RESUMEN
The development of head and neck squamous cell carcinoma (HNSCC) is a multi-step process, and its survival depends on a complex tumor ecosystem, which not only promotes tumor growth but also helps to protect tumor cells from immune surveillance. With the advances of existing technologies and emerging models for ecosystem research, the evidence for cell-cell interplay is increasing. Herein, we discuss the recent advances in understanding the interaction between tumor cells, the major components of the HNSCC tumor ecosystem, and summarize the mechanisms of how biological and abiotic factors affect the tumor ecosystem. In addition, we review the emerging ecological treatment strategy for HNSCC based on existing studies.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas/patología , Terapia por Relajación , EcosistemaRESUMEN
MAIN CONCLUSION: We review the application and the molecular regulation of anthocyanins in colorful Brassica crops, the creation of new germplasm resources, and the development and utilization of colorful Brassica crops. Brassica crops are widely cultivated: these include oilseed crops, such as rapeseed, mustards, and root, leaf, and stem vegetable types, such as turnips, cabbages, broccoli, and cauliflowers. Colorful variants exist of these crop species, and asides from increased aesthetic appeal, these may also offer advantages in terms of nutritional content and improved stress resistances. This review provides a comprehensive overview of pigmentation in Brassica as a reference for the selection and breeding of new colorful Brassica varieties for multiple end uses. We summarize the function and molecular regulation of anthocyanins in Brassica crops, the creation of new colorful germplasm resources via different breeding methods, and the development and multifunctional utilization of colorful Brassica crop types.
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Brassica napus , Brassica , Brassica/genética , Antocianinas , FitomejoramientoRESUMEN
The microbiota actively and extensively participates in the regulation of human metabolism, playing a crucial role in the development of metabolic diseases. Helicobacter pylori (H. pylori), when colonizing gastric epithelial cells, not only induces local tissue inflammation or malignant transformation but also leads to systemic and partial changes in host metabolism. These shifts can be mediated through direct contact, toxic components, or indirect immune responses. Consequently, they influence various molecular metabolic events that impact nutritional status and iron absorption in the host. Unraveling the intricate and diverse molecular interaction links between H. pylori and human metabolism modulation is essential for understanding pathogenesis mechanisms and developing targeted treatments for related diseases. However, significant challenges persist in comprehensively understanding the complex association networks among H. pylori itself, the infected host's status, the host microbiome, and the immune response. Previous metabolomics research has indicated that H. pylori infection and eradication may selectively shape the metabolite and microbial profiles of gastric lesions. Yet, it remains largely unknown how these diverse metabolic pathways, including isovaleric acid, cholesterol, fatty acids, and phospholipids, specifically modulate gastric carcinogenesis or affect the host's serum metabolism, consequently leading to the development of metabolic-associated diseases. The direct contribution of H. pylori to metabolisms still lacks conclusive evidence. In this review, we summarize recent advances in clinical evidence highlighting associations between chronic H. pylori infection and metabolic diseases, as well as its potential molecular regulatory patterns.
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Infecciones por Helicobacter , Helicobacter pylori , Enfermedades Metabólicas , Humanos , Helicobacter pylori/fisiología , Infecciones por Helicobacter/complicaciones , Estómago/patología , HomeostasisRESUMEN
N6-methyladenosine (m6A) mRNA modification plays critical roles in various biological events and is involved in multiple complex diseases. However, the role of m6A modification in autophagy in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we report that m6A modification was increased in livers of NAFLD mouse models and in free fatty acid (FFA)-treated hepatocytes, and the abnormal m6A modification was attributed to the upregulation of methyltransferase like 3 (METTL3) induced by lipotoxicity. Knockdown of METTL3 promoted hepatic autophagic flux and clearance of lipid droplets (LDs), while overexpression of METTL3 inhibited these processes. Mechanistically, METTL3 directly bound to Rubicon mRNA and mediated the m6A modification, while YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), as a partner of METTL3, interacted with the m6A-marked Rubicon mRNA and promoted its stability. Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked clearance of LDs. Taken together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via the autophagy pathway and provided a novel insight into m6A mRNA methylation in NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Adenosina/metabolismo , Animales , Autofagia/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Proteínas de Unión al ARNRESUMEN
Rapeseed has the ability to absorb cadmium in the roots and transfer it to aboveground organs, making it a potential species for remediating soil cadmium (Cd) pollution. However, the genetic and molecular mechanisms underlying this phenomenon in rapeseed are still unclear. In this study, a 'cadmium-enriched' parent, 'P1', with high cadmium transport and accumulation in the shoot (cadmium root: shoot transfer ratio of 153.75%), and a low-cadmium-accumulation parent, 'P2', (with a cadmium transfer ratio of 48.72%) were assessed for Cd concentration using inductively coupled plasma mass spectrometry (ICP-MS). An F2 genetic population was constructed by crossing 'P1' with 'P2' to map QTL intervals and underlying genes associated with cadmium enrichment. Fifty extremely cadmium-enriched F2 individuals and fifty extremely low-accumulation F2 individuals were selected based on cadmium content and cadmium transfer ratio and used for bulk segregant analysis (BSA) in combination with whole genome resequencing. This generated a total of 3,660,999 SNPs and 787,034 InDels between these two segregated phenotypic groups. Based on the delta SNP index (the difference in SNP frequency between the two bulked pools), nine candidate Quantitative trait loci (QTLs) from five chromosomes were identified, and four intervals were validated. RNA sequencing of 'P1' and 'P2' in response to cadmium was also performed and identified 3502 differentially expressed genes (DEGs) between 'P1' and 'P2' under Cd treatment. Finally, 32 candidate DEGs were identified within 9 significant mapping intervals, including genes encoding a glutathione S-transferase (GST), a molecular chaperone (DnaJ), and a phosphoglycerate kinase (PGK), among others. These genes are strong candidates for playing an active role in helping rapeseed cope with cadmium stress. Therefore, this study not only sheds new light on the molecular mechanisms of Cd accumulation in rapeseed but could also be useful for rapeseed breeding programs targeting this trait.
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Brassica napus , Cadmio , Humanos , Brassica napus/genética , Fitomejoramiento , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ARNRESUMEN
AIMS/HYPOTHESIS: Lipotoxicity constitutes the major driving force for type 2 diabetes. Circular RNAs (circRNAs) play important roles in regulating beta cell function and exosomes are essential mediators of intercellular communication. The role of exosomal circRNAs in type 2 diabetes remains largely unknown. We aimed to examine whether lipotoxicity induces dysregulation of circRNAs in beta cell-derived exosomes and to determine the contribution of exosomal circRNAs to the development of type 2 diabetes. METHODS: Exosomes were extracted from MIN6 cells treated with palmitate or BSA, and RNA sequencing was performed. CircGlis3 (Gli-similar 3) expression level was validated by qPCR. The impact of circGlis3 on beta cell function and the deleterious effects of exosomal circGlis3 on islet endothelial cells (islet ECs) were investigated in vitro and in vivo in human and mouse models by gain or loss of function assays. The molecular mechanism of circGlis3 was explored by RNA pull-down and immunoprecipitation assays. RESULTS: Beta cell-derived exosomal circGlis3 was significantly upregulated under lipotoxic conditions, and exosomal circGlis3 levels were also elevated in the serum of mouse models of diabetes and participants with type 2 diabetes. CircGlis3 participated in lipotoxicity-induced beta cell dysfunction in vitro and in vivo. Moreover, beta cell-derived exosomal circGlis3 could be transferred to islet ECs and reduce the cell viability, cell migration and angiogenesis of islet ECs. Mechanistically, circGlis3 promoted the degradation of glucocorticoid modulatory element-binding protein 1 (GMEB1) by facilitating the interaction between GMEB1 and mindbomb E3 ubiquitin protein ligase 2 (MIB2), thus suppressing the phosphorylation of heat shock protein 27 (HSP27). CONCLUSIONS/INTERPRETATION: Our study points to the involvement of circGlis3 in diabetes development, and exosomal circGlis3 transfer as a communication mode between beta cells and islet ECs, suggesting that circGlis3 might be a potential biomarker and therapeutic target for type 2 diabetes. DATA AVAILABILITY: The RNA-sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) database, with accession number PRJNA689673. Mass spectrometry data are available via ProteomeXchange with identifier PXD024693.
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Diabetes Mellitus Tipo 2 , Exosomas , ARN Circular , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliales/metabolismo , Exosomas/metabolismo , Humanos , Ratones , ARN Circular/genética , ARN Circular/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: The accumulation of reactive oxygen species (ROS) resulting from upregulated levels of oxidative stress is commonly implicated in preeclampsia (PE). Ferroptosis is a novel form of iron-dependent cell death instigated by lipid peroxidation that likely plays an important role in PE pathogenesis. This study aimed to investigate the expression profiles and functions of ferroptosis-related genes (FRGs) in early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE). METHODS: Gene expression data and clinical information were downloaded from the Gene Expression Omnibus (GEO) database. The "limma" R package was used to screen differentially expressed genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analyses were conducted to investigate the bioinformatics functions and molecular interactions of significantly different FRGs. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to verify the expression of hub FRGs in PE. RESULTS: A total of 4215 differentially expressed genes (DEGs) were identified between EOPE and preterm cases while 556 DEGs were found between LOPE and term controls. Twenty significantly different FRGs were identified in EOPE subtypes, while only 3 FRGs were identified in LOPE subtypes. Functional enrichment analysis revealed that the differentially expressed FRGs were mainly involved in EOPE and enriched in hypoxia- and iron-related pathways, such as the response to hypoxia, iron homeostasis and iron ion binding process. PPI network analysis and verification by RT-qPCR resulted in the identification of the following five FRGs of interest: FTH1, HIF1A, FTL, MAPK8 and PLIN2. CONCLUSIONS: EOPE and LOPE have distinct underlying molecular mechanisms, and ferroptosis may be mainly implicated in the pathogenesis of EOPE. Further studies are necessary for deeper inquiry into placental ferroptosis and its role in the pathogenesis of EOPE.
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Ferroptosis/genética , Perfilación de la Expresión Génica , Preeclampsia/genética , Adulto , Apoferritinas/genética , Regulación hacia Abajo , Femenino , Ferritinas/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Proteína Quinasa 8 Activada por Mitógenos/genética , Oxidorreductasas/genética , Perilipina-2/genética , Placenta/metabolismo , Embarazo , Trimestres del Embarazo/metabolismo , Análisis de Componente Principal , Mapas de Interacción de Proteínas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
BACKGROUND: Uterine sarcoma is a rare malignancy of women and fewer uterine sarcomas are detected preoperatively. The reported incidence of preoperatively diagnosed uterine sarcoma (PDUS) was 0.07%. This study aims to identify the prevalence of unexpected uterine sarcoma (UUS) after operation for presumed leiomyoma and compare clinical outcomes after primary therapy. METHODS: A retrospective study was performed evaluating all uterine sarcoma diagnosed in Tianjin Central Hospital of Gynecology and Obstetrics between May 2011 and July 2016.We used the χ2 and T tests to assess the incidence and clinical features of patients. The Kaplan-Meier method was used to calculate disease-related survival. RESULTS: The study retrospectively analyzed 6625 patients with uterine fibroids and found 45 UUS patients and 21 patients of PDUS. The incidence of UUS is (45/6625) 0.67%. The incidence of UUS in patients undergoing total hysterectomy was higher undergoing tumor resection (P < 0.001); the age of UUS is younger than PDUS (P = 0.046); the differences in menopausal status and primary complaints between the two groups are not statistically significant. The PDUS group had more patients with Stage II and III sarcomas than the UUS group (P < 0.001); the duration of symptoms in the PDUS group was longer than in the UUS group (P = 0.033). The 5-year overall survival (OS) rate of the UUS group (77.7%) is higher than the PDUS group (46.3%) (P < 0.001). CONCLUSIONS: The incidence of UUS is low. UUS has a younger age of onset, shorter history of the disease, earlier clinical stage, and better prognosis.
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Leiomioma , Sarcoma , Humanos , Femenino , Estudios Retrospectivos , China/epidemiología , Leiomioma/epidemiología , Leiomioma/cirugía , Sarcoma/epidemiologíaRESUMEN
OBJECTIVE: To investigate the effect and mechanism of Buyang Huanwu decoction (BYHWD) on angiogenesis of rat brain microvascular endothelial cells (RBMECs) after oxygen-glucose deprivation reperfusion (OGD/R) injury. METHODS: RBMECs were pretreated with BYHWD containing serum 24â h before OGD/R injury was induced. Cells were randomly divided into blank control group, model control group, BYHWD group (provided BYHWD containing serum) and LY294002 group [treated with phosphoinositide 3-kinase (PI3K) inhibitor LY294002 for 1â h before provided BYHWD containing serum]. The cell viability, migration and tube formation abilities of RBMECs were detected by CCK-8, scratch wound healing, Transwell migration and tube formation assays, respectively. The protein expression levels of PI3K, p-PI3K, protein kinase B (AKT), p-AKT, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were determined by Western blotting. RESULTS: Compared with model control group, cell viability, migration and tube formation abilities of RBMECs were significantly improved in BYHWD group (all P<0.01), the protein expression levels of p-PI3K, p-AKT, HIF-1α and VEGF were up-regulated (all P<0.05); while above effects were blocked by LY294002. CONCLUSION: BYHWD can promote angiogenesis of RBMECs after OGD/R injury, which may be related to the increased protein expression of HIF-1α and VEGF through activation of PI3K-AKT signaling pathway.
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Fosfatidilinositol 3-Quinasa , Daño por Reperfusión , Ratas , Animales , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasa/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Células Endoteliales/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Oxígeno/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Transducción de Señal , Encéfalo/metabolismoRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) infection of gastric epithelial cells induces inflammatory response. Outer membrane proteins (OMPs), Type 4 secretion system (T4SS) encoded by cagPAI, and the effector protein CagA are involved in the pathogenesis of H. pylori. H. pylori possesses a gene encoding LuxS which synthesizes AI-2, a quorum sensing signal molecule. The aim of this study was to investigate the role of AI-2 in the expression of virulence factors and the inflammatory response of gastric epithelial (AGS) cells induced by H. pylori. MATERIALS AND METHODS: H. pylori ΔluxS mutant was constructed, and AI-2 activity was measured with Vibrio harveyi BB170. NF-κB activation, IL-8 production, expression of OMPs (outer membrane proteins), CagA, and T4SS encoded by cagPAI were investigated in H. pylori wild type, and ΔluxS with or without supplementation of AI-2. RESULTS: H. pylori produced approximately 7 µM of AI-2 in the medium. AI-2 inhibited expression and translocation of CagA after infection of AGS cells. AI-2 upregulated the expression of CagM, CagE, and CagX, while had no effect to the interaction between T4SS and α5ß1 integrin. AI-2 also reduced expression of adhesins and bacterial adhesion to AGS cells. Finally, AI-2 reduced the activation of NF-κB and expression of IL-8 in H. pylori-infected AGS. CONCLUSIONS: AI-2 plays an important role in the pathogenesis of H. pylori. AI-2 inhibits the bacterial adhesion, expression, and translocation of CagA, and attenuates the inflammatory response of AGS cells induced by H. pylori.
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Infecciones por Helicobacter , Helicobacter pylori , Antígenos Bacterianos , Adhesión Bacteriana , Proteínas Bacterianas , Células Epiteliales , Humanos , VibrioRESUMEN
BACKGROUND: Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Mutations in Wolfram syndrome 1 (WFS1) gene may cause dysregulated endoplasmic reticulum (ER)-stress and cell apoptosis, contributing to WS symptoms. The aim of this study was to identify the molecular etiology of a case of WS and to explore the functional consequence of the mutant WFS1 gene in vitro. METHODS: A 27 years-old Chinese man was diagnosed as wolfram syndrome type 1 based on clinical data and laboratory data. DNA sequencing of WFS1 gene and mitochondrial m.3337G > A, m.3243A > G mutations were performed in the patient and his 4 family members. Functional analysis was performed to assessed the in vitro effect of the newly identified mutant. ER stress were evaluated by ER stress response element (ERSE)-luciferase assay. Cell apoptosis were performed by CCK-8, TUNEL staining and flow cytometric analysis. RESULTS: A novel heterozygous 10-base deletion (c. 2067_2076 del10, p.W690fsX706) was identified in the patient. In vitro studies showed that mutant p.W690fsX706 increased ERSE reporter activity in the presence or absence of thapsigargin instead of wild type WFS1. Knockdown of WFS1 activated the unfolded protein response (UPR) pathway and increased the cell apoptosis, which could not be restored by transfection with WFS1 mutant (p.W690fsX706) comparable to the wild type WFS1. CONCLUSIONS: A novel heterozygous mutation of WFS1 detected in the patient resulted in loss-of-function of wolframin, thereby inducing dysregulated ER stress signaling and cell apoptosis. These findings increase the spectrum of WFS1 gene mutations and broaden our insights into the roles of mutant WFS1 in the pathogenesis of WS.
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Apoptosis/genética , Estrés del Retículo Endoplásmico/genética , Proteínas de la Membrana/genética , Síndrome de Wolfram , Adulto , China , Genes Dominantes , Heterocigoto , Humanos , Masculino , Mutación , Polimorfismo de Nucleótido Simple , Síndrome de Wolfram/genética , Síndrome de Wolfram/metabolismo , Síndrome de Wolfram/patologíaRESUMEN
BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of gastric mucosal lesions. In China, teprenone is frequently prescribed as a mucoprotective agent, but the literature regarding their efficacy is limited. Our purpose was to address the effects of teprenone on long-term NSAID-associated gastric mucosal lesions. METHODS: This study examined 369 patients taking NSAIDs for at least 12 weeks. Patients without gastroduodenal ulcer and without Helicobacter pylori infection on endoscopy at baseline were randomized to receive either NSAID plus teprenone (150 mg/day) or NSAID only for 12 weeks. Lanza scores were examined using endoscopy before and after treatment, and dyspeptic symptom scores are also analyzed. RESULTS: A total of 158 patients were randomized to the teprenone group (n = 74) or the control group (n = 84) for 12 weeks. Seventy-one of patients in the teprenone group and 79 of patients in the control group were analyzed finally. After treatment, the Lanza scores and dyspeptic symptom scores decreased significantly in the teprenone group while increased in the control group (P < 0.05). The changes of Lanza scores and dyspeptic symptom scores were higher in the teprenone group than in the control group (P < 0.05). For subgroup analysis, the change in Lanza scores and dyspeptic symptom scores improved significantly in the teprenone group receiving long-term low-dose aspirin treatment, as well as in the teprenone group receiving other NSAIDs treatment (P < 0.05). CONCLUSIONS: Teprenone may be an effective treatment choice of gastric mucosal injuries and dyspepsia symptoms in patients who used NSAIDs chronically without H. pylori infection or history of gastroduodenal ulcer.
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Antiinflamatorios no Esteroideos/efectos adversos , Antiulcerosos/uso terapéutico , Diterpenos/uso terapéutico , Dispepsia/tratamiento farmacológico , Mucosa Gástrica/efectos de los fármacos , Adulto , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Antiulcerosos/efectos adversos , Beijing , Diterpenos/efectos adversos , Esquema de Medicación , Dispepsia/inducido químicamente , Dispepsia/patología , Femenino , Mucosa Gástrica/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Fear or anxiety could result in adverse consequences on the course of labour. To date, family members are still not permitted in the delivery rooms in the majority of hospitals in China, and continuous support from hospital professional staff is also limited. This study aimed to evaluate the benefits of continuous support by family members and hospital professional staff during labour in China. METHODS: In this Cross-Sectional study, 362 primiparous pregnancies who self-requested to receive continuous or one to one support with vaginal delivery and 362 primiparous pregnant women with routine hospital maternal care were included from a university teaching hospital. Data on the length of labour, postpartum haemorrhage (PPH), use of pain relief, use of oxytocin, fetal distress, emergency caesarean section and apgar score at 1 and 5 min were retrospectively collected from hospital medical data-base and compared between the two groups. RESULTS: Multiple linear regressions adjusting for maternal age, BMI and birth weight, revealed the estimated length of labour for women with routine hospital maternal care was 2.03 times (95%CI 1.86 to 2.21) the duration of women with supportive care (median time, 3.05 h vs 1.5 h). In addition, Fisher's exact test showed the emergency caesarean section rate was significantly lower in women with supportive care compared to women with routine hospital maternal care (3.3% vs 24%). CONCLUSION: Our results suggest that continuous support from family members together with hospital professional staff should be considered as part of intrapartum care in hospitals in China.
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Cesárea/estadística & datos numéricos , Familia , Sufrimiento Fetal/epidemiología , Trabajo de Parto , Personal de Enfermería en Hospital , Parto , Hemorragia Posparto/epidemiología , Apoyo Social , Adolescente , Adulto , Analgesia Obstétrica/estadística & datos numéricos , Ansiedad/psicología , Puntaje de Apgar , China/epidemiología , Estudios Transversales , Parto Obstétrico , Urgencias Médicas , Miedo/psicología , Femenino , Hospitales de Enseñanza , Hospitales Universitarios , Humanos , Partería , Enfermería Obstétrica , Oxitócicos , Oxitocina , Embarazo , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to investigate the potential association between dietary live microbe intake and sarcopenia. METHODS: Data from 5368 participants were gathered from the National Health and Nutrition Examination Survey (NHANES). Dietary information was assessed using a self-report questionnaire. The participants were categorized into low, medium, and high dietary live microbe groups. Sarcopenia was defined according to the National Institutes of Health (NIH) definition (appendicular skeletal muscle mass/body mass index <0.789 for men and <0.512 for women). Multivariate regression analysis and stratified analyses were performed. RESULTS: After adjusting for potential confounding factors, individuals in the high dietary live microbe group exhibited a lower prevalence of sarcopenia compared to those in the low dietary live microbe group. The adjusted odds ratio (with 95% confidence intervals) was 0.63 (0.44-0.89) (p for trend <0.05). Subgroup analyses indicated a potential difference in the impact of dietary live microbe intake on sarcopenia between individuals with and without diabetes (p for interaction = 0.094). CONCLUSION: Higher dietary live microbe intake was associated with a lower risk of sarcopenia.
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Dieta , Encuestas Nutricionales , Sarcopenia , Humanos , Sarcopenia/epidemiología , Sarcopenia/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Dieta/métodos , Dieta/estadística & datos numéricos , Anciano , Estudios Transversales , Factores de Riesgo , Prevalencia , Adulto , Índice de Masa CorporalRESUMEN
Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer with few effective therapies. Though immunotherapies such as targeting PD-1/PD-L1 axis have benefited patients with solid tumor, the druggable immune checkpoints are quite limited in ATC. In our study, we focused on the anti-tumor potential of sialic acid-binding Ig-like lectins (Siglecs) in ATC. Through screening by integrating microarray datasets including 216 thyroid-cancer tissues and single-cell RNA-sequencing, SIGLEC family members CD33, SIGLEC1, SIGLEC10 and SIGLEC15 were significantly overexpressed in ATC, among which SIGLEC15 increased highest and mainly expressed on cancer cells. SIGLEC15high ATC cells are characterized by high expression of serine protease PRSS23 and cancer stem cell marker CD44. Compared with SIGLEC15low cancer cells, SIGLEC15high ATC cells exhibited higher interaction frequency with tumor microenvironment cells. Further study showed that SIGLEC15high cancer cells mainly interacted with T cells by immunosuppressive signals such as MIF-TNFRSF14 and CXCL12-CXCR4. Notably, treatment of anti-SIGLEC15 antibody profoundly increased the cytotoxic ability of CD8+ T cells in a co-culture model and zebrafish-derived ATC xenografts. Consistently, administration of anti-SIGLEC15 antibody significantly inhibited tumor growth and prolonged mouse survival in an immunocompetent model of murine ATC, which was associated with increase of M1/M2, natural killer (NK) cells and CD8+ T cells, and decrease of myeloid-derived suppressor cells (MDSCs). SIGLEC15 inhibited T cell activation by reducing NFAT1, NFAT2, and NF-κB signals. Blocking SIGLEC15 increased the secretion of IFN-γ and IL-2 in vitro and in vivo. In conclusion, our finding demonstrates that SIGLEC15 is an emerging and promising target for immunotherapy in ATC.
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Inmunoterapia , Proteínas de la Membrana , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Animales , Humanos , Ratones , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Inmunoglobulinas , Inmunoterapia/métodos , Lectinas/genética , Lectinas/metabolismo , Carcinoma Anaplásico de Tiroides/terapia , Carcinoma Anaplásico de Tiroides/inmunología , Carcinoma Anaplásico de Tiroides/genética , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/inmunología , Neoplasias de la Tiroides/genética , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.
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Progresión de la Enfermedad , Homeostasis , Magnesio , Carcinoma Anaplásico de Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/genética , Magnesio/metabolismo , Línea Celular Tumoral , Animales , Proliferación Celular , Biosíntesis de Proteínas , Ratones , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Ratones Desnudos , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , Apoptosis , Transducción de Señal , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Anaplastic thyroid cancer (ATC) is one of the deadliest cancers, whose important malignant feature is dedifferentiation. Chromatin remodeling is critical for tumorigenesis and progression, while its roles and regulator in facilitating dedifferentiation of ATC had been poorly understood. In our study, an emerging function of hematological and neurological expressed 1 (HN1) in promoting dedifferentiation of ATC cells was uncovered. HN1 expression was negatively correlated with the thyroid differentiation markers both at mRNA and protein level. Knockdown of HN1 in ATC cells effectively upregulated the thyroid differentiation markers and impeded the sphere formation capacity, accompanying with the loss of cancer stemness. In contrast, overexpression of HN1 drove the gain of stemness and the loss of thyroid differentiation markers. Nude mouse and zebrafish xenograft models showed that inhibition of HN1 in ATC cells effectively hindered tumor growth due to the loss of cancer stemness. Further study showed that HN1 was negatively correlated with CTCF in an independent thyroid-cancer cohort, and inhibition of HN1 enhanced the expression of CTCF in ATC cells. Overexpression of CTCF significantly reversed the dedifferentiation phenotypes of ATC cells, whereas simultaneously inhibiting HN1 and CTCF was unable to recover the level of thyroid differentiation markers. The combination of ATAC-seq and ChIP-seq analysis confirmed that CTCF regulated genes relating with thyroid gland development through influencing their chromatin accessibility. HN1 inhibited the acetylation of H3K27 at the promoter of CTCF by recruiting HDAC2, thereby inhibiting the transcriptional activation of CTCF. These findings demonstrated an essential role of HN1 in regulating the chromatin accessibility of thyroid differentiation genes during ATC dedifferentiation.
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Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Animales , Humanos , Ratones , Antígenos de Diferenciación , Línea Celular Tumoral , Cromatina , Epigénesis Genética , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Pez Cebra/genéticaRESUMEN
Circular RNAs (circRNAs) are crucial regulators of ß-cell function and are involved in lipotoxicity-induced ß-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3, was upregulated in lipotoxic ß cells. However, the functional role and molecular mechanism of circGlis3 in ß cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that the overexpression of circGlis3 impaired ß-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in ß-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM.
RESUMEN
OBJECTIVE: To explore the prognostic value of the Mayo Additive Staging System (MASS) in real-world patients with newly diagnosed multiple myeloma(MM). METHODS: The clinical data of 307 patients with newly diagnosed MM from August 2015 to June 2022 were retrospectively analyzed. Survival analysis was conducted for each subgroup according to the MASS. The MASS was compared to the original staging systems to evaluate its prognostic value. Patients in the high-risk group were further stratified. RESULTS: Patients were divided into MASS stages I (93 cases), II (91 cases), and III (123 cases), with differences in overall survival (OS) and progression-free survival (PFS) among all groups (p < 0.0001). Patients were grouped according to treatment regimen, age, transplant status, renal function, and bone destruction; with differences in OS and PFS among patients at each MASS stage in all subgroups (P ≤ 0.05). The MASS was also used for further risk stratification of patients with Mayo Myeloma Stratification and Risk-adjusted Treatment Stratification System 3.0 (mSMART3.0) and Revised International Staging System (R-ISS). Furthermore, in the MASS high-risk group, patients with scores of 2 and 3 vs 4 had OS of 23.7 and 10.1 months (P = 0.004), and PFS of 17.6 and 8.2 months (P = 0.004), respectively. Patients in the high-risk complex karyotype group not covered by SMART staging criteria had shorter OS and PFS than those in the mSMART3.0 high-risk and MASS stage III groups. CONCLUSION: The prognostic value of the MASS in patients with MM has been verified, and has better evaluation efficiency than the SMART and R-ISS systems.