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Innovative for the scientific community and attracting attention in the extensive biomedical field are novel compact organic chemosensing systems built upon unique core molecular frameworks. These systems may demonstrate customized responses and may be adaptable to analytes, showing promise for potential in vivo applications. Our recent investigation focuses on a precursor of Mycophenolic acid, resulting in the development of LBM (LOD = 13 nM) - a specialized probe selective for H2O2. This paper details the synthesis, characterization, and thorough biological assessments of LBM. Notably, we conducted experiments involving living cells, daphnia, and zebrafish models, utilizing microscopy techniques to determine probe nontoxicity and discern distinct patterns of probe localization. Localization involved the distribution of the probe in the Zebrafish model within the gut, esophagus, and muscles of the antennae.
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In several biological processes, H2S is known to function as an endogenous gaseous agent. It is very necessary to monitor H2S and relevant physiological processes inâ vivo. Herein, a new type of fluorophore with a reliable leaving group allows for excited-state intramolecular transfer characteristics (ESIPT), inspired by mycophenolic acid. A morpholine ring was connected at the maleimide position of the probe to target the lysosome. Subsequently, the dinitrophenyl group known for a photoinduced electron transfer (PET) effect, was connected to allow for an effective "turn-on" probe Lyso-H2S. Lyso-H2S demonstrated strong selectivity towards H2S, a large Stokes shift (111â nm), and an incredibly low detection limit (41.8â nM). The imaging of endogenous and exogenous H2S in living cells (A549â cell line) was successfully achieved because of the specificity and ultra-low toxicity (100 % cell viability at 50â µM concentration of Lyso-H2S.) Additionally, Lyso-H2S was also employed to visualize the activity of H2S in the gallbladder and intestine in a living zebrafish model. This is the first report of a fluorescent probe to track H2S sensing in specific organ systems to our knowledge.
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Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors.
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Linfocitos T CD8-positivos , Inmunoterapia , Interleucina-7 , Linfocitos Infiltrantes de Tumor , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Interleucina-7/inmunología , Interleucina-7/metabolismo , Humanos , Animales , Inmunoterapia/métodos , Ratones , Neoplasias/inmunología , Neoplasias/terapia , Línea Celular Tumoral , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Efecto Espectador/inmunologíaRESUMEN
A physical sensor with a sensing medium comprising multiparallel-connected (MPC) piezoresistive pathways in both the vertical and horizontal directions was developed to achieve improved sensing performance. The MPC sensing medium reduces the total resistance and offsets noise, offering enhanced signal stability and device reliability and providing a high-performance sensing platform. The signal change and gauge factor (GF) of the 3PW-5L strain sensor (comprising three lines and five layers of piezoresistive pathways horizontally and vertically, respectively) were, respectively, 5.9 and 4.7 times higher than those of the 1PW-1L sensor composed of a monosensing pathway; the hysteresis of the detected signal was also significantly reduced. The linearity of the detected signal increased from 0.912 for 1PW-1L to 0.995 for 3PW-5L, indicating a greater sensing reliability. The direction of the applied tensile strain was successfully detected using the MPC sensing medium with an orthogonal configuration. The MPC piezoresistive sensor composing vertically stacked piezoresistive pathways demonstrated excellent performance as a pressure sensor; the 3PW-5L pressure sensor afforded a GF of 0.121 ± 0.002 kPa-1 with a linearity of 0.998 under an applied pressure ≥16.4 kPa. The MPC piezoresistive physical sensor offers a superior sensing performance and should contribute to the future development of wearable sensors and electronic devices.
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Purpose: This study aims to estimate (a) the relationship between disability acceptance and depressive symptoms, and (b) how the quality and quantity of social support might moderate the link between disability acceptance and depressive symptoms.Materials and methods: The data for this study included information from 5165 individuals with disability who participated in 3 waves of the Disability and Life Dynamic Panel spanning years 2018 to 2020. This study employed fixed effects models to estimate the association between disability acceptance and depressive symptoms. Interaction models were used to assess the moderating effects of both the quantity and quality of social support.Results: A lower acceptance of disability was positively associated with depressive symptoms. Moreover, both the quantity and quality of social support were associated with a decrease in depressive symptoms. Only the quality of social support played a significant role in moderating the relationship between disability acceptance and depressive symptoms.Conclusion: A lower acceptance of disability increases depressive symptoms in individuals with disabilities. This study underscores the need for interventions to focus on enhancing the quality of social support to mitigate the link between disability acceptance and depressive symptoms.
A lower acceptance of disability is positively associated with depressive symptoms among persons with disability.The association between lower disability acceptance and depressive symptoms attenuates as emotional support from family and friends increases.The number of family and friends does not significantly change the relationship between lower disability acceptance and depressive symptoms.The findings highlight the importance of interventions enhancing quality of social support in order to mitigate the association between disability acceptance and psychological health.
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Particulate matter (PM) is a global environmental hazard, which affects human health through free radical production, cell death induction, and immune responses. PM activates inflammasomes leading to excessive inflammatory responses and induces ferroptosis, a type of cell death. Despite ongoing research on the correlation among PM-induced ferroptosis, immune response, and inflammasomes, the underlying mechanism of this relationship has not been elucidated. In this study, we demonstrated the levels of PM-induced cell death and immune responses in murine macrophages, J774A.1 and RAW264.7, depending on the size and composition of particulate matter. PM2.5, with extraction ions, induced significant levels of cell death and immune responses; it induces lipid peroxidation, iron accumulation, and reactive oxygen species (ROS) production, which characterize ferroptosis. In addition, inflammasome-mediated cell death occurred owing to the excessive activation of inflammatory responses. PM-induced iron accumulation activates ferroptosis and inflammasome formation through ROS production; similar results were observed in vivo. These results suggest that the link between ferroptosis and inflammasome formation induced by PM, especially PM2.5 with extraction ions, is established through the iron-ROS axis. Moreover, this study can effectively facilitate the development of a new therapeutic strategy for PM-induced immune and respiratory diseases.
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Inflammation is a natural protective process through which the immune system responds to injury, infection, or irritation. However, hyperinflammation or long-term inflammatory responses can cause various inflammatory diseases. Although idebenone was initially developed for the treatment of cognitive impairment and dementia, it is currently used to treat various diseases. However, its anti-inflammatory effects and regulatory functions in inflammatory diseases are yet to be elucidated. Therefore, this study aimed to investigate the anti-inflammatory effects of idebenone in cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation. Murine models of cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation were generated, followed by treatment with various concentrations of idebenone. Additionally, lipopolysaccharide-stimulated macrophages were treated with idebenone to elucidate its anti-inflammatory effects at the cellular level. Idebenone treatment significantly improved survival rate, protected against tissue damage, and decreased the expression of inflammatory enzymes and cytokines in mice models of sepsis and systemic inflammation. Additionally, idebenone treatment suppressed inflammatory responses in macrophages, inhibited the NF-κB signaling pathway, reduced reactive oxygen species and lipid peroxidation, and normalized the activities of antioxidant enzyme. Idebenone possesses potential therapeutic application as a novel anti-inflammatory agent in systemic inflammatory diseases and sepsis.
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Mesoporous metal oxides exhibit excellent physicochemical properties and are widely used in various fields, including energy storage/conversion, catalysis, and sensors. Although several soft-template approaches are reported, high-temperature calcination for both metal oxide formation and template removal is necessary, which limits direct synthesis on a plastic substrate for flexible devices. Here, a universal synthetic approach that combines thermal activation and oxygen plasma to synthesize diverse mesoporous metal oxides (V2O5, V6O13, TiO2, Nb2O5, WO3, and MoO3) at low temperatures (150-200 °C), which can be applicable to a flexible polymeric substrate is introduced. As a demonstration, a flexible micro-supercapacitor is fabricated by directly synthesizing mesoporous V2O5 on an indium-tin oxide-coated colorless polyimide film. The energy storage performance is well maintained under severe bending conditions.
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BACKGROUND: The number of pregnant women with opioid use disorder (OUD) has increased over time. Although effective treatment options exist, little is known about the extent to which women receive treatment during pregnancy and at what stage of pregnancy care is initiated. METHODS: Using a national private health insurance claims database, we identified women aged 13-49 who gave birth in 2006-2019 and had an OUD or nonfatal opioid overdose (NFOO) diagnosis during the year prior to or at delivery. We then identified women who received their first OUD treatment prior to or during pregnancy. In this cross-sectional study, we investigated how rates and timing of the initial OUD treatment changed over time. Furthermore, we examined factors associated with early initiation of OUD treatment among birthing people. RESULTS: Of the 7057 deliveries from 6747 women with OUD or NFOO, 63.3 % received any OUD treatment. Rates of OUD treatment increased from 42.9 % in 2006 to 69 % in 2019. Of those treated, in 2006, 54.5 % received their first treatment prior to conception and 24.2 % initiated care during the 1st trimester. In 2019, 68.9 % received their first treatment prior to conception, and 15.1 % initiated care during the 1st trimester. The percentage of women who were first treated in the 2nd trimester or later decreased from 21.2 % in 2006 to 16.1 % in 2019. Factors associated with early treatment initiation include being 25 years or older (age 25-34: aOR, 1.51, 95 % CI, 1.28-1.78; age 35-49: aOR, 1.82, 95 % CI, 1.39-2.37), living in urban areas (aOR, 1.28; 95 % CI, 1.05-1.56), having pre-existing behavioral health comorbidities such as anxiety disorders (aOR, 1.8; 95 % CI, 1.40-2.32), mood disorders (aOR, 1.63; 95 % CI, 1.02-2.61), and substance use disorder other than OUD (aOR, 2.56; 95 % CI, 2.03-3.32). CONCLUSION: Overall, rates of OUD treatment increased over time, and more women initiated OUD treatment prior to conception. Despite these improvements, over one-third of pregnant women with OUD/NFOO either received no treatment or did not initiate care until the 3rd trimester in 2019. Future research should examine barriers to OUD treatment initiation among pregnant women.
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Trastornos Relacionados con Opioides , Humanos , Femenino , Trastornos Relacionados con Opioides/epidemiología , Embarazo , Adulto , Estudios Transversales , Adulto Joven , Adolescente , Persona de Mediana Edad , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Tratamiento de Sustitución de Opiáceos , Tiempo de Tratamiento/estadística & datos numéricos , Sobredosis de Opiáceos/epidemiología , Factores de TiempoRESUMEN
RATIONALE: Despite the existing body of research on the impact of child bereavement, little is known about whether time to the death of an adult child is longitudinally associated with changes in depressive symptoms among older parents. OBJECTIVE: This study examines (a) trajectories of depressive symptoms before and after the loss of an adult child and (b) whether these trajectories differ across parent-child gender dyads (father-son, father-daughter, mother-son, and mother-daughter). METHODS: Using eight waves of the Korean Longitudinal Study of Ageing (KLoSA), this study employs fixed effects models to mitigate potential bias due to unobserved individual-level heterogeneity. Gender-stratified fixed effects models were estimated to investigate potential heterogeneity in the trajectories of depressive symptoms by parent-child gender dyads. RESULTS: The result of this study revealed that depressive symptoms increased within the first year following the loss of an adult child among bereaved parents. Within a year of the loss of a child, both mothers and fathers experienced an increase in depressive symptoms. However, only fathers experienced lasting effects for up to two years. Different patterns in psychological adjustment to bereavement were observed across different parent-child gender dyads. Among daughter-bereaved fathers, depressive symptoms surged within the first year and persisted even beyond the fourth year of loss. In contrast, for other dyads, only an immediate rise in depressive symptoms within the first year of loss was observed. CONCLUSIONS: The loss of an adult child increases the depressive symptoms of parents. This study highlights the importance of considering the different trajectories of psychological adjustment to bereavement, particularly based on parent-child gender dyads, when formulating policies for providing psychological support to older parents who have experienced the loss of their child.
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Depresión , Padre , Masculino , Femenino , Adulto , Humanos , Padre/psicología , Depresión/epidemiología , Estudios Longitudinales , Padres/psicología , Madres/psicologíaRESUMEN
3-Fluoroethamphetamine (3-FEA) belongs to the amphetamine class of stimulant drugs and functions as a releasing agent for the monoamine neurotransmitters norepinephrine, dopamine, and serotonin. 3-FEA acts on the central nervous system and elicits physical and mental side effects, such as euphoria, increased heart rate, and excitement. However, little is known about the withdrawal symptoms and behavioral changes induced by 3-FEA administration. This study aimed to evaluate the short-term consequences of 3-FEA administration (twice a day, 7 days, i.p.; 1 and 10 mg/kg) in C57BL/6J mice (male, 7 weeks old) at three behavioral levels following 1-4 days of withdrawal. The evaluation included (1) withdrawal score, (2) hyperactivity (open field [OF], elevated plus maze [EPM], and cliff avoidance [CA] test), and (3) depression-like behavior (forced-swim test). In the withdrawal score test, withdrawal behavior increased in all 3-FEA groups at 16 and 40 h after withdrawal. In the OF, EPM, and CA tests, the 3-FEA administration group showed significant changes in terms of hyperactivity. In addition, in the forced-swim test, both the 1 mg/kg and 10 mg/kg 3-FEA groups showed increased immobility time. These findings indicate that 3-FEA administration may lead to physical dependence, demonstrated by the withdrawal score increase and significant changes in hyperactivity and depression-like behavior following repeated administration and drug cessation. In conclusion, this study reveals the adverse consequences of 3-FEA administration and highlights the need for awareness raising and regulatory action to control the use of this new psychoactive substance.
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Depresión , Síndrome de Abstinencia a Sustancias , Ratones , Masculino , Animales , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Ratones Endogámicos C57BL , Anfetamina/farmacología , Natación , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Conducta Animal , AnsiedadRESUMEN
OBJECTIVE: The aim of this study was to investigate the role of the follistatin-like 1 (Fstl1) and disco-interacting protein 2 homolog A (DIP2a) axis in relation to lipid metabolism during and after endurance exercise and to elucidate the mechanisms underlying the metabolic effects of Fstl1 on adipocytes, considering its regulation by exercise and muscle mass and its link to obesity. METHODS: Twenty-nine sedentary males participated in endurance exercise, and blood samples were collected during and after the exercise. Body composition, Fstl1, glycerol, epinephrine, growth hormone, and atrial natriuretic peptide were measured. 3T3-L1 adipocytes, with or without DIP2a knockdown, were treated with Fstl1 to assess glycerol release, cyclic AMP/cyclic GMP production, and hormone sensitive lipase phosphorylation. The association between DIP2a gene expression levels in human adipose tissues and exercise-induced lipolysis was examined. RESULTS: Fstl1 levels significantly increased during endurance exercise and following recovery, correlating with lean body mass and lipolysis. In 3T3-L1 adipocytes, Fstl1 increased glycerol release, cyclic GMP production, and hormone sensitive lipase activation, but these effects were attenuated by DIP2a knockdown. DIP2a gene expression in human adipose tissues correlated with serum glycerol concentrations during endurance exercise. CONCLUSIONS: Fstl1 is a myokine facilitating lipid mobilization during and after endurance exercise through DIP2a-mediated lipolytic effects in adipocytes.
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Proteínas Relacionadas con la Folistatina , Folistatina , Humanos , Masculino , GMP Cíclico/metabolismo , Folistatina/metabolismo , Proteínas Relacionadas con la Folistatina/genética , Proteínas Relacionadas con la Folistatina/metabolismo , Glicerol/metabolismo , Movilización Lipídica , Lipólisis/fisiología , Mioquinas , Esterol Esterasa/metabolismoRESUMEN
Mucic acid holds promise as a platform chemical for bio-based nylon synthesis; however, its biological production encounters challenges including low yield and productivity. In this study, an efficient and high-yield method for mucic acid production was developed by employing genetically engineered Saccharomyces cerevisiae expressing the NAD+-dependent uronate dehydrogenase (udh) gene. To overcome the NAD+ dependency for the conversion of pectin to mucic acid, xylose was utilized as a co-substrate. Through optimization of the udh expression system, the engineered strain achieved a notable output, producing 20 g/L mucic acid with a highest reported productivity of 0.83 g/L-h and a theoretical yield of 0.18 g/g when processing pectin-containing citrus peel waste. These results suggest promising industrial applications for the biological production of mucic acid. Additionally, there is potential to establish a viable bioprocess by harnessing pectin-rich fruit waste alongside xylose-rich cellulosic biomass as raw materials.
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Citrus , Saccharomyces cerevisiae , Azúcares Ácidos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Xilosa/metabolismo , Fermentación , Citrus/metabolismo , NAD/metabolismo , Pectinas , Ingeniería Metabólica/métodosRESUMEN
Adult hippocampal neurogenesis plays a pivotal role in maintaining cognitive brain function; however, this process diminishes with age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) are crucial for hippocampal neural stem (HCN) cell maintenance, their involvement in neurodegenerative disorders remains unclear. This study aims to elucidate the mechanisms through which miRNAs regulate HCN cell death and their potential involvement in neurodegenerative disorder. We performed a comprehensive microarray-based analysis to investigate changes in miRNA expression in insulin-deprived HCN cells, as an in vitro model for cognitive impairment. Remarkably, miR-150-3p, miR-323-5p, and miR-370-3p which increased significantly over time following insulin withdrawal, induced pronounced mitochondrial fission and dysfunction, ultimately leading to HCN cell death. Notably, these miRNAs collectively target the mitochondrial fusion protein OPA1, with miR-150-3p also targeting MFN2. Furthermore, data-driven analyses involving human subjects within the hippocampus and brain revealed significant reductions of OPA1 and MFN2 in the Alzheimer's disease (AD) patients. Our results indicate that miR-150-3p, miR-323-5p, and miR-370-3p contribute to deficits in hippocampal neurogenesis by modulating mitochondrial dynamics. Our findings provide a novel insight into the intricate connection between miRNAs and mitochondrial dynamics, shedding light on their potential involvement in conditions characterized by deficits in hippocampal neurogenesis, such as AD.
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A visible light- and reactive oxygen species (ROS)-responsive pressure/strain sensor based on carbon dot (CD)-loaded conductive hydrogel was developed for detecting high-fat diet (HFD) and preventing the risk of non-alcoholic fatty liver disease. The designed nanoparticle consisted of a diselenide polymer dot (dsPD) loaded with a visible light-responsive CD to form dsPD@CD (DSCD). The influence of visible light irradiation and ROS on DSCD facilitated the electron transport, enhancing the conductivity of DSCD-embedded hydrogel (DSCD hydrogel) from 1.3 to 35.9 mS/m. Alternatively, the tensile modulus of the DSCD hydrogel enhanced to 223 % after light-induced ROS treatment, which simultaneously impacted the capacitive response (120 %). The hydrogel implantation into inguinal white adipose tissue of HFD mice showed 82 % higher conductivity and 83 % enhanced pressure sensing response to HFD-generated high ROS levels compared with the normal diet-fed mice. Additionally, the ROS scavenging activity of DSCD hydrogel was confirmed by the downregulation of ROS-responsive genes, such as Sod2, Nrf2, and catalase (Cat) in murine primary hepatocytes isolated from fatty liver-induced mice. In addition, in vivo animal studies also confirmed the suppression of hepatic lipogenesis, as shown by decreased Pparγ and Fasn expression and hypertrophy of adipocytes in HFD mice. The distinguishable real-time wireless resistance response observed with pressure sensing indicates the potential application of the device for monitoring the risk of non-alcoholic fatty liver disease. STATEMENT OF SIGNIFICANCE: A visible-light-induced ROS-responsive carbon dot-loaded conductive hydrogel was developed for the detection of HFD-induced alterations in ROS levels by evaluating the conductivity and electrochemical responses with applied pressure/strain. The implanted hydrogel facilitates the recovery of the inflated adipocytes induced by NAFLD, which reduces fat accumulation in the liver, preventing the risk of NAFLD. Real-time detection based on the resistance response during local compression of the hydrogel is possibly performed utilizing a wireless sensing device, demonstrating the ease of NAFLD monitoring.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Hidrogeles/farmacología , Hidrogeles/metabolismo , Hígado/metabolismo , Tejido Adiposo/metabolismo , Carbono , Ratones Endogámicos C57BLRESUMEN
This study analyzed the effects of the announcement and publication of the 2019 Public Charge Rule on participation of the special supplemental nutrition program for women, infants, and children (WIC) among pregnant immigrants. A difference-in-differences approach was used to analyze the changes in prenatal WIC participation before and after the 2019 Public Charge Rule announcement and publication among immigrants relative to US natives. We identified 17,623,683 live singletons born in a hospital from 2015 to 2019. Compared to US natives, the odds of prenatal WIC participation among immigrants were 11.4% lower after the 2019 Public Charge Rule announcement, and 19% lower after the final rule was published. The results of this study suggest that pregnant immigrants may decide not to participate in the WIC program due to the fear of jeopardizing their immigration status after the announcement and publication of the 2019 Public Charge Rule.
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Emigrantes e Inmigrantes , Asistencia Alimentaria , Lactante , Niño , Embarazo , Humanos , FemeninoRESUMEN
Microbial fermentation is often used to improve the functionality of plant-based food materials. Herein, we investigated changes in the physicochemical and functional properties of cabbage during yeast fermentation to develop new products using fermented cabbage. Among the 8 types of food-grade yeast, both Saccharomyces cerevisiae and Saccharomyces boulardii fermented 10% cabbage powder solution (w/w) the most effectively, leaving no soluble sugars after 12 h of fermentation. In addition, the yeast fermentation of cabbage resulted in functionally positive outcomes in terms of sulforaphane content, antioxidant properties, and anti-inflammatory activity. Specifically, the yeast-fermented cabbages contained about 500% more sulforaphane. The soluble fraction (5 µg/ml) of yeast-fermented cabbage had no cytotoxicity in murine RAW 264.7 cells, and the radical-scavenging capacity was equivalent to 1 µg/ml of ascorbic acid. Moreover, cabbage fermented with S. boulardii significantly suppressed both lipopolysaccharides (LPS)-induced nitric oxide production and LPS-induced reactive oxygen species production in RAW 264.7 cells, suggesting a potential anti-inflammatory effect. These results support the idea that yeast fermentation is promising for developing functionally improved cabbage products.
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Brassica , Animales , Ratones , Brassica/química , Saccharomyces cerevisiae , Lipopolisacáridos , Fermentación , Antiinflamatorios/farmacologíaRESUMEN
â¢The role of patient language in pain management and treatment is understudied.â¢There are disparities in access to pain relievers among people with Limited English Proficiency (LEP).â¢We need to address the need of people with LEP to reach the objectives of Healthy People 2030.
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The prognosis of patients with colorectal cancer (CRC) is affected by invasion and metastasis. Leucyl-tRNA synthetase (LARS) was shown to be related to the growth and migration of lung cancer cells. Dickkopf 4 (DKK4) is known as a Wnt/ß-catenin pathway inhibitor, and its upregulation was reported in several cancers. However, the clinical significance of LARS and DKK4 in human CRC has not been clearly defined. We investigated the expression of LARS and DKK4 by immunohistochemical staining in tissue microarrays from 642 primary CRC patients and analyzed the relationship between their expression and the clinicopathological characteristics of CRC patients. LARS and DKK4 expressions were not related to gender, age at surgery, histologic grade, size, tumor location, tumor invasion, or metastasis, but LARS expression was significantly correlated with TNM stage, N stage, and lymph node metastasis. DKK4 expression was inversely related to the TNM stage and N stage. Survival analysis demonstrated that the OS and DFS in the LARS high expression group were not different compared to the LARS low expression group. OS and DFS in the DKK4 high expression group were significantly higher than in the DKK4 low expression group. In addition, OS and DFS in the group with the combination of the LARS high/DKK4 low expression were significantly lower than in the LARS high/DKK4 high expression group. The low expression of DKK4 alone can be used as a predictor of relapse in CRC patients. In addition, DKK4 low expression in the case of LARS high expression can be used as a poor prognostic factor in CRC patients. Thus, our findings suggest that DKK4 alone or in combination with LARS at diagnosis may be a useful prognostic factor for CRC.
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Aminoacil-ARNt Sintetasas , Neoplasias Colorrectales , Humanos , Pronóstico , Línea Celular Tumoral , Recurrencia Local de Neoplasia , Neoplasias Colorrectales/genética , BiomarcadoresRESUMEN
BACKGROUND: Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-ß (TGF-ß) and epidermal growth factor (EGF) signaling through clathrin- and caveolin-1 (CAV-1)-mediated endocytosis. METHODS: Analysis of the TCGA and GTEx dataset were performed to explore the expression and survival of LY6K in cancer patients. Short interfering RNA (siRNA) was used to knockdown the expression of LY6K in human cervical cancer patients. The effect of lack of LY6K on cell proliferation, migration, and invasion was performed, and RT-qPCR and immunoblotting were performed to identify LY6K-affected TGF-ß and EGF signaling pathways. Additionally, Immunofluorescence (IF) and transmission electron microscope (TEM) were performed to identify the role of LY6K in CAV-1- and Clathrin-mediated endocytosis. RESULTS: Lymphocyte antigen 6 complex locus K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-ß-enhanced migration and invasion. Both TGF-ß receptor-I (TßRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TßRI irrespective of the presence of TGF-ß; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired Smad2 phosphorylation upon TGF-ß treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TßRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. CONCLUSIONS: Our study demonstrates the key role of LY6K in both clathrin- and CAV-1-mediated endocytic pathways regulated by TGF-ß and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival.