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Early in development, the process of exploration helps children gather new information that fosters learning about the world. Yet, it is unclear how childhood experiences may influence the way humans approach new learning. What influences decisions to exploit known, familiar options versus trying a novel alternative? We found that childhood unpredictability, characterized by unpredictable caregiving and unstable living environments, was associated with reduced exploratory behavior. This effect holds while controlling for individual differences, including anxiety and stress. Individuals who perceived their childhoods as unpredictable explored less and were instead more likely to repeat previous choices (habitual responding). They were also more sensitive to uncertainty than to potential rewards, even when the familiar options yielded lower rewards. We examined these effects across multiple task contexts and via both in-person (N = 78) and online replication (N = 84) studies among 10- to 13-y-olds. Results are discussed in terms of the potential cascading effects of unpredictable environments on the development of decision-making and the effects of early experience on subsequent learning.
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Aprendizaje , Recompensa , Niño , Humanos , Incertidumbre , Ansiedad , Trastornos de AnsiedadRESUMEN
A critical component of human learning reflects the balance people must achieve between focusing on the utility of what they know versus openness to what they have yet to experience. How individuals decide whether to explore new options versus exploit known options has garnered growing interest in recent years. Yet, the component processes underlying decisions to explore and whether these processes change across development remain poorly understood. By contrasting a variety of tasks that measure exploration in slightly different ways, we found that decisions about whether to explore reflect (a) random exploration that is not explicitly goal-directed and (b) directed exploration to purposefully reduce uncertainty. While these components similarly characterized the decision-making of both youth and adults, younger participants made decisions that were less strategic, but more exploratory and flexible, than those of adults. These findings are discussed in terms of how people adapt to and learn from changing environments over time.Data has been made available in the Open Science Foundation platform (osf.io).
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Toma de Decisiones , Conducta Exploratoria , Adulto , Adolescente , Humanos , Incertidumbre , Motivación , RecompensaRESUMEN
Environmental arsenic exposure is a significant global public health concern. Previous studies have demonstrated the association between arsenic-induced liver injury and oxidative stress as well as ferroptosis. However, the knowledge of the interactions among these mechanisms remains limited. Moreover, there is a lack of research on potential therapeutic interventions for liver injury resulting from arsenic exposure. To address these limitations, we established a rat model with liver injury caused by arsenic exposure and investigated the impact of the nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4) signaling pathway and ferroptosis on arsenic-induced liver injury. Our findings revealed that arsenic increased Nrf2 expression and decreased GPx4 expression in the rat liver. This was accompanied by a substantial generation of reactive oxygen species and disruption of the antioxidant defense system, ultimately promoting liver injury through ferroptosis. Subsequently, we conducted intervention experiments using Rosa roxburghii Tratt (RRT) in rats exposed to arsenic. The results showed that the detrimental effects mentioned earlier were partially alleviated following RRT intervention. This study offers preliminary evidence that persistent activation of Nrf2 by arsenic triggers an adaptive antioxidant response, leading to liver injury through the promotion of ferroptosis. Additionally, we discovered that RRT inhibits Nrf2-mediated adaptive antioxidant responses by reducing hepatic ferroptosis, thereby mitigating liver injury caused by arsenic exposure in rats. Our study contributes to a deeper understanding of the molecular mechanisms underlying liver injury resulting from arsenic exposure. Furthermore, our findings may facilitate the identification of a potential edible and medicinal plant extracts that could be utilized to develop a more effective adjunctive treatment approach.
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Arsénico , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Animales , Ratas , Antioxidantes , Factor 2 Relacionado con NF-E2RESUMEN
Nuclear receptor coactivator 6 (NCOA6), a coactivator of numerous nuclear receptors and transcription factors, regulates multiple critical cellular functions. Nuclear receptor coactivator 6 is dysregulated in various cancers, including hepatocellular carcinoma (HCC); however, its role remains largely unknown. Here we reported that NCOA6 was highly expressed in HCC compared to the adjacent liver tissue, and NCOA6 overexpression was significantly correlated with poor HCC prognosis. Experiments revealed that the knockdown of NCOA6 damaged the proliferation, migration, and invasion of HCC cells. Multiomics and immune infiltration analyses showed a close relationship between NCOA6 expression, multiple cancer-related malignant pathways, and the immunosuppressive microenvironment. Finally, we established an effective NCOA6-related microRNA (miRNA) signature to distinguish HCC from hepatitis\liver cirrhosis patients. To the best of our knowledge, this study is the first to provide a comprehensive analysis of NCOA6 expression in HCC. We found that NCOA6 plays an important role in HCC development and has a potential mechanism of action. Establishing an NCOA6-related miRNA signature will help develop novel diagnostic strategies for HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Multiómica , Coactivadores de Receptor Nuclear/genética , Coactivadores de Receptor Nuclear/metabolismo , MicroARNs/genética , Aprendizaje Automático , Pronóstico , Microambiente TumoralRESUMEN
Hydrogen peroxide (H2O2) is the most common chemical threat that organisms face. Here, we show that H2O2 alters the bacterial food preference of Caenorhabditis elegans, enabling the nematodes to find a safe environment with food. H2O2 induces the nematodes to leave food patches of laboratory and microbiome bacteria when those bacterial communities have insufficient H2O2-degrading capacity. The nematode's behavior is directed by H2O2-sensing neurons that promote escape from H2O2 and by bacteria-sensing neurons that promote attraction to bacteria. However, the input for H2O2-sensing neurons is removed by bacterial H2O2-degrading enzymes and the bacteria-sensing neurons' perception of bacteria is prevented by H2O2. The resulting cross-attenuation provides a general mechanism that ensures the nematode's behavior is faithful to the lethal threat of hydrogen peroxide, increasing the nematode's chances of finding a niche that provides both food and protection from hydrogen peroxide.
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Conducta Animal/fisiología , Caenorhabditis elegans/fisiología , Peróxido de Hidrógeno , Células Receptoras Sensoriales/fisiología , Animales , Bacterias/metabolismo , Locomoción/fisiología , Percepción/fisiologíaRESUMEN
PURPOSE: The purpose of this study was to investigate the predictive value of changes in serum uric acid (SUA), the ratio of serum uric acid to serum creatinine (SUA/SCr), and serum gamma-glutamyltransferase (GGT) from before to after therapy in patients with locally advanced rectal cancer (LARC). METHODS: Data from 114 LARC patients from January 2016 to December 2021 were included in this retrospective study. All patients received neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME). The change in SUA was calculated as a ratio: (SUA level after nCRT-SUA level before nCRT)/SUA level before nCRT. The change ratios of SUA/SCr and GGT were calculated in the same way. The efficacy of nCRT was evaluated by magnetic resonance (MR) and postoperative pathological response. A nonlinear model was used to evaluate whether the change ratios of SUA, SUA/SCr, and GGT were associated with the efficacy of nCRT. The predictive power of the change ratios of SUA, SUA/SCr, and GGT was assessed by receiver operating characteristic (ROC) curves. Univariate and multivariate Cox regression analyses were employed to measure the associations between disease-free survival (DFS) and other predictive indicators. The Kaplan-Meier method was used to further compare DFS between groups. RESULTS: The nonlinear model indicated that the change ratios of SUA, SUA/SCr, and GGT were associated with the efficacy of nCRT. The change ratios of SUA, SUA/SCr, and GGT were used to predict the area under the ROC curve of efficacy for nCRT (0.95, 0.91-0.99), which was better than the prediction by the change ratio of SUA (0.94, 0.89-0.99), SUA/SCr (0.90, 0.84-0.96), or GGT alone (0.86, 0.79-0.93; pâ¯< 0.05). The optimal cut-off values of SUA, SUA/SCr, and GGT change were 0.02, 0.01, and 0.04, respectively. The Kaplan-Meier method indicated that patients with SUA, SUA/SCr, or GGT changes greater than the cut-off values had shorter DFS (pâ¯< 0.05). CONCLUSION: Change ratios of SUA, SUA/SCr, or GGT greater than the cut-off values implied a risk of poor pathological response after nCRT and shorter DFS in LARC patients.
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Probiotics have gained significant attention owing to their roles in regulating human health. Recently, spray drying has been considered as a promising technique to produce probiotic powders due to its advantages of high efficiency, cost-saving, and good powder properties. However, the severe environmental conditions from drying and digestion can significantly reduce cell viability, resulting in poor bioaccessibility and bioavailability of live cells. Therefore, there is a need to develop effective targeted delivery systems using spray drying to protect bacteria and to maintain their physiological functions in the targeted sites. This review highlights recent studies about spray-dried targeted delivery vehicles for probiotics, focusing on key strategies to protect bacteria when encountering external stresses, the formation mechanism of particles, the targeted release and colonization mechanisms of live cells in particles with different structures. Advances in the targeted delivery of live probiotics via spray-dried vehicles are still in their early stages. To increase the possibilities for industrialization and commercialization, functional improvement of microcapsules in terms of protection, targeted release, and colonization of bacteria, as well as the effect of spray drying on bacterial physiological functions in the host, need to be further investigated.
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Arsenic exposure is a major environmental public health challenge worldwide. As typical manifestations for arsenic exposure, the pathogenesis of arsenic-induced skin lesions has not been fully elucidated, as well as the lack of effective control measures. In this study, we first determined the short-term and high-dose arsenic exposure can increase the apoptosis rates, while long-term low-dose arsenic exposure decrease the apoptosis rates. Then, the HaCaT cells with knockdown and overexpression of CCAAT-enhancer-binding protein ß (CEBPB) and extracellular signal-regulated kinase (ERK) were constructed. The results demonstrate that knockdown of CEBPB and ERK can reduce NaAsO2 -induced cell apoptosis by inhibiting ERK/CEBPB signaling pathway and vice versa. Further cells were treated with Kaji-Ichigoside F1 (KF1). The results clearly show that KF1 can decrease the arsenic-induced cell apoptosis rates and the expression of ERK/CEBPB signaling pathway-related genes. These results provide evidence that ERK/CEBPB signaling pathway acts as a double-edged sword in arsenic-induced skin damage. Another interesting finding was that KF1 can alleviate arsenic-induced skin cell apoptosis by inhibiting the ERK/CEBPB signaling pathway. This study will contribute to a deeper understanding of the mechanisms of arsenic-induced skin cell apoptosis, and our findings will help to identify a potential food-borne intervention in arsenic detoxification.
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Arsénico , Quinasas MAP Reguladas por Señal Extracelular , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Arsénico/toxicidad , Transducción de Señal , Apoptosis , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/farmacologíaRESUMEN
Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the metastasis and recurrence of hepatocellular carcinoma (HCC). A kinds of lncRNAs were found to be involved in regulating epithelial-mesenchymal transition (EMT) or stem-like traits in human cancers, however, the molecular mechanism and signaling pathways targeting EMT and stemness remains largely unknown. Previously, we found that linc00261 was down-regulated in HCC and associated with multiple worse clinical pathological parameters and poor prognosis. Here, we show that linc00261 was down-regulated in TGF-ß1 stimulated cells, and forced expression of linc00261 attenuated EMT and stem-like traits in HCC. Linc00261 also inhibited the tumor sphere forming in vitro and decreased the tumorigenicity in vivo. Furthermore, we revealed that linc00261 suppressed the expression and phosphorylation of SMAD3 (p-SMAD3), which could be core transcriptional modulator in TGF-ß1 signaling mediated EMT and the acquisition of stemness traits. A negative correlation between linc00261 and p-SMAD3 was determined in HCC samples. Conclusion: Our study revealed that linc00261 suppressed EMT and stem-like traits in HCC cells by inhibiting TGF-ß1/SMAD3 signaling.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Humanos , Neoplasias Hepáticas/patología , ARN Largo no Codificante , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Melanoma , Neoplasias Cutáneas , Animales , Carcinoma de Células Renales/tratamiento farmacológico , Proteínas de Ciclo Celular , Humanos , Neoplasias Renales/genética , Melanoma/genética , Ratones , Proteínas Nucleares , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Úvea , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: The association between serum uric acid (SUA) and the components of dyslipidaemia and their dose-response relationships have not been thoroughly explored. This study assessed the relationship between SUA and each dyslipidaemia component in Dong, Miao, and Bouyei populations in Guizhou by sex and ethnicities and investigated the dose-response relationship. METHODS: In total, 16,092 participants aged 30-79 years from The China Multi-Ethnic Cohort (CMEC) Study were examined. Multivariable logistic regression models were applied to explore the relationship between SUA and each dyslipidaemia component by sex and three ethnicities. The dose-response associations between SUA and various dyslipidaemias were investigated using restricted cubic spline regression. RESULTS: After controlling for confounding factors, the SUA level in total participants positively correlated with each dyslipidaemia component, and women had higher odds ratios (ORs) for each dyslipidaemia component than men (P for trend < 0.001). At the SUA level > 6.37 mg/dL, ORs (95% CI) for dyslipidaemia in the Dong, Miao and Bouyei were 2.89 (2.00-4.19), 2.43 (1.70-3.48), and 3.26 (2.23-4.78), respectively. When the SUA concentration increased by 1 mg/dL, the ORs (95% CI) for total dyslipidaemia was 1.31 (1.24-1.37). A positive dose-response but nonlinear association was found between SUA and total dyslipidaemia, high total cholesterol, and low HDL, whereas an inverse U-shaped association was found between SUA and high LDL-C ( P-nonlinear< 0.0001). CONCLUSION: The SUA level was positively correlated with each dyslipidaemia component in Dong, Miao, and Bouyei adults, and sex and ethnic differences were also found. A nonlinear dose-response relationship was found between SUA levels and dyslipidaemia and its components. Further research is warranted to investigate the causal link between SUA levels and dyslipidaemia incidence.
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Dislipidemias , Ácido Úrico , Adulto , Anciano , China/epidemiología , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Environmental exposure to arsenic is a major public health challenge worldwide. Growing evidence indicates that coal-burning arsenic can cause hepatic oxidative damage. However, the value of Rosa roxburghii Tratt (RRT) with antioxidant properties on arsenic-caused hepatic oxidative damage has never been elucidated yet. In this study, the animals were exposed to coal-burning arsenic (10 mg/kg bw) for 90 days and the result showed a loss of body weight, impaired liver function and liver diseases, increased hepatic oxidative damage and metabolic disorder of multiple elements including selenium, copper, zinc which were related to synthesis of antioxidant enzymes. Another finding is that RRT restored the abnormal liver function and alleviated the procedures of liver diseases of arsenic poisoning rats. In addition, it could also effectively reduce the degree of oxidative damage in serum and liver, and restore the activity of some antioxidant enzymes. Importantly, RRT reversed the content of most disordered elements caused by arsenic in liver and reduced the excretion of several essential elements in urine, including selenium, copper and zinc. Our study provides some limited evidence that RRT can alleviate coal-burning arsenic-induced liver damage induced by regulating elemental metabolic disorders and liver oxidation and antioxidant balance. The study provides a scientific basis for further studies of the causes of the arsenic-induced liver damage, and effective intervention strategies.
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Intoxicación por Arsénico/patología , Arsénico/toxicidad , Hígado/efectos de los fármacos , Rosa/metabolismo , Animales , Antioxidantes/metabolismo , Arsénico/metabolismo , Hígado/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
Prior observation has indicated that Frizzled 2 (FZD2)-induced epithelial-mesenchymal transition (EMT) could be a key step in metastasis and early recurrence of hepatocellular carcinoma (HCC). However, the mechanism underlying tumor development and progression due to aberrant FZD2 expression is poorly defined. Here, we provide evidence that FZD2 is a driver for EMT, cancer stem cell properties, and vasculogenic mimicry (VM) in HCC. We found that FZD2 was highly expressed in two cohorts of Chinese hepatitis B virus-related HCC patients, and that high FZD2 expression was associated with poor prognosis. Concerning the mechanism, gain- and loss-of-function experiments showed the oncogenic action of FZD2 in HCC cell proliferation, apoptosis, migration, and invasion. Further investigations in vitro and in vivo suggested that FZD2 promotes the EMT process, enhances stem-like properties, and confers VM capacity to HCC cells. Notably, integrative RNA sequencing analysis of FZD2-knockdown cells indicated the enrichment of Hippo signaling pathway. Taken together, our data suggest for the first time that FZD2 could promote clinically relevant EMT, CD44+ stem-like properties, and the VM phenotype in HCC involving a potential Hippo signaling pathway-dependent mechanism, and should be considered as a promising therapeutic target for the treatment of HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Transición Epitelial-Mesenquimal/genética , Receptores Frizzled/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neovascularización Patológica/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Receptores Frizzled/metabolismo , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Vía de Señalización Hippo , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Células Madre Neoplásicas/metabolismo , Neovascularización Patológica/metabolismo , Fosfoproteínas/metabolismo , Pronóstico , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Cancer is a major public health concern and the second leading cause of death worldwide. Various studies have reported the use of serum microRNAs (miRNAs) as non-invasive biomarkers for cancer detection. However, large-scale pan-cancer studies based on serum miRNAs have been relatively scarce. METHODS: An optimized machine learning workflow, combining least absolute shrinkage and selection operator (LASSO) analyses, recursive feature elimination (RFE), and fourteen kinds of machine learning algorithms, was use to screen out candidate miRNAs from 2540 serum miRNAs and constructed a potent diagnostic signature (Cancer-related Serum miRNA Signatures) for pan-cancer detection, based on a serum miRNA expression dataset of 38,223 samples. RESULT: Cancer-related Serum miRNA Signatures performed well in pan-cancer detection with an area under curve (AUC) of 0.999, 94.51% sensitivity, and 99.49% specificity in the external validation cohort, and represented an acceptable diagnostic performance for identifying early-stage tumors. Furthermore, the ability of multi-classification of tumors by serum miRNAs in pancreatic, colorectal, and biliary tract cancers was lower than that in other cancers, which showed accuracies of 59%, 58.5%, and 28.9%, respectively, indicating that the difference in serum miRNA expression profiles among a small number of tumor subtypes was not as significant as that between cancer samples and non-cancer controls. CONCLUSION: We have developed a serum miRNA signature using machine learning that may be a cost-effective risk tool for pan-cancer detection. Our findings will benefit not only the predictive diagnosis of cancer but also a preventive and more personalized screening plan.
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RNA modifications affect fundamental biological processes and diseases and are a research hotspot. Several micro-RNAs (miRNAs) exhibit genetic variant-targeted RNA modifications that can greatly alter their biofunctions and influence their effect on cancer. Therefore, the potential role of these miRNAs in cancer can be implicated in new prevention and treatment strategies. In this study, we determined whether RMvar-related miRNAs were closely associated with tumorigenesis and identified cancer-specific signatures based on these miRNAs with variants targeting RNA modifications using an optimized machine learning workflow. An effective machine learning workflow, combining least absolute shrinkage and selection operator analyses, recursive feature elimination, and nine types of machine learning algorithms, was used to screen candidate miRNAs from 504 serum RMvar-related miRNAs and construct a diagnostic signature for cancer detection based on 43,047 clinical samples (with an area under the curve value of 0.998, specificity of 93.1%, and sensitivity of 99.3% in the validation cohort). This signature demonstrated a satisfactory diagnostic performance for certain cancers and different conditions, including distinguishing early-stage tumors. Our study revealed the close relationship between RMvar-related miRNAs and tumors and proposed an effective cancer screening tool.
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MicroARNs , Neoplasias , Humanos , MicroARNs/genética , Flujo de Trabajo , Aprendizaje Automático , Neoplasias/diagnóstico , Neoplasias/genética , MutaciónRESUMEN
Herein, we report a silver-catalyzed halogenation and electrophilic cyclization reaction based on the trifunctionalization of terminal alkynols with NBS or iodine monochloride in a step-efficient synthetic way to produce homo/heterodihalogenated naphthalene derivatives bearing two different halogen atoms in moderate to good yields. This methodology readily accommodates various functional groups, including electron-withdrawing nitro, cyano, acid-sensitive dioxazolyl, and alkoxy groups.
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.
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Mitofagia , Progeria , Progeria/metabolismo , Progeria/genética , Progeria/patología , Mitofagia/genética , Humanos , Ratones , Animales , Envejecimiento/metabolismo , Senescencia Celular/genéticaRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear. METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK+/- mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model. RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration. CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.
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Esclerosis Amiotrófica Lateral , Modelos Animales de Enfermedad , Ratones Transgénicos , FN-kappa B , Quinasa de Factor Nuclear kappa B , Proteínas Serina-Treonina Quinasas , Animales , Masculino , Ratones , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismoRESUMEN
Lipids are indispensable for energy storage, membrane structure and cell signalling. However, dynamic changes in various categories of endogenous lipids in mammalian early embryonic development have not been systematically characterized. Here we comprehensively investigated the dynamic lipid landscape during mouse and human early embryo development. Lipid signatures of different developmental stages are distinct, particularly for the phospholipid classes. We highlight that the high degree of phospholipid unsaturation is a conserved feature as embryos develop to the blastocyst stage. Moreover, we show that lipid desaturases such as SCD1 are required for in vitro blastocyst development and blastocyst implantation. One of the mechanisms is through the regulation of unsaturated fatty-acid-mediated fluidity of the plasma membrane and apical proteins and the establishment of apical-basal polarity during development of the eight-cell embryo to the blastocyst. Overall, our study provides an invaluable resource about the remodelling of the endogenous lipidome in mammalian preimplantation embryo development and mechanistic insights into the regulation of embryogenesis and implantation by lipid unsaturation.
Asunto(s)
Metabolismo de los Lípidos , Lipidómica , Embarazo , Humanos , Femenino , Ratones , Animales , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/fisiología , Blastocisto/metabolismo , Fosfolípidos/metabolismo , MamíferosRESUMEN
OBJECTIVE: To establish coal arsenic poisoning rat model by feeding the rats with the corn powder baked by high arsenic coal as the main raw material. METHODS: Fifty Wistar rats, healthy, were randomly divided into 5 groups according to the figures of their weights, including control group, drinking arsenic poisoning water group, low, medium and high arsenic contaminated grain group, 10 rats for each.Rats in control group and drinking arsenic poisoning water group were fed with standard feed without any arsenic containing. Rats in water group would drink 100 mg/L As2O3 solution and the rats in arsenic grain groups would be fed with the arsenic contaminated grain at the dose of 25, 50 and 100 mg/kg, respectively. The duration would last for 3 months.General situation and weight were observed. At the same time, the arsenic contents of urine, hair, liver and kidney of the rats in each group were detected, as well as the histopathology changes of liver and kidney, and the ultra structure of liver was observed. RESULTS: The arsenic contents of urine (median(min-max)) of the rats in the arsenic water group, low, medium and high arsenic grain groups were separately 3055.59 (722.43-6389.05), 635.96(367.85-1551.31), 1453.84 (593.27-5302.94) and 3101.11 (666.64-6858.61) µg/g Cr; while the arsenic contents of hair of the rats in the above groups were separately (23.07 ± 10.38), (8.87 ± 3.31), (12.43 ± 6.65) and (25.68 ± 7.16) µg/g; the arsenic contents of liver of the rats in the above groups were separately (5.68 ± 3.13), (2.64 ± 1.52), (3.89 ± 1.76) and (5.34 ± 2.78) µg/g; and the arsenic contents of kidney were separately (6.90 ± 1.94), (3.48 ± 1.96), (5.03 ± 2.08) and (7.02 ± 1.62) µg/g; which were all significantly higher than those in the control group (86.70 (49.71-106.104) µg/g Cr,(1.28 ± 0.37) µg/g, (1.01 ± 0.34) µg/g and (1.82 ± 1.09) µg/g, respectively). The difference showed significance (P < 0.05). Under electron microscope detection, we observed the reduction of mitochondrial, the blurred mitochondrial cristae, some disappeared ridges, the reduced rough endoplasmic reticulum, and irregular uneven nuclear in the liver cells of rats in arsenic contaminated grain group. The contents of aspartate transaminase (AST) and total bile acid (TBA) in medium and high arsenic contaminated grain group were respectively (196.17 ± 46.18), (212.40 ± 35.14) U/L and (11.74 ± 4.07), (19.19 ± 4.68)µmol/L, which were higher than it in the control group (separately (143.10 ± 29.13) U/L and (6.23 ± 2.95)µmol/L). The contents of glutathione-S-transferases(GST), γ-glutamyltranspeptidase (GGT)and blood urea nitrogen (BUN)in high arsenic contaminated grain group were separately (196.21 ± 47.38)U/L, (1.71 ± 0.66)U/L, (9.54 ± 1.95)mmol/L, which were higher than that in the control group ((134.93 ± 24.80 )U/L, (0.75 ± 0.36)U/L, (7.67 ± 1.02)mmol/L, respectively). The contents of cholinesterase (CHE) in low, medium and high arsenic contaminated grain group were separately (259.90 ± 52.71)U/L, (263.44 ± 66.06)U/L and (244.90 ± 36.14)U/L, the contents of total protein(TP) in rats of high arsenic contaminated grain group were (62.64 ± 5.50)g/L, which was all lower than that in the control group ((448.33 ± 59.67)U/L, (69.38 ± 4.24)g/L, respectively). The contents of TBA in high arsenic contaminated grain group ( (19.19 ± 4.68) µmol/L) was higher than that in drinking water arsenic poisoning group ((15.15 ± 2.64)µmol/L). The differences of the above indexes were all significant (P < 0.05). CONCLUSION: The results showed the arsenic poisoning rat model produced by coal-burning were successfully established.