homologous methodology towards IoT implemented in Python for extracting and integrating images in pedestrian and motorcyclist areas on the road for constructing a multiclass object classifier. It consists of two stages. The first stage deals with creating a non-debugged data set by acquiring images related to the semantic context previously mentioned, using an embedded device connected 24/7 via Wi-Fi to a free and public CCTV service in Medellin, Colombia. Through artificial vision techniques, and automatically performs a comparative chronological analysis to download the images observed by 80 cameras that report data asynchronously. The second stage proposes two algorithms focused on debugging the previously obtained data set. The first one facilitates the user in labeling the data set not debugged through Regions of Interest (ROI) and hotkeys. It decomposes the information in the nth image of the data set in the same dictionary to store it in a binary Pickle file. The second one is nothing more than an observer of the classification performed by the user through the first algorithm to allow the user to verify if the information contained in the Pickle file built is correct.
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BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-ß peptide (Aß) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.
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Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.
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In recent decades, a number of novel non-visual opsin photopigments belonging to the family of G protein- coupled receptors, likely involved in a number of non-image-forming processes, have been identified and characterized in cells of the inner retina of vertebrates. It is now known that the vertebrate retina is composed of visual photoreceptor cones and rods responsible for diurnal/color and nocturnal/black and white vision, and cells like the intrinsically photosensitive retinal ganglion cells (ipRGCs) and photosensitive horizontal cells in the inner retina, both detecting blue light and expressing the photopigment melanopsin (Opn4). Remarkably, these non-visual photopigments can continue to operate even in the absence of vision under retinal degeneration. Moreover, inner retinal neurons and Müller glial cells have been shown to express other photopigments such as the photoisomerase retinal G protein-coupled receptor (RGR), encephalopsin (Opn3), and neuropsin (Opn5), all able to detect blue/violet light and implicated in chromophore recycling, retinal clock synchronization, neuron-to-glia communication, and other activities. The discovery of these new photopigments in the inner retina of vertebrates is strong evidence of novel light-regulated activities. This review focuses on the features, localization, photocascade, and putative functions of these novel non-visual opsins in an attempt to shed light on their role in the inner retina of vertebrates and in the physiology of the whole organism.
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Opsinas , Retina , Animais , Opsinas/fisiologia , Células Ganglionares da Retina , Células Fotorreceptoras Retinianas Bastonetes , VertebradosRESUMO
Natural killer T (NKT) cells constitute a unique subset of T lymphocytes characterized by specifically interacting with antigenic glycolipids conjugated to the CD1d receptor on antigen-presenting cells. Functionally, NKT cells are capable of performing either effector or suppressor immune responses, depending on their production of proinflammatory or anti-inflammatory cytokines, respectively. Effector NKT cells are subdivided into three subsets, termed NKT1, NKT2, and NKT17, based on the cytokines they produce and their similarity to the cytokine profile produced by Th1, Th2, and Th17 lymphocytes, respectively. Recently, a new subgroup of NKT cells termed NKT10 has been described, which cooperates and interacts with other immune cells to promote immunoregulatory responses. Although the tissue-specific functions of NKT cells have not been fully elucidated, their activity has been associated with the pathogenesis of different inflammatory diseases with immunopathogenic similarities to periodontitis, including osteolytic pathologies such as rheumatoid arthritis and osteoporosis. In the present review, we revise and discuss the pathogenic characteristics of NKT cells in these diseases and their role in the pathogenesis of periodontitis; particularly, we analyze the potential regulatory role of the IL-10-producing NKT10 cells.
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Células T Matadoras Naturais/fisiologia , Periodontite/etiologia , Animais , Antígenos CD1d/química , Citocinas/fisiologia , Glicolipídeos/química , Humanos , Ativação Linfocitária , Células T Matadoras Naturais/citologia , Periodontite/imunologiaRESUMO
Purpose To describe the trends of orthopedic surgery in Chile since 2004 in terms of the number and gender of surgeons, the incidence of procedures per 100,000 inhabitants (IR), and access by health insurance and type of health center. Methods A cross-sectional study was designed. Three databases were analyzed: the free access database of the Chilean Department of Statistics and Health Information (DEIS), which had information on all procedures performed in health institutions in Chile from 2004 to 2020. Then, the orthopedic surgeon registry was requested from the National Superintendence of Health (NSH). Finally, the database of the Chilean Society of Orthopaedic Surgeons (SCHOT) was analyzed. Spearman's correlation was used to determine significant trends during the analyzed period. Results The NSH reported 1770 orthopedic surgeons in 2020; 56% were affiliated with SCHOT. An upward trend in the proportion of female orthopedic surgeons was found, from 4.8% in 2004 to 7.6% in 2020. Since 2004, the IR of orthopaedic surgeries has been increasing significantly in both health insurances; the growth in public insurance follows a linear model (R2 = 0.970) of parameters ß0 = - 55982.6 (p <0.000) and ß1 = 28.02 (p <0.000) while in private insurance, the growth is also linear (R2 = 0.890) but with a greater slope: ß0 = - 104136 (p <0.000) and ß1 = 52.15 (p <0.000). A significant downward trend was found in the proportion of surgeries performed in the public health network (rho = -0.797, p = 0.0002). Conclusions There is a significant increase in the number of orthopedic surgeons and the number of procedures per 100,000 inhabitants. Nevertheless, there is evident inequity in access to orthopedic surgery in Chile and low gender diversity.
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Parkinson's disease (PD) is a neurodegenerative disorder that affects adult people whose treatment is palliative. Thus, we decided to test three dammarane triterpenes 1, 1a, 1b, and we determined that 1 and 1a inhibit ß-aggregation through thioflavine T rather than 1b. Since compound 1 was most active, we determined the interaction between α-synuclein and 1 at 50 µM (Kd) through microscale thermophoresis. Also, we observed differences in height and diameter of aggregates, and α-synuclein remains unfolded in the presence of 1. Also, aggregates treated with 1 do not provoke neurites' retraction in N2a cells previously induced by retinoic acid. Finally, we studied the potential sites of interaction between 1 with α-synuclein fibrils using molecular modelling. Docking experiments suggest that 1 preferably interact with the site 2 of α-synuclein through hydrogen bonds with residues Y39 and T44.
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Simulação de Acoplamento Molecular , Triterpenos/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Animais , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Magnoliopsida/química , Camundongos , Conformação Molecular , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação , Células Tumorais Cultivadas , alfa-Sinucleína/isolamento & purificação , alfa-Sinucleína/metabolismo , DamaranosRESUMO
Introduction The purpose of this study is to describe the incidence rate (IR) per 100,000 inhabitants of arthroplasty in Chile between 2004 and 2019, emphasizing knee and hip arthroplasty. Methods This is a cross-sectional study. Patients who underwent arthroplasty between 2004 and 2019 were identified in the free access database of the Chilean Department of Statistics and Health Information (DEIS), which depends directly on the Ministry of Health. This register stores all hospital discharges of the country from private or public health centers. The trend during the period of study was analyzed using Spearman's correlation. Results From a total of 111,303 patients, 133,518 arthroplasties were performed. Hip arthroplasty (HA) accounted for 73.35%, followed by knee arthroplasty (KA) (23,92%). A significant upward trend was found in HA (rho=0.95, p<0.000) and KA (rho=0.98, p<0.000). Most of the surgeries were done within the Public Health Network (61,6%), but 20% of patients affiliated with public insurance underwent arthroplasty in a private center. Patients above 60 years of age affiliated with private insurance underwent 1.8 HA and 2.5 KA for every one HA and KA undergone by patients of the same age group who were affiliated with public insurance. Conclusion HA was more frequent than KA. A significant gap was found in the incidence of arthroplasty as compared to countries belonging to the Organization for Cooperation and Economic Development, given by a less aged population and by inequity in health access. Wider coverage and a national registry for arthroplasty must be considered in Chilean health policies.
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Cell migration is critical for several physiological and pathophysiological processes. It depends on the coordinated action of kinases, phosphatases, Rho-GTPases proteins, and Ca2+ signaling. Interestingly, ubiquitination events have emerged as regulatory elements of migration. Thus, the role of proteins involved in ubiquitination processes could be relevant to a complete understanding of pro-migratory mechanisms. KCTD5 is a member of Potassium Channel Tetramerization Domain (KCTD) proteins that have been proposed as a putative adaptor for Cullin3-E3 ubiquitin ligase and a novel regulatory protein of TRPM4 channels. Here, we study whether KCTD5 participates in cell migration-associated mechanisms, such as focal adhesion dynamics and cellular spreading. Our results show that KCTD5 CRISPR/Cas9- and shRNA-based depletion in B16-F10 cells promoted an increase in cell migration and cell spreading, and a decrease in the focal adhesion area, consistent with an increased focal adhesion disassembly rate. The expression of a dominant-negative mutant of Rho-GTPases Rac1 precluded the KCTD5 depletion-induced increase in cell spreading. Additionally, KCTD5 silencing decreased the serum-induced Ca2+ response, and the reversion of this with ionomycin abolished the KCTD5 knockdown-induced decrease in focal adhesion size. Together, these data suggest that KCTD5 acts as a regulator of cell migration by modulating cell spreading and focal adhesion dynamics through Rac1 activity and Ca2+ signaling, respectively.
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Sinalização do Cálcio/fisiologia , Canais de Potássio/metabolismo , Animais , Cálcio/metabolismo , Adesão Celular/genética , Linhagem Celular , Movimento Celular/genética , Adesões Focais/genética , Humanos , Camundongos , Canais de Potássio/fisiologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Mesenchymal stromal cells (MSC) have been used in over 800 clinical trials with encouraging results in the field of transplant medicine and chronic inflammatory diseases. Today, Umbilical Cord (UC)-derived MSC are the second leading source used for clinical purposes, mainly due to its easy access and superior immune modulatory effects. Although the underlying molecular mechanisms of immune suppressive activities have not been fully understood, research over the last decade strongly suggests that MSC-mediated benefits are closely related to activation of secretome networks. Nevertheless, recent findings also point to cytokine-independent mechanisms as key players of MSC-mediated immune modulation. Here, we set up a robust in vitro immune assay using phytohemagglutinin- or anti-CD3/CD28-treated human peripheral blood mononuclear cells in cell-to-cell interaction or in cell-contact independent format with UC-MSC and conducted integrated transcriptome and secretome analyses to dissect molecular pathways driving UC-MSC-mediated immune modulation. Under inflammatory stimuli, multiparametric analyses of the secretome led us to identify cytokine/chemokine expression patterns associated with the induction of MSC-reprogrammed macrophages and T cell subsets ultimately leading to immune suppression. UC-MSC transcriptome analysis under inflammatory challenge allowed the identification of 47 differentially expressed genes, including chemokines, anti- and pro-inflammatory cytokines and adhesion molecules found also in UC-MSC-immunosupressive secretomes, including the novel candidate soluble IL-2R. This study enabled us to track functionally activated UC-MSC during immune suppression and opened an opportunity to explore new pathways involved in immunity control by UC-MSC. We propose that identified immunomodulatory molecules and pathways could potentially be translated into clinical settings in order to improve UC-MSC-therapy quality and efficacy.
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Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , Linfócitos T/metabolismo , Transcriptoma , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Citocinas/genética , Citocinas/metabolismo , Sangue Fetal/citologia , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Inflamação/imunologia , Ativação Linfocitária , Células-Tronco Mesenquimais/imunologia , Fenótipo , Via Secretória , Transdução de Sinais , Linfócitos T/imunologiaRESUMO
OBJECTIVE: Dental caries is one of the most prevalent chronic diseases in children. Currently, no data are available on dental caries prevalence in the Dominican Republic. The purpose of this study was to estimate the prevalence of dental caries in schoolattending 12-year-olds in San Pedro de Macorís, Dominican Republic. METHODS: A cross-sectional epidemiological study using a probabilistic sample, stratified by type of school (public/private) and gender, was conducted. Two calibrated examiners conducted the evaluations of oral soft/hard tissues. Caries experience was summarized in terms of prevalence; the number of decayed, missing, and filled teeth (DMFT) and surfaces (DMFS); and the significant caries (SiC) index, in all the participants, and by gender and school type. Logistic and Poisson regression models were used to compare caries experience by sex and school type. RESULTS: Four hundred and two 12-year-olds enrolled in 14 public and 11 private schools were evaluated. The overall dental caries prevalence was 73%. The mean DMFS was 3.87, the mean DMFT was 2.64, and the SiC index was 5.07. Girls had significantly higher mean DMFS, DMFT, and SiC indices than did boys. Public school attendees had significantly higher DMFS, DMFT, and SiC indices than did those children attending private schools. The decayed (D) component accounted for 71% of the DMFT value. CONCLUSION: The WHO's goal of all 12-year-olds having a DMFT less than or equal to 3 was met by all the participants in our study. Girls and public-school attendees carry the burden of the disease. The high D component of the index suggests that there are unmet dental-caries needs. This information will assist in the design and implementation of future primary and secondary prevention programs.
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Cárie Dentária/epidemiologia , Saúde Bucal , Criança , Estudos Transversais , Índice CPO , República Dominicana/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Instituições Acadêmicas/estatística & dados numéricos , Fatores SexuaisRESUMO
Transient receptor potential melastatin 4 (TRPM4) is a Ca2+ -activated nonselective cationic channel that regulates cell migration and contractility. Increased TRPM4 expression has been related to pathologies, in which cytoskeletal rearrangement and cell migration are altered, such as metastatic cancer. Here, we identify the K+ channel tetramerization domain 5 (KCTD5) protein, a putative adaptor of cullin3 E3 ubiquitin ligase, as a novel TRPM4-interacting protein. We demonstrate that KCTD5 is a positive regulator of TRPM4 activity by enhancing its Ca2+ sensitivity. We show that through its effects on TRPM4 that KCTD5 promotes cell migration and contractility. Finally, we observed that both TRPM4 and KCTD5 expression are increased in distinct patterns in different classes of breast cancer tumor samples. Together, these data support that TRPM4 activity can be regulated through expression levels of either TRPM4 or KCTD5, not only contributing to increased understanding of the molecular mechanisms involved on the regulation of these important ion channels, but also providing information that could inform treatments based on targeting these distinct molecules that define TRPM4 activity.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Canais de Potássio/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Mama/metabolismo , Mama/patologia , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Células MCF-7 , Prognóstico , Ubiquitina-Proteína Ligases/metabolismoRESUMO
In the design of self-assembled compounds, small variations in the linkers connecting the coordinating moieties can produce large differences in the obtained structures. Here, we report three novel zinc(II) complexes with phenanthroline-derived ligands as building blocks (L1-L3): A mononuclear complex, a bimetallic helicate, and a trimetallic circular helicate. The even-number spacer in L2 promotes the formation of a bimetallic helicate stabilized by π-π interactions of adjacent phenanthrolines. The addition of an extra methylene in L3 increases the distance between where the phenanthrolines can stack, and CH-π noncovalent interactions give stability to the circular helicate. When irradiated at 308 nm in acetonitrile, long-lived excited states are formed with all three complexes, which are able to participate in oxidation of 2-propanol and in reduction of methylviologen, MV2+. While the overall behavior of the three complexes is similar, the bimetallic helicate is able to form a ground-state adduct with MV2+, while the trimer reaches the excited state to form an exciplex with MV2+.
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Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.
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Acetilcolina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Acetilcolina/agonistas , Acetilcolina/síntese química , Acetilcolina/química , Regulação Alostérica , Sítios de Ligação , Dopamina/química , Agonistas de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/agonistas , Ésteres/química , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Nicotina/agonistas , Nicotina/síntese química , Nicotina/química , Agonistas Nicotínicos/química , Pirrolidinas/química , Ensaio Radioligante , Proteínas da Membrana Plasmática de Transporte de Serotonina/agonistas , Relação Estrutura-AtividadeRESUMO
Activated α2-macroglobulin (α2M*) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have been linked to proliferative retinal diseases. In Müller glial cells (MGCs), the α2M*/LRP1 interaction induces cell signaling, cell migration, and extracellular matrix remodeling, processes closely associated with proliferative disorders. However, the mechanism whereby α2M* and LRP1 participate in the aforementioned pathologies remains incompletely elucidated. Here, we investigate whether α2M* regulates both the intracellular distribution and sorting of LRP1 to the plasma membrane (PM) and how this regulation is involved in the cell migration of MGCs. Using a human Müller glial-derived cell line, MIO-M1, we demonstrate that the α2M*/LRP1 complex is internalized and rapidly reaches early endosomes. Afterward, α2M* is routed to degradative compartments, while LRP1 is accumulated at the PM through a Rab10-dependent exocytic pathway regulated by PI3K/Akt. Interestingly, Rab10 knockdown reduces both LRP1 accumulation at the PM and cell migration of MIO-M1 cells induced by α2M*. Given the importance of MGCs in the maintenance of retinal homeostasis, unravelling this molecular mechanism can potentially provide new therapeutic targets for the treatment of proliferative retinopathies.
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Membrana Celular/metabolismo , Células Ependimogliais/metabolismo , Exocitose , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , alfa-Macroglobulinas/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Movimento Celular , Células Cultivadas , Células Ependimogliais/citologia , Humanos , Transporte Proteico , Transdução de SinaisRESUMO
Cell migration is a key process in cancer metastasis, allowing malignant cells to spread from the primary tumor to distant organs. At the molecular level, migration is the result of several coordinated events involving mechanical forces and cellular signaling, where the second messenger Ca2+ plays a pivotal role. Therefore, elucidating the regulation of intracellular Ca2+ levels is key for a complete understanding of the mechanisms controlling cellular migration. In this regard, understanding the function of Transient Receptor Potential (TRP) channels, which are fundamental determinants of Ca2+ signaling, is critical to uncovering mechanisms of mechanotransduction during cell migration and, consequently, in pathologies closely linked to it, such as cancer. Here, we review recent studies on the association between TRP channels and migration-related mechanotransduction events, as well as in the involvement of TRP channels in the migration-dependent pathophysiological process of metastasis.
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Neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4ß2 nAChRs subtypes. The most important therapeutic use for α4ß2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4ß2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4ß2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.
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Nicotina/química , Nicotina/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Ligação Competitiva , Relação Dose-Resposta a Droga , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Nicotina/análogos & derivados , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0â¯mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8â¯mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2â¯mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2â¯mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10â¯mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment.
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Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Di-Hidro-beta-Eritroidina/análogos & derivados , Antagonistas Nicotínicos/farmacologia , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Di-Hidro-beta-Eritroidina/farmacologia , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Ratos Wistar , Receptores Nicotínicos/metabolismo , RecompensaRESUMO
OBJECTIVE: Gingivitis, an inflammation of the gingival tissues, typically progresses to periodontitis. The objective of this study is to estimate the prevalence of gingivitis in 35- to 70-year-olds residing in San Juan, Puerto Rico, and assess the differences in gingivitis distribution between age and gender groups. METHODS: A cross-sectional epidemiological study was conducted with a sample of patients from a private practice and patients/employees of the Puerto Rico Medical Center. Participants completed a medical history questionnaire and received soft/hard tissue and gingival assessments based on a modified Löe-Silness index. Descriptive statistics were employed to estimate the overall gingivitis prevalence, severity (mild, moderate, severe), and mean gingival index (GI). Bleeding on probing (BOP) prevalence and the mean percentage of BOP sites were calculated by gender and age. Multinomial logistic regression was used to evaluate the associations between age, gender, and severity in 3 categories; multivariate logistic regression was used for having >=40% sites with BOP (vs. having <40% sites with BOP as reference). Odds ratios were also estimated. RESULTS: All 300 participants (52% women; 48% men) had gingivitis. The mean GI was 1.38. Moderate gingivitis was detected in 83% of the participants, mild in 7.3%, and severe in 9.3%. BOP was observed in 99% of the subjects (mean % BOP sites = 34%). After adjusting for age, men had significantly higher odds of moderate (OR = 4.66) and severe gingivitis (OR =10.06), compared to women, as well as 1.76 times higher odds of having 40% or more sites with BOP. CONCLUSION: Gingivitis was observed in all participants. Men had significantly higher GI, compared to women. The prevalence of gingivitis was higher in Puerto Rico than in the US.