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Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.
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MicroARNs , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Función Ventricular Derecha , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratas , Humanos , Ratones , Masculino , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Modelos Animales de Enfermedad , Monocrotalina , Proliferación Celular/genética , Miocitos del Músculo Liso/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/metabolismo , Remodelación Vascular/genética , Ratas Sprague-DawleyRESUMEN
Mosquito-borne diseases kill millions of people each year. Therefore, many innovative research and population control strategies are being implemented but, most of them require large-scale production of mosquitoes. Mosquito rearing depends on fresh blood from human donors, experimentation animals or slaughterhouses, which constitutes a strong drawback since high blood quantities are needed, raising ethical and financial constraints. To eliminate blood dependency and the use of experimentation animals, we previously developed BLOODless, a patented diet that represents an important advance towards sustainable mosquito breeding in captivity. BLOODless diet was used to maintain a colony of Anopheles stephensi for 40 generations. Bloodmeal appetite, fitness, Plasmodium berghei infectivity, whole genome sequencing and microbiota were evaluated over time. Here we show that BLOODless can be implemented in Anopheles insectaries since it allows long-term rearing of mosquitoes in captivity, without a detectable effect on their fitness, infectivity, nor on their midgut and salivary microbiota composition.
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Anopheles , Microbiota , Plasmodium berghei , Animales , Anopheles/microbiología , Anopheles/parasitología , Plasmodium berghei/fisiología , Mosquitos Vectores/microbiología , Mosquitos Vectores/parasitología , Malaria/transmisión , Humanos , Ratones , Femenino , Sangre/microbiologíaRESUMEN
OBJECTIVE: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). DESIGN: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. SETTING: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). POPULATION OR SAMPLE: A total of 100 participants. METHODS: Descriptive and comparative analysis from flares questionnaire. MAIN OUTCOME MEASURES: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. RESULTS: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. CONCLUSIONS: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden.
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Background/objectives: Impulsive aggressive behaviour, although not a core symptom, is often part of the clinical presentation of attention-deficit/hyperactivity disorder (ADHD). Recently, impulsive aggression has been attributed to emotion dysregulation, which is currently conceptualised as a transdiagnostic factor and seems to contribute to the co-occurrence of other problems in ADHD. Thus, this study investigated the presence of impulsive aggressive behaviour and explored whether emotion dysregulation mediates the relationship between inhibitory control difficulties and aggressive behaviour in children with ADHD. Because ADHD may act as a risk factor for the development of other conditions, such as internalising problems, we aimed to understand whether depressive symptoms contribute to this relationship. Methods: Seventy-two children were recruited from a hospital and the community, 38 of whom had ADHD and 34 were typically developing (TD). Parents completed the Child Behaviour Checklist, the Behaviour Rating Inventory of Executive Function, and the Emotion Regulation Checklist. Simple mediation and serial mediation models were performed to test our hypotheses. Results: Aggressive behaviour was significantly higher in ADHD children compared to TD children. Emotion dysregulation fully mediated the relationship between inhibitory control difficulties and aggressive behaviour in ADHD children. Adding depressive symptoms to the model increased the explained variance in aggressive behaviour. Conclusion: The main result of our study supports the role of emotion dysregulation and depressive symptoms in mediating the relationship between inhibitory control difficulties and impulsive aggressive behaviour in children with ADHD. This highlights that aggressive behaviour is, in part, a result of the inability of the child to appropriately regulate their emotions. Future interventions may be tailored to improve emotion regulation skills to address aggressive behaviour.
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Xylanases are key biocatalysts in the degradation of the ß-1,4-glycosidic linkages in the xylan backbone of hemicellulose. These enzymes are potentially applied in a wide range of bioprocessing industries under harsh conditions. Metagenomics has emerged as powerful tools for the bioprospection and discovery of interesting bioactive molecules from extreme ecosystems with unique features, such as high temperatures. In this study, an innovative combination of function-driven screening of a compost metagenomic library and automatic extraction of halo areas with in-house MATLAB functions resulted in the identification of a promising clone with xylanase activity (LP4). The LP4 clone proved to be an effective xylanase producer under submerged fermentation conditions. Sequence and phylogenetic analyses revealed that the xylanase, Xyl4, corresponded to an endo-1,4-ß-xylanase belonging to glycosyl hydrolase family 10 (GH10). When xyl4 was expressed in Escherichia coli BL21(DE3), the enzyme activity increased about 2-fold compared to the LP4 clone. To get insight on the interaction of the enzyme with the substrate and establish possible strategies to improve its activity, the structure of Xyl4 was predicted, refined, and docked with xylohexaose. Our data unveiled, for the first time, the relevance of the amino acids Glu133 and Glu238 for catalysis, and a close inspection of the catalytic site suggested that the replacement of Phe316 by a bulkier Trp may improve Xyl4 activity. Our current findings contribute to enhancing the catalytic performance of Xyl4 towards industrial applications. KEY POINTS: ⢠A GH10 endo-1,4-ß-xylanase (Xyl4) was isolated from a compost metagenomic library ⢠MATLAB's in-house functions were developed to identify the xylanase-producing clones ⢠Computational analysis showed that Glu133 and Glu238 are crucial residues for catalysis.
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Compostaje , Endo-1,4-beta Xilanasas , Escherichia coli , Metagenómica , Filogenia , Endo-1,4-beta Xilanasas/genética , Endo-1,4-beta Xilanasas/metabolismo , Endo-1,4-beta Xilanasas/química , Endo-1,4-beta Xilanasas/aislamiento & purificación , Escherichia coli/genética , Escherichia coli/metabolismo , Metagenoma , Biblioteca de Genes , Microbiología del Suelo , Xilanos/metabolismo , Clonación Molecular , Fermentación , Expresión Génica , Simulación del Acoplamiento MolecularRESUMEN
Gut microorganisms have been shown to significantly impact on central function and studies that have associated brain disorders with specific bacterial genera have advocated an anomalous gut microbiome as the pathophysiological basis of several psychiatric and neurological conditions. Thus, our knowledge of brain-to-gut-to microbiome communication in this bidirectional axis seems to have been overlooked. This review examines the known mechanisms of the microbiome-to-gut-to-brain axis, highlighting how brain-to-gut-to-microbiome signaling may be key to understanding the cause of disrupted gut microbial communities. We show that brain disorders can alter the function of the brain-to-gut-to-microbiome axis, which will in turn contribute to disease progression, while the microbiome-to gut-to brain direction presents as a more versatile therapeutic axis, since current psychotropic/neurosurgical interventions may have unwanted side effects that further cause disruption to the gut microbiome. A consideration of the brain-to-gut-to-microbiome axis is imperative to better understand how the microbiome-gut-brain axis overall is involved in brain illnesses, and how it may be utilized as a preventive and therapeutic tool.
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Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.
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The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.
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Astrocitos , Cannabinoides , Ratones , Animales , Receptores de Cannabinoides , Receptor de Adenosina A2A , Plasticidad Neuronal , Receptor Cannabinoide CB1/genéticaRESUMEN
INTRODUCTION: Exacerbations are common in individuals with alpha-1 antitrypsin deficiency (AATD)-related lung disease. This study intended to identify independent predictive factors for exacerbations in AATD using the Portuguese European Alpha-1 Research Collaboration (EARCO) registry. METHODS: This study includes patients from the Portuguese EARCO registry, a prospective multicenter cohort (NCT04180319). From October 2020 to April 2023, this registry enrolled 137 patients, 14 of whom were excluded for analysis for either missing 12 months of follow-up or baseline pulmonary function. RESULTS: Among the 123 AATD patients, 27 (22.0%) had at least one exacerbation in the last 12 months of follow-up. Patients with Pi*ZZ phenotype were three times more likely than the rest of the population to experience any exacerbation (32.7 vs. 14.1%, p = 0.014; OR 3.0). BODE index was significantly higher in exacerbators than in non-exacerbators (3.9 ± 2.4 vs. 1.3 ± 1.2; p < 0.001), including on multivariate analysis (p = 0.002). Similar results were found for BODEx (multivariate p < 0.001). DLCO was the only functional parameter independently associated with exacerbations (p = 0.024). CONCLUSIONS: DLCO, BODE, and BODEx were independent predictors of exacerbations at 12 months in AATD patients. Understanding these risk factors can aid decision-making on AATD-related lung disease management and improve patient outcomes.
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Progresión de la Enfermedad , Sistema de Registros , Pruebas de Función Respiratoria , Deficiencia de alfa 1-Antitripsina , Humanos , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/fisiopatología , Deficiencia de alfa 1-Antitripsina/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Portugal/epidemiología , Estudios Prospectivos , Anciano , Adulto , Volumen Espiratorio ForzadoRESUMEN
Introduction: Peripheral neuropathic pain (PNP) is one of the most challenging diseases to treat with a significant negative impact on the patients' health-related quality of life (HRQoL). Capsaicin 8% patch has arisen in the last decades as an alternative to oral drugs in the treatment of PNP with fewer side effects and promising results in efficacy. Objectives: This work aims to evaluate the effectiveness of the topical application of capsaicin in PNP and its impact on patients' HRQoL based on the use of capsaicin in a tertiary hospital of Oporto. Methods: This study included 100 patients with localized PNP with poor pain control and without improvement with previous treatments that were treated at least once with an 8% capsaicin patch. Effectiveness on pain relief, number of treatments needed, safety and impact on HRQoL were assessed through a set of questionnaires. Results: Regarding the aetiology of PNP, 67.6% (N = 46) have post-surgery or trauma induced PNP with 64.7% (N = 44) of patients reporting pain in the lower limb. After the treatment, 30.9% (N = 21) felt minimally improved, 22.1 (N = 15) felt much improved and 13.2 (N = 9) felt very much improved. On a scale from 1 to 10, in the week prior to the survey, the median intensity of pain was 6 and the median interference in quality of life was 7. The majority of patients still report limitations in mobility and daily activities and moderate pain. Conclusion: Capsaicin 8% patch is effective in PNP treatment at least in the short term. Repeated applications may be important for long-term analgesia. The low systemic dose and few side effects mean that the treatment is generally well tolerated by patients. Due to the analgesic effect, capsaicin can improve the HRQoL of patients with PNP.
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Conocimientos, Actitudes y Práctica en Salud , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Portugal/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Concienciación , Encuestas y CuestionariosRESUMEN
Immune checkpoint blocking therapy targeting the PD-1/PD-L1 inhibitory signalling pathway has produced encouraging results in the treatment of a variety of cancers. Durvalumab (Imfinzi®) targeting PD-L1 is currently used for immunotherapy of several tumour malignancies. The Fc region of this IgG1 antibody has been engineered to reduce FcγR interactions with the aim of enhancing blockade of PD-1/PD-L1 interactions without the depletion of PD-L1-expressing immune cells. Here, we used Nicotiana benthamiana to produce four variants of Durvalumab (DL): wild-type IgG1 and its 'Fc-effector-silent' variant (LALAPG) carrying further modifications to increase antibody half-life (YTE); IgG4S228P and its variant (PVA) with Fc mutations to decrease binding to FcγRI. In addition, DL variants were produced with two distinct glycosylation profiles: afucosylated and decorated with α1,6-core fucose. Plant-derived DL variants were compared to the therapeutic antibody regarding their ability to (i) bind to PD-L1, (ii) block PD-1/PD-L1 inhibitory signalling and (iii) engage with the neonatal Fc receptor (FcRn) and various Fcγ receptors. It was found that plant-derived DL variants bind to recombinant PD-L1 and to PD-L1 expressed in gastrointestinal cancer cells and are able to effectively block its interaction with PD-1 on T cells, thereby enhancing their activation. Furthermore, we show a positive impact of Fc amino acid mutations and core fucosylation on DL's therapeutic potential. Compared to Imfinzi®, DL-IgG1 (LALAPG) and DL-IgG4 (PVA)S228P show lower affinity to CD32B inhibitory receptor which can be therapeutically favourable. Importantly, DL-IgG1 (LALAPG) also shows enhanced binding to FcRn, a key determinant of serum half-life of IgGs.
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Anticuerpos Monoclonales , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Receptor de Muerte Celular Programada 1/genética , Antígeno B7-H1/genética , Inmunoglobulina G/genéticaRESUMEN
3D bioprinting enables the fabrication of biomimetic cell-laden constructs for cartilage regeneration, offering exclusive strategies for precise pharmacological screenings in osteoarthritis (OA). Synovial inflammation plays a crucial role in OA's early stage and progression, characterized by the increased of the synovial pro-inflammatory mediators and cytokines and chondrocyte apoptosis. Therefore, there is an urgent need to develop solutions for effectively managing the primary events associated with OA. To address these issues, a phenolic-based biocompatible ionic liquid approach, combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), was used to produce easily printable bioinks. Through the use of this strategy 3D constructs with good printing resolution and high structural integrity were obtained. The encapsulation of chondrocytes like ATDC5 cells provided structures with good cell distribution, viability, and growth, for up to 14 days. The co-culture of the constructs with THP-1 macrophages proved their ability to block pro-inflammatory cytokines (TNF-α and IL-6) and mediators (GM-CSF), released by the cultured cells. Moreover, incorporating the biocompatible ionic liquid into the system significantly improved its bioactive performance without compromising its physicochemical features. These findings demonstrate that ALG/ACE/Ch[Caffeate] bioinks have great potential for bioengineering cartilage tissue analogs. Besides, the developed ALG/ACE/Ch[Caffeate] bioinks protected encapsulated chondrocyte-like cells from the effect of the inflammation, assessed by a co-culture system with THP-1 macrophages. These results support the increasing use of Bio-ILs in the biomedical field, particularly for developing 3D bioprinting-based constructs to manage inflammatory-based changes in OA. STATEMENT OF SIGNIFICANCE: Combining natural resources with active biocompatible ionic liquids (Bio-IL) for 3D printing is herein presented as an approach for the development of tools to manage inflammatory osteoarthritis (OA). We propose combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), a phenolic-based Bio-IL with anti-inflammatory and antioxidant features, to produce bioinks that allow to obtain 3D constructs with good printing resolution, structural integrity, and that provide encapsulated chondrocyte-like cells good viability. The establishment of a co-culture system using the printed constructs and THP-1-activated macrophages allowed us to study the encapsulated chondrocyte-like cells behaviour within an inflammatory scenario, a typical event in early-stage OA. The obtained outcomes support the beneficial use of Bio-ILs in the biomedical field, particularly for the development of 3D bioprinting-based models that allow the monitoring of inflammatory-based events in OA.
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Bioimpresión , Líquidos Iónicos , Osteoartritis , Humanos , Líquidos Iónicos/farmacología , Citocinas , Osteoartritis/tratamiento farmacológico , Inflamación , Antiinflamatorios/farmacología , Alginatos/farmacología , Alginatos/química , Impresión Tridimensional , Ingeniería de Tejidos/métodos , Bioimpresión/métodos , Andamios del Tejido/químicaRESUMEN
Astrocytes, the most abundant glial cells in the central nervous system (CNS), sense synaptic activity and respond through the release of gliotransmitters, a process mediated by intracellular Ca2+ level changes and SNARE-dependent mechanisms. Ionotropic N-methyl-D-aspartate (NMDA) receptors, which are activated by glutamate along with D-serine or glycine, play a crucial role in learning, memory, and synaptic plasticity. However, the precise impact of astrocyte-released D-serine on neuronal modulation remains insufficiently characterized. To address this, we have used the dominant negative SNARE (dnSNARE) mouse model, which selectively inhibits SNARE-dependent exocytosis from astrocytes. We recorded field excitatory postsynaptic potentials (fEPSPs) in CA3-CA1 synapses within hippocampal slices obtained from dnSNARE mice and wild-type (Wt) littermates. Our results demonstrate that hippocampal θ-burst long-term potentiation (LTP), a critical form of synaptic plasticity, is impaired in hippocampal slices from dnSNARE mice. Notably, this LTP impairment was rescued upon incubation with D-serine. To further investigate the involvement of astrocytes in D-serine-mediated mechanisms of LTP maintenance, we perfused hippocampal slices with L-serine - a substrate used by both neurons and astrocytes for D-serine production. The enhancement in LTP observed in dnSNARE mice was exclusively associated with D-serine presence, with no effects evident in the presence of L-serine. Additionally, both D- and L-serine reduced basal synaptic strength in the hippocampal slices of both Wt and dnSNARE mice. These results provide compelling evidence that distinct processes underlie the modulation of basal synaptic transmission and LTP through D-serine. Our findings underscore the pivotal contribution of astrocytes in D-serine-mediated processes that govern LTP establishment and basal transmission. This study not only provides essential insights into the intricate interplay between neurons and astrocytes but also emphasizes their collective role in shaping hippocampal synaptic function.
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Older adult maltreatment (OAM) is a global problem that has attracted increasing attention due to the ageing population and its severe impact on victim health. Thus, this study aims to analyse the prevalence of certain health conditions in people ≥ 60 years old whom physicians from a local healthcare unit suspected to be victims of maltreatment. The specific objectives are to determine the prevalence rates of health-related risk factors, traumatic injuries and intoxications, mental disorders, and physical disorders. We conducted a real-world, retrospective, observational, and cross-sectional study based on secondary data analyses of electronic health records and healthcare registers of patients at the Local Healthcare Unit of Matosinhos (2001-2021). Information was obtained based on codes from the International Classification of Diseases, codes from the International Classification of Primary Care, and clinical notes (according to previously defined keywords). We identified 3092 suspected victims of OAM, representing 4.5% of the total population analysed. This prevalence is lower than the known rates. We also found that some health risk factors, traumatic injuries and intoxications, mental health disorders, and physical disorders presented higher rates in the suspected victims than among the total population. In this age group, we cannot assume that these health problems are only related to a possible current victimisation process; they could also be associated with adverse childhood experiences or intimate partner violence, among other forms of violence, all of which can lead to cumulative effects on the victim's health. This evidence increases healthcare providers' responsibility in detecting and reporting all cases of suspected maltreatment.
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Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide and, therefore, it is urgent to develop new and more efficient therapeutic approaches. Foretinib (FRT) is an oral multikinase inhibitor targeting MET (hepatocyte growth factor receptor) and RON (recepteur d'origine nantais) receptor tyrosine kinases (RTKs) that has been used in clinical trials for several solid tumors. Targeted uptake of therapeutic polymeric nanoparticles (NPs) represents a powerful approach in cancer cell drug delivery. Previously, a nanodelivery system composed of polymeric NPs functionalized with B72.3 antibody, which targets the tumor-associated antigen Sialyl-Tn (STn), has been developed. Herein, these NPs were loaded with FRT to evaluate its capacity in delivering the drug to multicellular tumors spheroids (MCTS) and mouse models. The data indicated that B72.3 functionalized FRT-loaded PLGA-PEG-COOH NPs (NFB72.3) specifically target gastric MCTS expressing the STn glycan (MKN45 SimpleCell (SC) cells), leading to a decrease in phospho-RTKs activation and reduced cell viability. In vivo evaluation using MKN45 SC xenograft mice revealed that NFB72.3 were able to decrease tumor growth, reduce cell proliferation and tumor necrosis. NFB72.3-treated tumors also showed inactivation of phospho-MET and phospho-RON. This study demonstrates the value of using NPs targeting STn for FRT delivery, highlighting its potential as a therapeutic application in GC. STATEMENT OF SIGNIFICANCE: Despite the advances in gastric cancer therapeutics, it remains one of the diseases with the highest incidence and mortality in the world. Combining targeted therapies with a controlled drug release is an attractive strategy to reduce drug cytotoxic effects and improve specific drug delivery efficiency to the cancer cells. Thus, we developed nanoparticles loaded with a tyrosine kinase inhibitor and targeting a specific tumor glycan exclusive of cancer cells. In in vivo gastric cancer xenograft mice models, these nanoparticles efficiently reduced tumor growth, cell proliferation and tumor necrosis area and inactivated phosphorylation of targeting receptors. This approach represents an innovative therapeutic strategy with high impact in gastric cancer.
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Nanopartículas , Neoplasias Gástricas , Humanos , Animales , Ratones , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Polímeros/uso terapéutico , Polisacáridos , Necrosis , Línea Celular TumoralRESUMEN
Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.