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BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.
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Aneurisma de la Aorta , Disección Aórtica , Ácido Ascórbico , Factores Protectores , Vitamina E , Humanos , Masculino , Estudios Prospectivos , Persona de Mediana Edad , Femenino , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Vitamina E/administración & dosificación , Factores de Riesgo , Anciano , Incidencia , Disección Aórtica/epidemiología , Disección Aórtica/prevención & control , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/prevención & control , Medición de Riesgo , Reino Unido/epidemiología , Factores de Tiempo , Dieta/efectos adversos , AdultoRESUMEN
BACKGROUND: Weight loss is a significant improvement for individuals with overweight or obesity, especially for cardiovascular patients. The driving effects of weight self-perception and attempts to lose weight are vital in weight management, yet weight misperception is a direct culprit for the undesirability of weight control and obesity prevention. This study aimed to investigate weight self-perception and misperception and weight loss attempts in Chinese adults, especially among cardiovascular and non-cardiovascular patients. METHODS: We collected data from China HeartRescue Global Evaluation Baseline Household Survey 2015. Questionnaires were used to assess self-reported weight and cardiovascular patients. We used kappa statistics to check the consistency between weight self-perception and BMI. Logistic regression models were fitted to identify risk factors associated with weight misperception. RESULTS: A total of 2690 participants were enrolled in the household survey, while 157 respondents were cardiovascular patients. According to questionnaire results, 43.3% of cardiovascular patients thought they were overweight and obese, while the percentage is 35.3% among non-cardiovascular patients. Kappa statistics indicated higher consistency of self-reported weight and actual weight among cardiovascular patients. Multivariate analysis showed weight misperception was significantly associated with gender, education level, and actual BMI. Lastly, 34.5% of non-cardiovascular patients and 35.0% of cardiovascular patients were trying to lose weight or keep weight. The majority of these people adopted combined strategies of controlling diet and exercise to lose or maintain weight. CONCLUSIONS: Weight misperception was highly prevalent among cardiovascular or non-cardiovascular patients. Obese respondents, women, and individuals with lower education levels were more vulnerable to make weight misperception. However, no difference in the purpose of weight loss attempts was indicated among cardiovascular and non-cardiovascular patients.
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Enfermedades Cardiovasculares , Pueblos del Este de Asia , Obesidad , Sobrepeso , Pérdida de Peso , Adulto , Humanos , Índice de Masa Corporal , Peso Corporal , Obesidad/epidemiología , Obesidad/terapia , Sobrepeso/epidemiología , Sobrepeso/terapia , Autoimagen , Enfermedades Cardiovasculares/complicacionesRESUMEN
To explore the value of the Helicobacter pylori test in combination with the determination of plasma pepsinogen (PG) and gastrin 17 in screening the precancerous status of gastric cancer and gastric cancer in the healthy population, between 2019 and 2022, we enrolled a total of 402 subjects who went to the physical examination in the Center of Health Management of Ganzhou people's Hospital and additionally underwent the urea (14C) breath test and determination of PGI, PGII and G-17. Anomalies in Hp, PG or G-17 ≥ 2, or a single anomaly in PG determination would be taken as positive, and the diagnosis should be further confirmed by the gastroscopy and pathological test. According to the results, subjects would be further divided into the gastric cancer group, precancerous lesion group, precancerous disease group and control group, aiming to clarify the relationship between Hp, PG and G-17 levels and the precancerous status and development of gastric cancer and the screening value. Results showed that Hp-positive infection was found in 341 subjects (84.82%). Hp infection rate in the control group was much lower than those in the precancerous disease group, precancerous lesion group and gastric cancer group (P < 0.05). The CagA positive rates in the gastric cancer group and precancerous lesion group were significantly higher than those in the precancerous disease group and control group, while the serum level of G-17 in the gastric cancer group was much higher than those in the precancerous lesion group, precancerous disease group and control group (P < 0.05), and the PG I/II ratio in the gastric cancer patients was also lower than those in the precancerous lesion group, precancerous disease group and control group (P < 0.05). As the disease progressed, the G-17 level also increased but PG I/II ratio decreased gradually (P < 0.001). Hp test in combination with PG and G-17 shows a high value in determining the precancerous status of gastric cancer and screening for gastric cancer in healthy subjects.
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Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Detección Precoz del Cáncer , Pepsinógeno A , Pepsinógeno C , Infecciones por Helicobacter/diagnóstico , Lesiones Precancerosas/diagnósticoRESUMEN
BACKGROUND & AIMS: HBV remains a global threat to human health. It remains incompletely understood how HBV self-restricts in the host during most adult infections. Thus, we performed multi-omics analyses to systematically interrogate HBV-host interactions and the life cycle of HBV. METHODS: RNA-sequencing and ribosome profiling were conducted with cell-based models for HBV replication and gene expression. The novel translational events or products hereby detected were then characterized, and functionally assessed in both cell and mouse models. Moreover, quasi-species analyses of HBV subpopulations were conducted with patients at immune tolerance or activation phases, using next- or third-generation sequencing. RESULTS: We identified EnhI-SL (Enhancer I-stem loop) as a new cis element in the HBV genome; mutations disrupting EnhI-SL were found to elevate viral polymerase expression. Furthermore, while re-discovering HpZ/P', a previously under-explored isoform of HBV polymerase, we also identified HBxZ, a novel short isoform of HBX. Having confirmed their existence, we functionally characterized them as potent suppressors of HBV gene expression and genome replication. Mechanistically, HpZ/P' was found to repress HBV gene expression partially by interacting with, and sequestering SUPV3L1. Activation of the host immune system seemed to reduce the abundance of HBV mutants deficient in HpZ/P' or with disruptions in EnhI-SL. Finally, SRSF2, a host RNA spliceosome protein that is downregulated by HBV, was found to promote the splicing of viral pre-genomic RNA and HpZ/P' biogenesis. CONCLUSION: This study has identified multiple self-restricting HBV-host interactions. In particular, SRSF2-HpZ/P' appeared to constitute another negative feedback mechanism in the HBV life cycle. Targeting host splicing machinery might thus represent a strategy to intervene in HBV-host interactions. LAY SUMMARY: There remain many unknowns about the natural history of HBV infection in adults. Herein, we identified new HBV-host mechanisms which could be responsible for self-restricting infections. Targeting these mechanisms could be a promising strategy for the treatment of HBV infections.
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Productos del Gen pol/metabolismo , Virus de la Hepatitis B , Hepatitis B Crónica , Interacciones Microbiota-Huesped/inmunología , Replicación Viral , Animales , Descubrimiento de Drogas , Genoma Viral/fisiología , Virus de la Hepatitis B/enzimología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Ratones , Regiones Promotoras Genéticas , Modificación Traduccional de las Proteínas , Autoempalme del ARN Ribosómico/metabolismo , ADN Polimerasa Dirigida por ARN/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Replicación Viral/genética , Replicación Viral/inmunologíaRESUMEN
BACKGROUND: Primary effusion lymphoma (PEL) is a rare subtype of large B-cell lymphoma associated with human herpesvirus 8 (HHV8). It has the highest incidence in HIV-positive individuals. It often presents as a malignant pleural, peritoneal and/or pericardial effusion without a detectable solid mass. Most cases are co-infected with Epstein-Barr virus (EBV). Rare cases of HHV8-positive lymphoma with features similar to PEL can present as tumor masses and are considered to represent an extracavitary or solid variant of PEL. We report a case of EBV negative, extracavitary/solid variant of primary effusion lymphoma presenting as a gastric mass. CASE PRESENTATION: A 48-year-old man was admitted to an outside hospital with abdominal pain and weight loss. At the outside hospital, he was found to be HIV positive and have a 3 × 2 cm gastric mass. He was subsequently diagnosed with ALK negative anaplastic large cell lymphoma by gastric biopsy. The patient was referred to Harbor-UCLA Medical Center for further management. Review of the outside slides and additional stains performed at our hospital revealed sheets of large anaplastic lymphoma cells that were positive for CD30, CD138, MUM1 and HHV8, focally weakly positive for CD3, and negative for other T- and B-cell markers and EBER, consistent with extracavitary/solid variant of primary effusion lymphoma. Interestingly, for the first time, cyclin D1 positivity was also demonstrated in PEL. CONCLUSION: Primary effusion lymphoma, particularly the extracavitary/solid variant, is very rare, and the diagnosis can be challenging. In some cases, when CD30 is uniformly positive, this lymphoma can be misdiagnosed as ALK negative anaplastic large cell lymphoma. This lymphoma can also aberrantly express T-cell markers as seen in this case, making diagnosis even more difficult. Awareness of the existence and the features of solid variant PEL and assessment for HHV8 infection are essential for correct diagnosis.
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Linfocitos B/patología , Linfoma de Células B/patología , Linfoma de Efusión Primaria/patología , Neoplasias Cutáneas/patología , Neoplasias Gástricas/patología , Biopsia , Diagnóstico Diferencial , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Efusión Primaria/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/diagnóstico , Neoplasias Gástricas/diagnósticoRESUMEN
The precise mechanisms underlying the inhibitory effects of SIRT3, a mitochondrial sirtuin protein, on hepatocellular carcinoma (HCC) development, as well as its impact on mitochondrial respiration, remain poorly understood. We assessed sirtuins 3 (SIRT3) levels in HCC tissues and Huh7 cells cultured under hypoxic condition. We investigated the effects of SIRT3 on cell proliferation, glycolytic metabolism, mitochondrial respiration, mitophagy, and mitochondrial biogenesis in Huh7 cells. Besides, we explored the potential mechanisms regulating SIRT3 expression in hypoxically cultured Huh7 cells. Gradual reduction in SIRT3 expressions were observed in both adjacent tumor tissues and tumor tissues. Similarly, SIRT3 expressions were diminished in Huh7 cells cultured under hypoxic condition. Forced expression of SIRT3 attenuated the growth of hypoxically cultured Huh7 cells. SIRT3 overexpression led to a decrease in extracellular acidification rate while increasing oxygen consumption rate. SIRT3 downregulated the levels of hexokinase 2 and pyruvate kinase M2. Moreover, SIRT3 enhanced mitophagy signaling, as indicated by mtKeima, and upregulated key proteins involved in various mitophagic pathways while reducing intracellular reactive oxygen species levels. Furthermore, SIRT3 increased proxisome proliferator-activated receptor-gamma coactivator 1α levels and the amount of mitochondrial DNA in Huh7 cells. Notably, ß-catenin expressions were elevated in Huh7 cells cultured under hypoxic condition. Antagonists and agonists of ß-catenin respectively upregulated and downregulated SIRT3 expressions in hypoxically cultured Huh7 cells. The modulationsof glycolysis and mitochondrial respiration represent the primary mechanism through which SIRT3, suppressed by ß-catenin, inhibits HCC cell proliferation.
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Carcinoma Hepatocelular , Hipoxia de la Célula , Glucólisis , Neoplasias Hepáticas , Sirtuina 3 , beta Catenina , Humanos , beta Catenina/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Hexoquinasa/metabolismo , Hexoquinasa/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Mitocondrias/metabolismo , Mitofagia/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Sirtuina 3/metabolismo , Sirtuina 3/genéticaRESUMEN
Neurite outgrowth represents a critical stage in the correct development of neuronal circuitries, and is dependent on the complex regulation of actin filament and microtubule dynamics by intrinsic as well as extrinsic signals. Previous studies have implicated the tumor suppressor factor, p53, in the regulation of axonal outgrowth through a nontranscriptional effect involving local regulation of the Rho kinase signaling pathway that controls these dynamics. In the present study, we first showed that semaphorin 3A-induced growth cone collapse in cultured hippocampal neurons was associated with the partial truncation of phosphorylated p53, and that both effects were prevented by calpain inhibition with either m-calpain-specific siRNA or inhibitors. We further determined that semaphorin 3A-mediated calpain activation and growth cone collapse were associated with m-calpain phosphorylation and prevented by inhibition of MAPK, ERK, or p38. In vitro studies confirmed that p53 and especially phosphorylated p53 were partially truncated by calpain. Thus, our results indicate that semaphorin 3A-mediated growth cone collapse is mediated in part by m-calpain activation, possibly through MAPK-mediated phosphorylation, and the resulting truncation of phosphorylated p53, leading to Rho kinase activation and cytoskeletal reorganization. They provide a pathway by which extrinsic signals regulate axonal growth through activation of m-calpain and p53 truncation.
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Axones/metabolismo , Calpaína/metabolismo , Eliminación de Gen , Semaforina-3A/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Calpaína/genética , Células Cultivadas , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Conos de Crecimiento/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos BALB C , Fosforilación , Proteína p53 Supresora de Tumor/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The most common histological type of urinary bladder cancer is urothelial carcinoma (UC). Clear cell adenocarcinoma (CCA) of the urinary bladder is a rare histologic subtype of adenocarcinoma in the urinary tract. The tumor primarily affects women and has histomorphological features resembling CCA of the female genital tract (or Müllerian origin). Clear cell adenocarcinoma consists of cells with abundant clear cytoplasm, arranged in solid, glandular, or tubulocystic patterns. Patients typically present with gross hematuria, dysuria, and discharge. In this study, we report a case of a 50-year-old male, presenting with gross hematuria, which was subsequently diagnosed with CCA at our pathology department. Furthermore, we provide a short systematic review of the literature for this rare histopathological entity and a brief discussion about its morphological and immunohistochemical (IHC) characteristics.
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AIM: To examine the associations between serum albumin and the incidences of diabetes and diabetic microvascular complications in participants of the UK Biobank cohort. METHODS: There were 398,146 participants without diabetes and 30,952 patients with diabetes from the UK Biobank cohort included in this study. Multivariate-adjusted Cox proportional hazard models were used to analyze the association of albumin with the incidences of diabetes and diabetic microvascular complications. Mendelian randomization (MR) analysis was used to determine the genetic relationships between serum albumin and diabetes. RESULTS: After a median 12.90 years follow-up, 14,710 participants developed incident diabetes (58.83 ± 7.52 years, 56.10% male). After multivariate adjustment, serum albumin was inversely associated with incident diabetes: hazard ratio (HR) [95% confidence interval] per 10 g/l increase 0.88 [0.82;0.94]. MR analyses suggested a potential genetic influence of serum albumin on diabetes in both the UK Biobank and the FinnGen consortium: odds ratios (ORs) [95% confidence interval per 1 g/l increase 0.99 [0.98;1.00] and 0.78 [0.67;0.92], respectively. In patients with diabetes, higher serum albumin levels were significantly associated with lower risk for diabetic microvascular complications. Specifically, per 10 g/l increase in serum albumin, the HRs for diabetic nephropathy, ophthalmopathy, and neuropathy were 0.42 [0.30;0.58], 0.61 [0.52;0.72], and 0.67 [0.51;0.88], respectively. CONCLUSION: In this large prospective study, serum levels of albumin were inversely associated with the incidences of diabetes and diabetic microvascular complications. These findings underscore the importance of maintaining optimal nutrient status in reducing the risk of diabetes and its complications.
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Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Nefropatías Diabéticas , Humanos , Masculino , Femenino , Estudios Prospectivos , Albúmina Sérica , Bancos de Muestras Biológicas , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/complicaciones , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/complicaciones , Reino Unido/epidemiología , Factores de Riesgo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genéticaRESUMEN
Niemann-Pick Type C (NPC) disease is associated with accumulation of cholesterol and other lipids in late endosomes/lysosomes in virtually every organ; however, neurodegeneration represents the fatal cause for the disease. Genetic analysis has identified loss-of-function mutations in NPC1 and NPC2 genes as the molecular triggers for the disease. Although the precise function of these proteins has not yet been clarified, recent research suggests that they orchestrate cholesterol efflux from late endosomes/lysosomes. NPC protein deficits result in impairment in intracellular cholesterol trafficking and dysregulation of cholesterol biosynthesis. Disruption of cholesterol homeostasis is also associated with deregulation of autophagic activity and early-onset neuroinflammation, which may contribute to the pathogenesis of NPC disease. This chapter reviews recent achievements in the investigation of disruption of cholesterol homeostasis-induced neurodegeneration in NPC disease, and provides new insight for developing a potential therapeutic strategy for this disorder.
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Colesterol/metabolismo , Enfermedad de Niemann-Pick Tipo C/fisiopatología , Animales , Autofagia , Transporte Biológico , Encéfalo/metabolismo , Colesterol/biosíntesis , Endosomas/metabolismo , Humanos , Lisosomas/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/terapiaRESUMEN
Hepatitis B Virus (HBV) constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing were conducted on a recently established HBV replication system, through which we identified multiomic differentially expressed genes (DEGs) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical open reading frames (ncORFs) including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown of SIRT6 had opposite effect. Furthermore, the expression of SIRT6 was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infection in vitro and in vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.
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The transcription factor p53 suppresses tumorgenesis by regulating cell proliferation and migration. We investigated whether p53 could also control cell motility in postmitotic neurons. p53 isoforms recognized by phospho-p53-specific (at Ser-15) or "mutant" conformation-specific antibodies were highly and specifically expressed in axons and axonal growth cones in primary hippocampal neurons. Inhibition of p53 function by inhibitors, small interfering RNAs, or by dominant-negative forms, induced axonal growth cone collapse, whereas p53 overexpression led to larger growth cones. Furthermore, deletion of the p53 nuclear export signal blocked its axonal distribution and induced growth cone collapse. p53 inhibition-induced axonal growth cone collapse was significantly reduced by the Rho kinase (ROCK) inhibitor, Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide]. Our results reveal a new function for p53 as a critical regulator of axonal growth cone behavior by suppressing ROCK activity.
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Movimiento Celular/fisiología , Conos de Crecimiento/fisiología , Proteína p53 Supresora de Tumor/fisiología , Quinasas Asociadas a rho/metabolismo , Animales , Movimiento Celular/genética , Células Cultivadas , Conos de Crecimiento/enzimología , Conos de Crecimiento/metabolismo , Ratones , Ratones Endogámicos BALB C , Neurogénesis/genética , Neurogénesis/fisiología , Unión Proteica/genética , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/fisiologíaRESUMEN
The immature brains of newborns often respond differently from the brains of adults when exposed to similar insults. Previous studies have indicated that although hypoxia-ischemia (HI) induces persistent thrombosis in adult brains, it only modestly impairs blood perfusion in newborn brains. Here, we used the Vannucci model of HI encephalopathy to study age-related responses to cerebral HI in rat pups. We found that HI triggered fibrin deposition and impaired blood perfusion in both neonatal and adult brains. However, these effects were only transient in neonatal brains (<4 hours) and were accompanied by acute induction of both tissue-type and urinary-type plasminogen activators (tPA and uPA), which was not observed in adult brains subjected to the same insult. Interestingly, activation of the plasminogen system persisted up to 24 hours in neonatal brains, long after the clearance of fibrin-rich thrombi. Furthermore, astrocytes and macrophages outside blood vessels expressed tPA after HI, suggesting the possibility of tPA/plasmin-mediated cytotoxicity. Consistent with this hypothesis, injection of alpha2-antiplasmin into cerebral ventricles markedly ameliorated HI-induced damage to neurofilaments and white matter oligodendrocytes, providing a dose-response reduction of brain injury after 7 days of recovery. Conversely, ventricular injection of tPA increased HI-induced brain damage. Together, these results suggest that tPA/plasmin induction, which may contribute to acute fibrinolysis, is a critical component of extravascular proteolytic damage in immature brains, representing a new therapeutic target for the treatment of HI encephalopathy.
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Encéfalo/irrigación sanguínea , Hipoxia-Isquemia Encefálica/patología , Activador de Tejido Plasminógeno/fisiología , Activador de Plasminógeno de Tipo Uroquinasa/fisiología , Animales , Animales Recién Nacidos , Astrocitos/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Fibrina/metabolismo , Fibrinolisina/fisiología , Fibrinólisis , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/fisiopatología , Inyecciones Intraventriculares , Macrófagos/patología , Oligodendroglía/patología , Ratas , Ratas Wistar , Activador de Tejido Plasminógeno/farmacología , alfa 2-Antiplasmina/farmacologíaRESUMEN
NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa.
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Proteínas Quinasas Activadas por AMP/metabolismo , Proteína Homeótica Nanog/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/metabolismo , Animales , Línea Celular Tumoral , Proteínas Cullin/metabolismo , Genes Supresores de Tumor , Humanos , Masculino , Ratones Desnudos , Mutación/genética , Neoplasias de la Próstata/genética , Factores de Transcripción/metabolismo , Ubiquitinación/fisiologíaRESUMEN
Previous studies using dominant-mutant constructs have implicated Rac1 GTPase in neuritogenesis and neuronal migration. However, overexpression of dominant mutants generally blocks Rho-GTPase activity; thus, it may not reveal the specific or physiological functions of Rac1. To address this issue, we have applied a conditional gene-targeting strategy, using Foxg1-Cre mice to delete Rac1 in the ventricular zone (VZ) of telencephalon and Dlx5/6-Cre-IRES (internal ribosomal entry site)-EGFP (enhanced green fluorescent protein) (Dlx5/6-CIE) in the subventricular zone (SVZ) of ventral telencephalon, respectively. Surprisingly, the deletion of Rac1 in VZ progenitors did not prevent axonal outgrowth of telencephalic neurons. However, the anterior commissure was absent, and the corpus callosal as well as hippocampal commissural axons failed to cross the midline in Rac1/Foxg1-Cre knock-out embryos. The thalamocortical and corticothalamic axons also showed defasciculation or projection defects. These results suggest that Rac1 controls axon guidance rather than neuritogenesis. In addition, although Rac1/Foxg1-Cre knock-out embryos showed delayed radial migration of cortical projection neurons and severe impairment of tangential migration by the ventral telencephalon-derived interneurons, deletion of Rac1 in the SVZ by Dlx5/6-CIE mice produced no discernible defects in tangential migration. These contrasting effects of Rac1 deletion on tangential migration suggest that Rac1 is dispensable for cellular motility per se during neuronal migration. Together, these results underscore the challenge of deciphering the biological functions of Rac1, and Rho-GTPases in general, during mammalian brain development. Moreover, they indicate that Rac1 has a critical role in axon guidance and in acquisition of migratory competency during differentiation of the progenitors for the ventral telencephalon-derived interneurons.
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Movimiento Celular/fisiología , Neuronas/fisiología , Neuropéptidos/fisiología , Telencéfalo/embriología , Telencéfalo/fisiología , Proteínas de Unión al GTP rac/fisiología , Animales , Axones/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Movimiento Celular/genética , Células Cultivadas , Femenino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/citología , Neuropéptidos/genética , Embarazo , Telencéfalo/citología , Proteínas de Unión al GTP rac/genética , Proteína de Unión al GTP rac1RESUMEN
YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Núcleo Celular/enzimología , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/enzimología , N-Metiltransferasa de Histona-Lisina/metabolismo , Neoplasias Pulmonares/enzimología , Fosfoproteínas/metabolismo , Procesamiento Proteico-Postraduccional , Células A549 , Transporte Activo de Núcleo Celular , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular , Núcleo Celular/genética , Núcleo Celular/patología , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Células HEK293 , Células HeLa , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Lisina , Metilación , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas/genética , Pronóstico , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Factores de Transcripción , Carga Tumoral , Proteínas Señalizadoras YAPRESUMEN
Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.
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Virus ADN/inmunología , Proteínas de la Membrana/fisiología , Ubiquitina Tiolesterasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Animales , Chlorocebus aethiops , Células HEK293 , Humanos , Inmunidad Innata , Factor 3 Regulador del Interferón/fisiología , Interferón Tipo I/fisiología , Ratones , Fosforilación , Células VeroRESUMEN
Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Liver injury from alcohol administration causes balloon hepatocytes and MDB formation impeding liver regeneration. By comparing AH livers where MDBs had formed with normal liver transcriptomes obtained by RNA sequencing (RNA-Seq), there was significant upregulation of BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. The transcriptional architecture of differentially expressed genes from AH livers reflected step-wise transcriptional changes progressing to AH. Key molecules such as BRCA1, p15 and p21 were significantly upregulated both in AH livers and in the livers of the DDC re-fed mice model where MDBs had formed. The increase of G1/S cell cycle checkpoint inhibitors p15 and p21 results in cell cycle arrest and inhibition of liver regeneration, implying that p15 and p21 could be exploited for the identification of specific targets for the treatment of liver disease. Provided here for the first time is the RNA-Seq data that represents the fully annotated catalogue of the expression of mRNAs. The most prominent alterations observed were the changes in BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. These new findings expand previous and related knowledge in the search for gene changes that might be critical in the understanding of the underlying progression to the development of AH.
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Proteína BRCA1/metabolismo , Hepatitis Alcohólica/metabolismo , Hepatitis Alcohólica/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Cuerpos de Mallory/patología , Animales , Ciclo Celular/genética , Puntos de Control del Ciclo Celular/genética , Perfilación de la Expresión Génica , Hepatitis Alcohólica/genética , Humanos , Immunoblotting , Inmunohistoquímica , Cuerpos de Mallory/metabolismo , Ratones , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , TranscriptomaRESUMEN
Niemann-Pick type C (NPC) disease is a genetic disorder associated with intracellular cholesterol accumulation in the brain and other organs, and neurodegeneration is generally believed to be the fatal cause of the disease. In view of the emerging role of matrix metalloproteinase-12 (MMP-12) in neuronal injury, we investigated its expression and potential roles in axonal degeneration in Npc1-/- mouse brain. Microarray and quantitative real-time reversed transcription PCR analysis indicated a marked increase in MMP-12 mRNA levels in cerebellum of 3 week-old Npc1-/- mice, as compared to wild-type littermates. Western blots showed that the ratio of mature MMP-12 over pro-MMP-12 was significantly increased in cerebellum of Npc1-/-, as compared to wild-type mice. Immunohistochemical studies confirmed that MMP-12 expression was increased, especially in the cell bodies of Purkinje neurons in Npc1-/- mice. Neuritic growth was significantly reduced by Npc1 siRNA knockdown in nerve growth factor-differentiated PC-12 cells, and this effect was completely reversed by treatment with an MMP-12 specific inhibitor. Furthermore, in vivo experiments showed that chronic treatment with the MMP-12 inhibitor ameliorated Npc1 deficiency-induced axonal pathology in the striatum. Our results indicate that abnormal neuronal expression of MMP-12 may contribute to axonal degeneration in NPC disease, thus providing a potential novel target for treatment.
Asunto(s)
Axones/patología , Metaloproteinasa 12 de la Matriz/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Proteínas/genética , Animales , Astrocitos/metabolismo , Cerebelo/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Ratones Endogámicos BALB C , Ratones Noqueados , Degeneración Nerviosa/patología , Proteína Niemann-Pick C1 , Células de Purkinje/patologíaRESUMEN
The phosphodiesterase 10A (PDE10A) is highly expressed within dopaminoreceptive medium spiny neurons (MSNs) of the striatum, which are implicated in various neurodegenerative diseases and psychiatric disorders, such as Huntington's disease and schizophrenia. With its dual action on cAMP and cGMP, PDE10A has been proposed to affect several signaling cascades in the corticostriatothalamic circuits. In particular, papaverine, a selective PDE10A inhibitor has been shown to activate/phosphorylate ERK in striatum. We used acute rat striatal slices to further characterize the effects of papaverine on ERK activation/phosphorylation in D1- and D2-responsive striatal neurons. Incubation of striatal slices from male rats with papaverine increased the levels of phospho-ERK1/2 (p-ERK), an effect enhanced with a D1 agonist or a D2 antagonist, but decreased with a D1 receptor antagonist or a D2 receptor agonist. Papaverine-induced increase in p-ERK was localized in striatal neurons receiving D1-enriched presynaptic terminals, as well as in postsynaptic D2-enriched neurons in striatal slices. Interestingly, papaverine had almost no stimulatory effects on ERK1/2 phosphorylation in slices prepared from female rats. In striatal slices prepared from ovariectomized female rats, papaverine treatment stimulated ERK1/2 phosphorylation to levels similar to those in slices from male rats. Moreover, estrogen was found to regulate the levels of D2 but not D1 receptors in striatum. These results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Considering the variety of events modulated by ERK1/2 activity, these findings suggest that sex difference needs to be taken into consideration for the further investigation of the effects of PDE10A inhibitors.