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OBJECTIVE: To compare fully guided flapless implant surgery using a light-cured surgical guide (FG group) with partially guided open flap surgery (PG group) in the posterior maxilla when performing simultaneous sinus floor elevation in terms of the accuracy, time requirements, and patient/clinician-reported outcomes (PROMs and CROMs). MATERIALS AND METHODS: In this study, 56 tissue-level implants were placed with crestal sinus floor elevation in 56 patients at single-tooth sites, with 28 implants allocated to the PG group and 28 to the FG group. The deviations of the placed implants from the virtually planned positions were measured at the implant platform and apex and for the angular deviation. The presurgical preparation time and the duration of surgery were measured. PROMs and CROMs were made by administering questionnaires at multiple time points. RESULTS: Horizontal deviations at the platform and apex and the angular deviation were significantly smaller in the FG group than the PG group (p < .05). Presurgical preparation and surgery times were significantly shorter in the FG group (p < .001). Patient satisfaction and willingness to receive repeat treatment were significantly better in the FG group than in the PG group (p < .005 and .025, respectively). Clinicians were more satisfied in the FG group than the PG group (p < .05). CONCLUSION: When placing an implant with sinus floor elevation, the flapless approach using a fully guided surgical system can be more accurate, faster, and increase the satisfaction of both the clinician and patient compared to the partially guided surgery.
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BACKGROUND: Radioimmunotherapy with cetuximab and conjugates with various radioisotopes is a feasible treatment option for different tumor models. Scandium-47 (47Sc), one of several ß--particle-emitting radioisotopes, displays favorable physical and chemical properties for conjugation to monoclonal antibodies. However, the therapeutic efficacy of 47Sc in preclinical and clinical studies is largely unknown. Given that intrinsic alterations in tumors greatly contribute to resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy, research on overcoming resistance to radioimmunotherapy using cetuximab is required. METHODS: 47Sc was produced by irradiation of a CaCO3 target at the HANARO research reactor in KAERI (Korea Atomic Energy Research Institute) and prepared by chromatographic separation of the irradiated target. Cetuximab was conjugated with 47Sc using the bifunctional chelating agent DTPA. Radiochemical purity was determined using instant thin-layer chromatography. The immunoreactivity of 47Sc-DTPA-cetuximab was evaluated using the Lindmo method and an in vitro cell-binding assay. The inhibitory effects of cetuximab and 47Sc-DTPA-cetuximab were confirmed using cell growth inhibition and BrdU cell proliferation assays. Differences in protein expression levels between cetuximab- and 47Sc-DTPA-cetuximab-treated cells were confirmed using western blotting. Complex formation between RUNX3 and DNA repair components was confirmed using immunoprecipitation and western blotting. RESULTS: Cetuximab induces cell cycle arrest and cell death in EGFR-overexpressing NSCLC cells. Radiolabeling of cetuximab with 47Sc led to increased therapeutic efficacy relative to cetuximab alone. Application of 47Sc-DTPA-cetuximab induced DNA damage responses, and activation of RUNX3 significantly enhanced the therapeutic efficacy of 47Sc-DTPA-cetuximab. RUNX3 mediated susceptibility to EGFR-targeted NSCLC therapy using 47Sc-DTPA-cetuximab via interaction with components of the DNA damage and repair machinery. CONCLUSIONS: 47Sc-DTPA-cetuximab promoted cell death in EGFR-overexpressing NSCLC cells by targeting EGFR and inducing DNA damage as a result of ß irradiation emitted from the conjugated 47Sc. Activation of RUNX3 played a key role in DNA damage and repair processes in response to the ionizing radiation and inhibited cell growth, thus leading to more effective tumor suppression. RUNX3 can potentially moderate susceptibility to 47Sc-conjugated cetuximab by modulating DNA damage and repair process mechanisms.
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Carcinoma de Pulmón de Células no Pequeñas , Subunidad alfa 3 del Factor de Unión al Sitio Principal , Neoplasias Pulmonares , Humanos , Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Receptores ErbB , Neoplasias Pulmonares/tratamiento farmacológico , Ácido PentéticoRESUMEN
BACKGROUND: For successful treatment of early gastric cancers (EGCs), it is crucial to define the horizontal border of the lesion with high accuracy. Acetic acid-indigo carmine (AI) chromoendoscopy has been used to determine the horizontal border in EGCs, but this technique is less potent in certain situations. Mucin phenotype in gastric cancers refers to biological differences in precursor lesions and differences in histopathologic findings, and it might affect AI chromoendoscopy findings. We aimed to investigate the association between mucin phenotype and AI chromoendoscopy findings in EGCs. METHODS: We prospectively evaluated 126 lesions in 126 patients with endoscopically diagnosed EGCs. Conventional endoscopy and AI chromoendoscopy findings of these lesions before treatment were prospectively analyzed. The border distinction between the lesion and surrounding mucosa was classified as distinct or indistinct on conventional endoscopy and AI chromoendoscopy, respectively. Mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null type by immunohistochemistry. RESULTS: The lesion borders were distinct in 46.8% (59/126) of the lesions assessed using conventional endoscopy and in 73.0% (92/126) of those assessed with AI chromoendoscopy (p < 0.001). The border distinction rate of differentiated-type cancers on AI chromoendoscopy was significantly higher than that on conventional endoscopy (66/71 [93.0%] vs. 34/71 [47.9%], p < 0.001), but the border distinction rate of undifferentiated-type cancers on AI chromoendoscopy was not different from that on conventional endoscopy (26/55 [47.3%] vs. 25/55 [45.5%], p = 0.848). Compared with conventional endoscopy, AI chromoendoscopy identified borders in a significantly higher percentage of gastric, intestinal, and gastrointestinal mucin types; however, there was no difference in AI chromoendoscopy findings according to the mucin phenotype (p = 0.271). CONCLUSION: AI chromoendoscopy was effective in horizontal border delineation in differentiated-type EGCs, but not in undifferentiated-type EGCs. Mucin phenotype had no effect on border distinction using AI chromoendoscopy.
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Mucinas , Neoplasias Gástricas , Ácido Acético , Endoscopía Gastrointestinal/métodos , Humanos , Carmin de Índigo , Mucinas/genética , Fenotipo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologíaRESUMEN
Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-ß-d-allopyranosyl-5ß,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-ß-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2-6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0-76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.
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Antiinflamatorios/farmacología , Simulación por Computador , Frutas/química , Glicósidos/química , Glicósidos/farmacología , Hipoglucemiantes/farmacología , Momordica charantia/química , Triterpenos/química , Triterpenos/farmacología , Animales , Antiinflamatorios/química , Bioensayo , Espectroscopía de Resonancia Magnética con Carbono-13 , Glicósidos/aislamiento & purificación , Hipoglucemiantes/química , Ligandos , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Espectroscopía de Protones por Resonancia Magnética , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triterpenos/aislamiento & purificación , alfa-Amilasas/química , alfa-Amilasas/metabolismo , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismoRESUMEN
Respiratory epithelial adenomatoid hamartoma (REAH) in the head and neck is a rare benign lesion containing glandular tissue covered with ciliated respiratory epithelium. In the head and neck, REAH of the nasal cavity, paranasal sinuses, and nasopharynx have been reported in literature. Due to rareness of REAH and insufficient knowledge of its imaging features, the diagnosis can be challenging when we encounter a non-specific cystic mass at an uncommon site in the head or neck. Here, we report the case of a pathologically confirmed REAH showing a cystic mass centered at the buccal space (retromaxillary fat pad) with CT and MRI findings.
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Insulin secretion from pancreatic ß cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that ß-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced ß-cell injury in aging. ß-cell-specific-Ghsr-deficient (Ghsr-ßKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected ß-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-ßKO mice were subjected to STZ. We found that middle-aged and old Ghsr-ßKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that ß-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced ß-cell injury in aging.
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Envejecimiento , Células Secretoras de Insulina , Insulina , Ratones Noqueados , Obesidad , Receptores de Ghrelina , Estreptozocina , Animales , Masculino , Células Secretoras de Insulina/metabolismo , Receptores de Ghrelina/metabolismo , Receptores de Ghrelina/genética , Obesidad/metabolismo , Ratones , Insulina/metabolismo , Secreción de Insulina , Transducción de Señal , Ratones Endogámicos C57BL , Resistencia a la Insulina , Glucemia/metabolismo , Hiperglucemia , Diabetes Mellitus ExperimentalRESUMEN
This retrospective study aimed to determine risk factors associated with post-operative bleeding after dentoalveolar surgery in patients taking anticoagulants. Patients taking anticoagulants who were planned to undergo periodontal flap operation, tooth extraction or implant surgery were included. Patients were divided into two subgroups according to the maintenance of anticoagulants following medical consultation: (1) maintenance group and (2) discontinuation group. The analysed patient-related factors included systemic diseases, maintenance of anticoagulants and types of anticoagulant. Intra- and post-operative treatment-related factors, haemostatic methods and post-operative bleeding were collected for statistical analyses. There were 35 post-operative bleeding complications (6.5%) in the 537 included patients: 21 (8.6%) in maintenance group and 14 (4.8%) in discontinuation group. The type of anticoagulant (p = 0.037), tooth extraction combined with bone grafting (p = 0.016) and type of implant surgery (p = 0.032) were significantly related to the post-operative bleeding rate. In the maintenance group, atrial fibrillation [odds ratio (OR) = 6.051] and vitamin K inhibitors (OR = 3.679) were associated with a significantly higher bleeding risk. From this result, it can be inferred that the decision to continue anticoagulants should be made carefully based on the types of anticoagulant and the characteristics of dentoalveolar surgeries performed: extraction with bone grafting, multiple implantations and involvement of maxillary arch.
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Anticoagulantes , Fibrilación Atrial , Humanos , Anticoagulantes/efectos adversos , Estudios de Cohortes , Estudios Retrospectivos , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/inducido químicamente , Extracción Dental/efectos adversos , Fibrilación Atrial/complicaciones , Administración OralRESUMEN
OBJECTIVE: Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). METHODS: LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. RESULTS: We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM-Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway. CONCLUSIONS: These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity.
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Resistencia a la Insulina , Receptores de Ghrelina , Ratones , Animales , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Resistencia a la Insulina/fisiología , Lipopolisacáridos/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones Noqueados , Obesidad/metabolismo , NutrientesRESUMEN
BACKGROUND AND PURPOSE: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. EXPERIMENTAL APPROACH: We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6 weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. KEY RESULTS: Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. CONCLUSIONS AND IMPLICATIONS: These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.
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Homeostasis , Inflamación , Ratones Endogámicos C57BL , Nanopartículas , Obesidad , Protoporfirinas , Animales , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Masculino , Ratones , Nanopartículas/química , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Protoporfirinas/farmacología , Protoporfirinas/administración & dosificación , Homeostasis/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Glucosa/metabolismo , Dieta Alta en Grasa/efectos adversosRESUMEN
PURPOSE: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations. PATIENTS AND METHODS: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. RESULTS: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4-18.3], while the placebo group had a PFS of 10.9 months (9.0-13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. CONCLUSIONS: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Femenino , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Niacinamida/uso terapéutico , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Receptores ErbB/genéticaRESUMEN
Papillary thyroid cancer (PTC) is the most common type of endocrine cancer worldwide. Generally, PTC has an excellent prognosis; however, lymph node metastases and recurrences occur frequently. Over the last decade, circular RNAs (circRNAs), a large class of noncoding RNAs (ncRNAs), have emerged as key regulators of various tumor progression pathways. Here, we aimed to identify novel circRNAs as PTC biomarkers. Differentially expressed circRNAs and mRNAs were analyzed using public datasets from the Gene Expression Omnibus and Cancer Genome Atlas. In addition, we screened for target miRNAs using online prediction databases. Based on these results, we established a circRNA-miRNA-mRNA regulatory network associated with PTC, in which protein-protein interaction networks led to the identification of hub genes. Functional enrichment and survival analyses were performed to gain insights into the biological mechanisms of circRNA involvement. As a result, we found that two circRNAs (hsa_circ_0041829 and has_circ_0092299), four miRNAs (miR-369, miR-486, miR-574, and miR-665), and nine hub genes (BBC3, E2F1, FYN, MAG, SDC1, SDC3, SNAP25, TK1, and TYMS) play significant roles in PTC progression. This study provides a novel framework for understanding the roles of circRNA-miRNA-mediated gene regulation in PTC. It also introduces potential therapeutic targets and prognostic biomarkers, which may serve as a basis for developing targeted therapeutic interventions for PTC.
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The liver is a key metabolic organ that maintains whole-body nutrient homeostasis. Aging-induced liver function alterations contribute to systemic susceptibility to aging-related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA-Seq and single-cell RNA-Seq analyses to investigate the underlying mechanisms of the aging-induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro-inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro-inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro-inflammatory levels; in monocyte-derived macrophages (MDMs), aging had a limited effect on pro-inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging-responsive KC-specific (ARKC) gene set that potentially mediates aging-induced pro-inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging-induced pro-inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging-induced functional quiescence in MDMs. These results indicate that aging induces pro-inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging-induced pro-inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age-associated chronic diseases.
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Hígado Graso , Intolerancia a la Glucosa , Animales , Ratones , Hígado Graso/metabolismo , Intolerancia a la Glucosa/metabolismo , Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Macrófagos/metabolismoRESUMEN
Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-ß1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-ß1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-ß1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-ß1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-ß1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-ß1âFoxo1âTGF-ß1 looping by deleting TGF-ß1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-ß1âFoxo1âTGF-ß1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS: Hepatic TGF-ß1 levels are increased in obese humans and mice. Hepatic TGF-ß1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-ß1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-ß1âFoxo1âTGF-ß1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Metabolismo Energético , Gluconeogénesis , Animales , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Gluconeogénesis/genética , Glucosa/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Bisphenols are environmental toxins with endocrine disruptor activity, yet bisphenol A (BPA) and its analogs are still widely used in manufacturing plastic products. There is evidence showing that BPA elicits inflammation in humans and animals, but the target cell types of BPA are not well understood. In this study, we sought to determine BPA's direct effect on macrophages and BPA immunotoxicity in mouse intestine. Ghrelin is an important nutrient-sensing hormone, acting through its receptor growth hormone secretagogue receptor (GHSR) to regulate metabolism and inflammation. We found that BPA promotes intestinal inflammation, showing increased infiltrating immune cells in colons and enhanced expression of Ghsr and pro-inflammatory cytokines and chemokines, such as Il6 and Ccl2, in colonic mucosa. Moreover, we found that both long- and short-term BPA exposure elevated pro-inflammatory monocytes and macrophages in mouse peripheral blood mononuclear cells (PBMC) and peritoneal macrophages (PM), respectively. To determine the role of GHSR in BPA-mediated inflammation, we generated Ghsr deletion mutation in murine macrophage RAW264.7 using CRISPR gene editing. In wild-type RAW264.7 cells, the BPA exposure promotes macrophage pro-inflammatory polarization and increases Ghsr and cytokine/chemokine Il6 and Ccl2 expression. Interestingly, Ghsr deletion mutants showed a marked reduction in pro-inflammatory cytokine/chemokine expression in response to BPA, suggesting that GHSR is required for the BPA-induced pro-inflammatory response. Further understanding how nutrient-sensing GHSR signaling regulates BPA intestinal immunotoxicity will help design new strategies to mitigate BPA immunotoxicity and provide policy guidance for BPA biosafety.
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Leucocitos Mononucleares , Receptores de Ghrelina , Animales , Ratones , Quimiocinas , Citocinas/genética , Citocinas/metabolismo , Inflamación/inducido químicamente , Interleucina-6/genética , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Nutrientes , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismoRESUMEN
Oncogenic K-RAS mutations occur in approximately 25% of human lung cancers and are most frequently found in codon 12 (G12C, G12V, and G12D). Mutated K-RAS inhibitors have shown beneficial results in many patients; however, the inhibitors specifically target K-RASG12C and acquired resistance is a common occurrence. Therefore, new treatments targeting all kinds of oncogenic K-RAS mutations with a durable response are needed. RUNX3 acts as a pioneer factor of the restriction (R)-point, which is critical for the life and death of cells. RUNX3 is inactivated in most K-RAS-activated mouse and human lung cancers. Deletion of mouse lung Runx3 induces adenomas (ADs) and facilitates the development of K-Ras-activated adenocarcinomas (ADCs). In this study, conditional restoration of Runx3 in an established K-Ras-activated mouse lung cancer model regressed both ADs and ADCs and suppressed cancer recurrence, markedly increasing mouse survival. Runx3 restoration suppressed K-Ras-activated lung cancer mainly through Arf-p53 pathway-mediated apoptosis and partly through p53-independent inhibition of proliferation. This study provides in vivo evidence supporting RUNX3 as a therapeutic tool for the treatment of K-RAS-activated lung cancers with a durable response.
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Adenocarcinoma , Neoplasias Pulmonares , Animales , Humanos , Ratones , Adenocarcinoma/patología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Genes ras , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The polarization of Macs alters their functional phenotype in response to their surrounding microenvironment. Macs are the major immune cells implicated in the pathogenesis of atherosclerosis. A hallmark pathology of atherosclerosis is the accumulation of pro-inflammatory M1-like macrophages in coronary arteries induced by pro-atherogenic stimuli; these M1-like pro-inflammatory macrophages are incapable of digesting lipids, thus resulting in foam cell formation in the atherosclerotic plaques. Recent findings suggest that the progression and stability of atherosclerotic plaques are dependent on the quantity of infiltrated Macs, the polarization state of the Macs, and the ratios of different types of Mac populations. The polarization of Macs is defined by signature markers on the cell surface, as well as by factors in intracellular and intranuclear compartments. At the same time, pro- and anti-inflammatory polarized Macs also exhibit different gene expression patterns, with differential cellular characteristics in oxidative phosphorylation and glycolysis. Macs are reflective of different metabolic states and various types of diseases. In this review, we discuss the major differences between M1-like Macs and M2-like Macs, their associated metabolic pathways, and their roles in atherosclerosis.
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Aterosclerosis , Placa Aterosclerótica , Aterosclerosis/genética , Aterosclerosis/patología , Humanos , Activación de Macrófagos , Macrófagos/metabolismo , Fenotipo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismoRESUMEN
We investigated whether a fibrinogen-thrombin collagen sponge patch reduces postoperative complications of parotid gland surgery. This single-blinded, randomized controlled study included 165 patients who underwent parotid surgery for benign tumors (2018-2019) at a tertiary center. Primary outcomes were postoperative drain amount, days until drain removal, and discharge. Patients were scheduled for follow-up at 1 and 4 weeks, and 3 months after surgery. Complications including surgical site infection, pain, seroma, sialocele, salivary fistula, facial nerve palsy, Frey's syndrome with subjective symptoms, and facial asymmetry were analyzed. After identifying confounding variables, multivariate approaches were used. Histologic analysis was performed in a mouse model of salivary gland surgery. In total, 162 patients (77, fibrinogen-thrombin collagen patch group; 85, controls) were included, with no significant between-group differences other than resected tissue. Among postoperative total drain amount and days until drain removal and discharge, the only postoperative total drain was significantly lower in the patch group than in the control group in the adjusted model. Additionally, although validation through robust trials with longer follow-up is needed, we found the potential benefit of the fibrinogen patch on Frey's syndrome and facial asymmetry. In conclusion, fibrinogen-thrombin-impregnated collagen patches in parotidectomy can reduce postoperative drainage and improve outcomes.
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BACKGROUND: Rapid disease progression in neuroemergencies is associated with blood-brain barrier (BBB) disruption. We investigated a less invasive strategy for assessing BBB status by evaluating S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) at early stages of the hypoxic-ischemic brain injury (HIBI) cascade. METHODS: This retrospective study used prospectively collected data from patients with out-of-hospital cardiac arrest (August 2019-July 2021). Albumin specimens obtained from serum and cerebrospinal fluid via arterial catheter and lumbar puncture were used to measure the albumin quotient (Qa), which is widely accepted as the gold standard method for detecting BBB disruption. Serum S100B and NSE levels were measured simultaneously following the return of spontaneous circulation. We conducted linear regression to evaluate the relationship between S100B and Qa and the predictive performance of S100B for abnormal Qa. The primary study outcome was abnormal Qa (>0.007). RESULTS: Forty-one patients were enrolled; 30 showed an abnormal Qa suggestive of BBB disruption. S100B levels were significantly higher than in those with a normal Qa (0.244 µg/L [interquartile range [IQR], 0.146-0.823 vs 0.754 µg/L [IQR, 0.317-2.228], P = .03). We report a positive correlation between serum S100B and Qa (R2 = 0.110; P = .04). The area under the receiver operating characteristics curve (AUROC) evaluating the predictive performance of S100B with respect to abnormal Qa was 0.718 (95% confidence interval, 0.556-0.847). The cutoff value for S100B (with respect to BBB disruption) in the total cohort was 0.283 µg/L (sensitivity, 80.0%; specificity, 72.7%). Subgroup analyses in patients with serum neuron-specific enolase (NSE) levels of <40.8 ng/mL (excluding those with established neuronal cell injury) showed an improved correlation coefficient (R2 = 0.382; P < .01) and predictive performance (AUROC, 0.836 [95% confidence interval, 0.629-0.954]) compared with the total cohort. CONCLUSIONS: Serum S100B obtained at an early stage of the HIBI cascade is associated with abnormal Qa, suggesting BBB disruption. The predictive performance of S100B and the correlation between serum S100B and Qa can be improved using a complementary strategy (i.e., evaluations of S100B and NSE levels) that combines considerations of cell damage in astrocytes and neurons.
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Barrera Hematoencefálica , Fosfopiruvato Hidratasa , Subunidad beta de la Proteína de Unión al Calcio S100 , Biomarcadores , Barrera Hematoencefálica/patología , Paro Cardíaco/complicaciones , Humanos , Hipoxia Encefálica/complicaciones , Fosfopiruvato Hidratasa/sangre , Estudios Retrospectivos , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Albúmina Sérica/líquido cefalorraquídeoRESUMEN
BACKGROUND: We compared the ability of head computed tomography (HCT) and MRI, respectively, obtained before or after target temperature management to predict neurologic outcomes in out-of-hospital cardiac arrest (OHCA) survivors. METHODS: This retrospective study included adult comatose OHCA survivors who underwent neuroimaging scans within 6 h (first HCT) or 72-96 h (second HCT and MRI) after the return of spontaneous circulation (ROSC). We calculated the gray-white matter ratio (GWR), hypoxic-ischemic brain injury presence (loss of boundary at the basal ganglia level [LOB at BG], sulcal effacement at the centrum semiovale [SE at CS], and pseudo-SAH sign), and the overall score based on MRI findings (a total score of 21 brain regions individually scored according to the degree of signal abnormality). RESULTS: Overall, 78 patients were included in this analysis, of whom 45 (58%) showed poor outcomes. The second HCT scan showed greater prognostic performance than the first HCT scan for GWR (area under curve 0.92 vs. 0.70), LOB at BG (0.93 vs. 0.65), SE at CS (0.89 vs. 0.64), and pseudo-SAH sign (0.75 vs. 0.51). The overall score on MRI (0.99) showed the highest prognostic performance. However, on the second HCT scan, the combination of GWR and LOB at BG showed prognostic performance (0.96) comparable to the overall score on MRI (P = 0.12); the corresponding sensitivity and specificity values were 85.7% and 100%. CONCLUSIONS: Overall score on MRI and the combination of GWR and LOB at BG findings on second HCT scans may help predict poor outcomes in OHCA survivors.
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Paro Cardíaco Extrahospitalario , Adulto , Sustancia Gris/diagnóstico por imagen , Humanos , Paro Cardíaco Extrahospitalario/diagnóstico por imagen , Paro Cardíaco Extrahospitalario/terapia , Pronóstico , Estudios Retrospectivos , Sobrevivientes , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC. METHODS: In vitro and in vivo lentiviral shRNA library screening was performed. The expression of Synaptotagmin (SYT11) in the tumor tissues of patients with GC was confirmed by performing Immunohistochemistry, and the correlation between the expression level and the patient's survival rate was analyzed. Phospho-kinase array was performed to detect Jun N-terminal kinase (JNK) phosphorylation. SYT11, JNK, and MKK7 complex formation was confirmed by western blot and immunoprecipitation assays. We studied the effects of SYT11 on GC proliferation and metastasis, real-time cell image analysis, adhesion assay, invasion assay, spheroid formation, mouse xenograft assay, and liver metastasis. RESULTS: SYT11 is highly expressed in the stem-like molecular subtype of GC in transcriptome analysis of 527 patients with GC. Moreover, SYT11 is a potential prognostic biomarker for histologically classified diffuse-type GC. SYT11 functions as a scaffold protein, binding both MKK7 and JNK1 signaling molecules that play a role in JNK1 phosphorylation. In turn, JNK activation leads to a signaling cascade resulting in cJun activation and expression of downstream genes angiopoietin-like 2 (ANGPTL2), thrombospondin 4 (THBS4), Vimentin, and junctional adhesion molecule 3 (JAM3), which play a role in epithelial-mesenchymal transition (EMT). SNU484 cells infected with SYT11 shRNA (shSYT11) exhibited reduced spheroid formation, mouse tumor formation, and liver metastasis, suggesting a pro-oncogenic role of SYT11. Furthermore, SYT11-antisense oligonucleotide (ASO) displayed antitumor activity in our mouse xenograft model and was conferred an anti-proliferative effect in SNU484 and MKN1 cells. CONCLUSION: SYT11 could be a potential therapeutic target as well as a prognostic biomarker in patients with diffuse-type GC, and SYT11-ASO could be used in therapeutic agent development for stem-like molecular subtype diffuse GC.