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Objective: This study aimed to analyze the incidence trends and spatial distribution characteristics of thyroid cancer among Chinese females from 1990 to 2019, thereby providing a scientific foundation and data support for the development of prevention and control policies. Methods: Thyroid cancer incidence data from the Global Burden of Disease (GBD) research and the annual report from the Chinese Tumor Registration were utilized. The standardized thyroid cancer incidence rate among Chinese females 1990 to 2019 was described to understand the changes in developmental trends. The JoinPoint Regression Model was employed using Excel 2019, GraphPad Prism 8, JoinPoint Regression Program 4.8.0.1, and ArcGIS 10.2. Results: Thyroid cancer's standardized incidence among female Chinese continued to increase at 1.7% per year (annual average percentage change [AAPC] = 1.7, P < 0.001), and the spatial distribution was clustered. The main high-incidence areas were North, East, and Northwest China. Conclusions: Thyroid cancer incidence in Chinese women is rapidly increasing, and its spatial distribution is concentrated. Strengthening monitoring, prevention, and control efforts in the relevant areas is warranted.
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Background: The association between health literacy and healthy dietary behaviors has been explored in the European population. However, there is currently no evidence available specifically pertaining to Chinese college students particularly for interactive health literacy. Aims: The objective of this study was to investigate the association between interactive health literacy (IHL) and dietary behaviors in Chinese college students. Methods: This study included 11,856 Chinese college students (mean age = 18.8 years, SD = 1.2 years). We defined nine healthy dietary behaviors as consumption of water, egg, milk and milk products, vegetables, fruit, red meat, soy and soy products, seafood, and sugar-sweetened beverages. For each food group, participants who met the criterion for being a regular consumer of the item were assigned a score of 1, and otherwise were assigned a score of 0. Thus, the dietary behaviors score ranged from 0 to 9, with higher scores indicating healthier dietary behaviors. We used the revised 28-item Chinese Adolescent Interactive Health Literacy Questionnaire (CAIHLQ) to evaluate IHL; a higher score on this scale indicates a greater health literacy. Multivariate logistic regression was used to analyze the association between IHL level and frequency of different numbers of dietary behaviors. Results: After adjusting for sex, age, annual family income, place of residence, father's education level, and mother's education level, there was a clear and significant positive association between IHL and the likelihood of exhibiting diverse dietary behaviors. The adjusted odds ratio (95% CI) of exhibiting given nine dietary behaviors with reference to tertile 1 according to categories of IHL was as follows: 1.055 (0.694, 1.603) for tertile 2 and 1.849 (1.269, 2.696) for tertile 3 (p for trend = 0.001). Similarly, there are significant positive associations between IHL and the likelihood of exhibiting 2-8 dietary behaviors, except for exhibiting any one dietary behavior. We further found that, in addition to the health awareness factor, there were significant positive associations between physical activity and nutrition factors, and healthier dietary behaviors. Further, there was a significant negative association between interpersonal relationships and dietary behavior. Conclusion: The findings indicate a positive relationship between IHL and dietary behavior, such that the higher the level of IHL among college students, the healthier the dietary behavior they tend to adopt in their daily lives. These findings suggest the importance of developing stages of change-based educational interventions, which could help individuals with limited IHL to not only acquire necessary health-related knowledge but also to strengthen their motivation to engage in healthy dietary behaviors. Future studies should employ longitudinal prospective designs or randomized controlled trials to establish a causal association between IHL and healthy dietary behaviors.
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Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.
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Carcinogénesis , Carcinoma Ductal Pancreático , N-Metiltransferasa de Histona-Lisina , FN-kappa B , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Animales , Ratones , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Modelos Animales de Enfermedad , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
In diabetes, macrophages and inflammation are increased in the islets, along with ß-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in ß-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. ß-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic ß-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.
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Dieta Alta en Grasa , Galectina 3 , Secreción de Insulina , Células Secretoras de Insulina , Animales , Humanos , Masculino , Ratones , Calcio/metabolismo , Canales de Calcio/metabolismo , Canales de Calcio/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversos , Galectina 3/metabolismo , Galectina 3/genética , Glucosa/metabolismo , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
RATIONALE: Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for merely 1% of all non-Hodgkin lymphoma cases and comprises approximately 3% of all brain tumors. The involvement of the cerebellum is observed in only 9% of these cases. Recently, we came across an unusual instance: a young man presenting with multiple lesions located specifically within the cerebellum. PATIENT CONCERNS: A 26-year-old male was admitted to the hospital due to severe headaches. He has a medical history of sporadic headaches, accompanied by dizziness, nausea, and vomiting persisting for a month. Over the last 10 days, his headaches have intensified, coupled with decreased vision and protrusion of the eyeballs. Magnetic resonance imaging (MRI) revealed abnormal signals in both cerebellar hemispheres. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Diagnostic procedures included cerebellar biopsy, posterior fossa decompression, and lateral ventricle drainage. Histopathological examination identified diffuse large B-cell lymphoma (DLBCL) with high proliferative activity. To minimize neurotoxicity, chemotherapy involved intrathecal methotrexate (MTX) injections combined with the CHOP program. The patient has shown good tolerance to the treatment so far. LESSONS: While the definitive optimal treatment approach remains elusive, current chemotherapy centered on high-dose MTX stands as the standard induction therapy. Integrating surgery with radiotherapy and chemotherapy significantly extends patient survival.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Cerebelosas , Linfoma de Células B Grandes Difuso , Humanos , Masculino , Adulto , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/terapia , Neoplasias Cerebelosas/patología , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Vincristina/uso terapéutico , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Terapia Combinada , Imagen por Resonancia Magnética , Cerebelo/patología , Cerebelo/diagnóstico por imagenRESUMEN
BACKGROUND: Previous studies have proven the positive relationship between healthy lifestyles and cognitive function in older adults. However, the specific impacts and mechanisms require further investigation. Therefore, this study aimed to investigate whether healthy lifestyles and cognitive function were associated with Chinese older adults and whether depressive symptoms mediated their association. METHODS: 8272 valid samples were included using the latest data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Pearson's test was applied to investigate the relationship between the key variables. Regression models were employed to examine the mediating effects of healthy lifestyles, using Sobel's test and the bootstrap method to confirm path effects. RESULTS: There was a significant correlation between healthy lifestyles, depressive symptoms, and cognitive function (p < 0.01). Healthy lifestyles directly impact cognitive function (ß = 0.162, p < 0.01). Healthy lifestyles had a significant effect on depressive symptoms (ß=-0.301, p < 0.01), while depressive symptoms have a significant impact on cognitive function (ß=-0.108, p < 0.01). Depressive symptoms partially mediated the effect of healthy lifestyles on cognitive function (ß = 0.032, p < 0.01). The Sobel and bootstrap tests confirmed the robustness of the regression analysis results. CONCLUSION: Depressive symptoms mediate the relationship between healthy lifestyles and cognitive function. Our findings suggest that prevention strategies for cognitive impairment in older adults should focus on healthy lifestyles and mental health.
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Disfunción Cognitiva , Depresión , Humanos , Anciano , Depresión/diagnóstico , Depresión/epidemiología , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Estilo de Vida Saludable , China/epidemiología , Estudios LongitudinalesRESUMEN
ß-Cell dysfunction and ß-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, ß-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on ß-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes ß-cell ER stress, dedifferentiation, and apoptosis and inhibits ß-cell transcriptional identity. Inhibition of TMAO production improves ß-cell GSIS, ß-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in ß-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.
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Diabetes Mellitus Tipo 2 , Humanos , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Glucosa/farmacología , Metilaminas/farmacología , Transducción de Señal , Insulina/farmacologíaRESUMEN
Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.
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Neoplasias Gástricas , Animales , Humanos , Ratones , Carcinogénesis/genética , Transformación Celular Neoplásica , Epigénesis Genética , Sirtuina 1/genética , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND: Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. METHODS: Kidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel-Lindau (VHL) double-knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis. RESULTS: SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor-ß (TGF-ß)/Smad signalling pathway, thereby preventing the activation of the TGF-ß/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF-ß/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL. CONCLUSIONS: Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-ß/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.
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N-Metiltransferasa de Histona-Lisina , Insuficiencia Renal Crónica , Factor de Crecimiento Transformador beta , Animales , Humanos , Ratones , Fibrosis , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/patología , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
BACKGOUND: Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4. METHODS: CRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC. RESULTS: The deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4Vil-KO ; Setd2Vil-KO mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4Vil-KO ;Setd2Vil-KO mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2KO ; SMAD4KO SW620 cells. CONCLUSIONS: Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.
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Neoplasias Colorrectales , Transducción de Señal , Animales , Humanos , Ratones , Neoplasias Colorrectales/tratamiento farmacológico , Regulación hacia Abajo , Fosfatasas de Especificidad Dual/metabolismo , Células Epiteliales/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Transducción de Señal/genética , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMEN
Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Ratones , Humanos , Carcinoma de Células Renales/patología , Esfingomielinas , Neoplasias Renales/patología , Genes Supresores de Tumor , Transformación Celular Neoplásica/genética , N-Metiltransferasa de Histona-LisinaRESUMEN
Internet addiction (IA) is a prevalent trend among college students, and the relationship between severe IA and poor health status among college students has been well established. However, whether IA is associated with suboptimal health status (SHS) in college students is unclear. This study aimed to investigate the association between IA and SHS risk in Chinese college students. We conducted a cross-sectional study to assess whether IA was related to SHS risk in 2265 college students in Shenyang, China. SHS was assessed using the Suboptimal Health Status Questionnaire with a cutoff score of ≥35 to document SHS. IA was assessed using the validated 20-item Young's Internet Addiction Test with cutoff scores of 31-49 and 50-100 for mile and moderate-to-severe cases, respectively. The prevalence rate of SHS was 54.0%. After adjusting for potential confounding factors, the IA categories were positively related to a higher risk of SHS. The odds ratios (95% confidence intervals) for SHS across IA categories were 1.00, 7.66 (6.00, 9.78), and 27.93 (20.95, 37.24) (P for trend: <.001) after adjusting for multiple confounding factors. This is the first cross-sectional study to demonstrate that IA is independently associated with SHS. This finding suggests that IA is a negative risk factor for SHS.
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Pueblos del Este de Asia , Trastorno de Adicción a Internet , Humanos , Estudios Transversales , Estado de Salud , EstudiantesRESUMEN
BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.
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Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de Leucotrieno B4/metabolismo , Leucotrieno B4/efectos adversos , Leucotrieno B4/metabolismo , Ratones Obesos , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Obesidad/complicaciones , Obesidad/genética , Lipogénesis/fisiología , Dieta Alta en GrasaRESUMEN
Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Receptor EphB4 , Receptor de Insulina , Animales , Clatrina , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/genética , Hígado/metabolismo , Ratones , Receptor EphB4/metabolismo , Receptor de Insulina/metabolismoRESUMEN
[This corrects the article DOI: 10.1155/2019/4935237.].
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Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient's baseline characteristics to achieve a better prognosis.
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BACKGROUNDS: Glucose fluctuation (GF) may have detrimental effects in individuals with diabetes; however, clinical data on the association between short-term GF, inflammation/oxidative stress markers, and islet ß-cell function based on a population with normal glucose tolerance (NGT) are insufficient. Therefore, we aimed to explore these associations in a Chinese population of 209 individuals with NGT in a cross-sectional analysis. METHODS: Individuals were categorized based on GF tertiles, calculated as the maximum-minimum glucose levels among four time points (0, 30, 60, 120 min) during 2-hour oral glucose tolerance test (OGTT). Plasma inflammation markers tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and oxidative stress markers superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Islet ß-cell function was estimated according to the disposition index (DI) at the early (30 min) and total (120 min) phase of the OGTT, adjusted for insulin sensitivity. RESULTS: Individuals in the middle and highest tertile of GF had reduced ß-cell function, and increased plasma SOD and TNF-α levels compared with those in the lowest tertile of GF (P<0.05). Multiple linear regression analysis indicated that GF was positively associated with TNF-α, 8-oxo-dG and SOD levels, but negatively associated with ß-cell function, whereas IL-6, TNF-α, 8-oxo-dG and SOD levels were negatively associated with ß-cell function (P<0.05). CONCLUSIONS: GF may increase inflammation and oxidative stress markers in individuals with NGT, which could contribute to reduced ß-cell function. Thus, maintaining glucose stability after a meal may have beneficial effects on delaying ß-cell dysfunction, suggesting that diet and exercise strategies to decrease diet related GF are warranted.
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Background: The data on the relationship between normal-ranged serum uric acid (SUA), ß-cell function, and non-alcoholic fatty liver disease (NAFLD) are complicated and insufficient. Moreover, uric acid is excreted by kidney, and SUA levels may be affected by renal function. Thus, we introduced a renal function-normalized index [serum uric acid to creatinine ratio (SUA/Cr)] into the study and explored the association between SUA/Cr, C-peptide and NAFLD in a Chinese population with normal SUA levels by a cross-sectional analysis. Materials and Methods: A total of 282 individuals with normal SUA levels and different glucose tolerance status from a diabetes project were included in the study (mean age = 53.7± 10.5 years; women = 64.50%). NAFLD was diagnosed by abdominal ultrasonography (NAFLD, n=86; without NAFLD, n=196). Trapezoid formula was used to calculate area under the curve of C-peptide (AUCCP) from 4 points (including 0, 30,60, and 120min) during 2-h oral glucose tolerance test. Spearman correlation analysis was used to explore the correlation between SUA/Cr, AUCCP and NAFLD risk factors. Multiple logistic regression analysis was used to explore the association between SUA/Cr or AUCCP and NAFLD. Mediation analysis was used to explore whether AUCCP mediated the association between SUA/Cr and NAFLD. Results: Individuals with NAFLD had significantly higher SUA/Cr and AUCCP than those without NAFLD(P<0.05). Spearman correlation analysis showed that both SUA/Cr and AUCCP were significantly associated with many NAFLD risk factors, and SUA/Cr was positively correlated with AUCCP (P<0.05). Multiple logistic regression analysis indicated that SUA/Cr and AUCCP were positively associated with NAFLD incidence (P<0.05). Medication analysis indicated that SUA/Cr had a significant direct effect on NAFLD (ß =0.5854, 95% CI: 0.3232-0.8966), and AUCCP partly mediated the indirect effect of SUA/Cr on NAFLD incidence (ß =0.1311, 95% CI: 0.0168-0.4663). Conclusions: SUA/Cr was positively associated with NAFLD incidence, and AUCCP partly mediated the association in a Chinese population with normal SUA levels. Thus, we should pay more attention to high-normal SUA and C-peptide levels due to their predictive power in NAFLD incidence.
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Biomarcadores/sangre , Péptido C/sangre , Creatinina/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Ácido Úrico/sangre , China/epidemiología , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Pronóstico , Factores de RiesgoRESUMEN
Background: Alterations in mitochondrial DNA are potentially associated with oxidative stress and may be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the association between mitochondrial DNA copy number (mtDNAcn) and NAFLD was not consistent. In addition, the association between inflammation and NAFLD has not been established yet. The present study, based on a Chinese population of individuals with different glucose statuses, aimed to explore the association between leukocyte mtDNAcn, markers of oxidative stress, and inflammation and NAFLD. Methods: A total of 318 participants from a diabetes project were included. NAFLD was diagnosed by ultrasonography. Leukocyte mtDNAcn was determined by PCR assay. The levels of the inflammation markers tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) and the oxidative stress markers glutathione reductase (GR), superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were also measured. Results: Participants with NAFLD (n = 105) exhibited significantly higher leukocyte mtDNAcn, IL-6, and 8-oxo-dG (all P < 0.05). Pearson correlation analysis indicated mtDNAcn was negatively associated with age, uric acid, SOD, and TNF-α, but was positively associated with 8-oxo-dG (all P < 0.05). Univariate logistic regression analysis revealed that mtDNAcn was positively associated with NAFLD [odds ratio (OR) = 1.617, 95% confidence interval (CI) = 1.036-2.525; P = 0.034]. However, after adjustment for 8-oxo-dG, this association was no longer statistically significant (OR = 1.534, 95% CI = 0.979-2.403, P = 0.062). Moreover, the stress marker 8-oxo-dG was independently associated with NAFLD after adjustment for mtDNAcn, IL-6, glucose tolerance status, and other conventional NAFLD risk factors (OR = 1.707, 95% CI =1.142-2.550, P = 0.009). Mediation analysis indicated that 8-oxo-dG fully mediated the effect of mtDNAcn on the incidence of NAFLD (direct effect ß = 0.5221, 95% CI = -0.0648 to 1.2504; indirect effect ß = 0.0946, 95% CI = 0.0049-0.2463). Conclusions: In a Chinese population, the association between leukocyte mtDNAcn and NAFLD was fully mediated by high levels of 8-oxo-dG. Thus, oxidative stress may be an important driver of NAFLD, and clinical interventions aimed at decreasing oxidative stress to improve NAFLD warrant further research.
RESUMEN
We aimed to explore the association between antioxidant vitamin intake, oxidative stress related markers and non-alcoholic fatty liver disease (NAFLD) by a cross-sectional analysis. A total of 241 non-diabetic participants from a Chinese rural cohort were included. NAFLD was diagnosed by abdominal ultrasound (NAFLD, n = 71; Non-NAFLD, n = 171). Dietary intake was assessed by a 24-h food recall. Plasma oxidative stress related markers superoxide dismutase (SOD), glutathione reductase (GR) and 8-oxo-2'-deoxyguanosine(8-oxo-dG) were measured. The association between dietary antioxidant vitamin intake, oxidative stress related markers and NAFLD were analysed by Spearman correlation analysis and multiple logistic regression analysis. Mediation models were established to examine whether SOD mediated the association between dietary vitamin A or α-tocopherol intake and NAFLD. Spearman correlation analysis indicated that dietary vitamin A and α-tocopherol intake were positively correlated with SOD (p < .05). Multiple logistic regression analysis found plasma SOD, dietary vitamin A and α-tocopherol intake were inversely associated with NAFLD (all p < .05). Mediation analysis indicated that SOD significantly mediated the indirect effect of dietary α-tocopherol (mediated effect = 13.21% total effect) or vitamin A (mediated effect = 3.12% total effect) intake on NAFLD. Our study indicated that dietary vitamin A and α-tocopherol intake may contribute to protect from NAFLD in Chinese non-diabetics, and the associations were partly mediated by SOD. However, SOD only accounted for a minor percentage of the association between vitamin A intake and NAFLD. Thus, other mechanisms underlying antioxidant vitamin' protective effect on NAFLD need further exploration.