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BACKGROUND: Skeletal muscle is a major insulin-sensitive tissue with a pivotal role in modulating glucose homeostasis. This study aimed to investigate the effect of resveratrol (RES) intervention during the suckling period on skeletal muscle growth and insulin sensitivity of neonates with intrauterine growth retardation (IUGR) in a pig model. RESULTS: Twelve pairs of normal birth weight (NBW) and IUGR neonatal male piglets were selected. The NBW and IUGR piglets were fed basal formula milk diet or identical diet supplemented with 0.1% RES from 7 to 21 days of age. Myofiber growth and differentiation, inflammation and insulin sensitivity in skeletal muscle were assessed. Early RES intervention promoted myofiber growth and maturity in IUGR piglets by ameliorating the myogenesis process and increasing thyroid hormone level. Administering RES also reduced triglyceride concentration in skeletal muscle of IUGR piglets, along with decreased inflammatory response, increased plasma fibroblast growth factor 21 (FGF21) concentration and improved insulin signaling. Meanwhile, the improvement of insulin sensitivity by RES may be partly regulated by activation of the FGF21/AMP-activated protein kinase α/sirtuin 1/peroxisome proliferator activated receptor-γ coactivator-1α pathway. CONCLUSION: Our results suggest that RES has beneficial effects in promoting myofiber growth and maturity and increasing skeletal muscle insulin sensitivity in IUGR piglets, which open a novel field of application of RES in IUGR infants for improving postnatal metabolic adaptation. © 2023 Society of Chemical Industry.
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Factores de Crecimiento de Fibroblastos , Resistencia a la Insulina , Femenino , Porcinos , Animales , Masculino , Humanos , Resveratrol/farmacología , Resveratrol/metabolismo , Hígado/metabolismo , Retardo del Crecimiento Fetal/tratamiento farmacológico , Retardo del Crecimiento Fetal/veterinaria , Retardo del Crecimiento Fetal/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Músculo Esquelético/metabolismo , Insulina/metabolismo , Desarrollo de MúsculosRESUMEN
Hypoxia, one of the key features of the hepatocellular carcinoma (HCC) microenvironment, transcriptionally regulates the expression of mRNAs and non-coding RNAs via hypoxia-inducible factors (HIFs), thereby promoting tumor progression. However, hypoxia-responsive long non-coding RNAs (lncRNAs) in HCC required further investigation. We found that HLA complex group 15 (HCG15) was a new hypoxia-related lncRNA in HCC cells. Both hypoxia and HIF prolyl-hydroxylase inhibitor significantly increased HCG15 expression in HCC cells. At the same time, HIF-1α knockdown blocked hypoxia-induced the upregulation of HCG15. TCGA data revealed that HCG15 was markedly overexpressed and closely associated with the poor prognosis of HCC. HCG15 knockdown prominently suppressed the migration, invasion and proliferation of Hep3B and Huh7 cells. HCG15 overexpression markedly enhanced the proliferation and mobility of Huh7 cells. Zinc finger protein 641 (ZNF641) mRNA was frequently overexpressed and positively associated with HCG15 level in HCC samples from the TCGA database. Either HCG15 or upstream transcription factor 1 (USF1) silencing markedly reduced the ZNF641 level in HCC cells. RNA immunoprecipitation assay confirmed the interaction between HCG15 and USF1. Either HCG15 or USF1 knockdown prominently reduced the luciferase activity of reporter plasmid containing ZNF642 promoter. HCG15 knockdown remarkably abolished USF1-activated ZNF641 transcription in Hep3B cells. Finally, we confirmed that restoring ZNF641 expression remarkably abolished the effects of HCG15 knockdown on HCC cell migration, invasion and proliferation. Collectively, our study demonstrated that HCG15 was a new HIF-1 target gene and played a tumor-promoting role in HCC cells by enhancing USF1-mediated ZNF641 transcription.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Transactivadores , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Neoplasias Hepáticas/patología , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transactivadores/genética , Hipoxia Tumoral , Microambiente TumoralRESUMEN
BACKGROUND: The tumour-stroma ratio (TSR) is identified as a promising prognostic parameter for breast cancer, but the cutoff TSR value is mostly assessed by visual assessment, which lacks objective measurement. The aims of this study were to optimize the cutoff TSR value, and evaluate its prognosis value in patients with breast cancer both as continuous and categorical variables. METHODS: Major clinicopathological and follow-up data were collected for a series of patients with breast cancer. Tissue microarray images stained with cytokeratin immunohistochemistry were evaluated by automated quantitative image analysis algorithms to assess TSR. The potential cutoff point for TSR was optimized using maximally selected rank statistics. The association between TSR and 5-year disease-free survival (5-DFS) was assessed by Cox regression analysis. Kaplan-Meier analysis and log-rank test were used to assess the significance in survival analysis. RESULTS: The optimal cut-off TSR value was 33.5%. Using this cut-off point, categorical variable analysis found that low TSR (i.e., high stroma, TSR ≤ 33.5%) predicts poor outcomes for 5-DFS (hazard ratio [HR] = 2.82, 95% confidence interval [CI] = 1.81-4.40, P = 0.000). When TSR was considered as a continuous parameter, results showed that increased stroma content was associated with worse 5-DFS (HR = 1.71, 95% CI = 1.34-2.18, P = 0.000). Similar results were also obtained in three molecular subtypes in continuous and categorical variable analyses. Moreover, in the Kaplan-Meier analysis, log-rank test showed that low TSR displayed a worse 5-DFS than high TSR (P = 0.000). Similar results were also obtained in patients with triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and luminal-HER2-negative breast cancer. CONCLUSION: TSR is an independent predictor for 5-DFS in breast cancer with worse survival outcomes in low TSR. The prognostic value of TSR was also observed in other three molecular subtypes.
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Células del Estroma , Neoplasias de la Mama Triple Negativas , Humanos , Supervivencia sin Enfermedad , Células del Estroma/patología , Pronóstico , Neoplasias de la Mama Triple Negativas/patología , QueratinasRESUMEN
OBJECTIVE: To conduct a comprehensive systematic review and meta-analysis to estimate the relationship between endocrine-disrupting chemicals (EDCs), including polychlorinated biphenyls (PCBs), poly-brominated diphenyl ethers (PBDEs), phthalates (PAEs), and per- and polyfluoroalkyl substances (PFAS) exposure and risk of gestational diabetes mellitus (GDM). METHODS: Relevant studies from their inception to November 2021 were identified by searching EMBASE, PubMed, and Web of Science. The cohort and case-control studies that reported effect size with 95% confidence intervals (CIs) of EDC exposure and GDM were selected. The heterogeneity among the included studies was quantified by I2 statistic. Publication bias was evaluated through the Begg and Egger tests. RESULTS: Twenty-five articles with a total of 23,796 participants were found. Results indicated that exposure to PCBs has a significant influence on the incidence of GDM (OR = 1.14; 95% CI = 1.00--1.31; n = 8). The risk of GDM was found to be associated with PBDE exposure (OR = 1.32; 95% CI = 1.15-1.53; n = 4). PAEs and PFASs exposure were also positively associated with the risk of GDM, with summary ORs of 1.10 (95% CI = 1.03-1.16; n = 7 for PAEs) and 1.09 (95% CI = 1.02-1.16; n = 11 for PFASs), respectively. When only cohort studies were considered, the summary OR between PCBs exposure and the risk of GDM was 0.99 (95% CI = 0.91-1.09; n = 5). Meanwhile, the summary ORs from cohort studies for PBDEs, PAEs, and PFASs exposure were 1.12 (95% CI = 1.00-1.26; n = 2), 1.08 (95% CI = 1.02-1.15; n = 5), and 1.06 (95% CI = 1.00-1.12; n = 8), respectively. The Beggs and Egger tests did not show publication bias, and the sensitivity analyses did not change the results in this meta-analysis. CONCLUSION: These results support that exposure to certain EDCs, including PCBs, PBDEs, PAEs, and PFAS, increase the risk of GDM. Further large-sample epidemiologic researches and mechanistic studies are needed to verify the potential relationship and biological mechanisms. These results are of public health significance because the daily EDC exposure is expected to increase the risk of GDM development.
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Diabetes Gestacional , Disruptores Endocrinos , Contaminantes Ambientales , Fluorocarburos , Bifenilos Policlorados , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/epidemiología , Disruptores Endocrinos/efectos adversos , Femenino , Éteres Difenilos Halogenados/toxicidad , Humanos , Bifenilos Policlorados/toxicidad , EmbarazoRESUMEN
BACKGROUND: Platinum-based chemotherapy is a mainstay for treating esophageal cancer patients. In this manuscript, we have provided clues for influence of platinum on overall m6A level and further investigated the potential regulatory mechanism. METHODS: qRT-PCR was used to measure SNHG3 and miR-186-5p expression; ELISA and western blot were used to measure the expression of METTL3. CCK8 was used to measure the cell proliferation rate. Caspase 3/7 activity was used to measure the apoptosis rate. Dual luciferase reporter gene assay and RNA pull down assay were used to investigate the potential crosstalk between miR-186-5p and SNHG3; and miR-186-5p and METTL3. RESULTS: m6A level was increased when treated with platinum (CDDP, CPB and L-OHP). Besides, SNHG3 expression was induced and miR-186-5p expression was suppressed by platinum. Furthermore, SNHG3 could promote the m6A level, however miR-186-5p inhibited the m6A level through targeting METTL3. SNHG3 interacts with miR-186-5p to negatively regulate the expression of miR-186-5p; and miR-186-5p might bind to the 3'UTR of METTL3 to regulate its expression. CONCLUSION: Platinum can increase the overall m6A level of esophageal cancer. SNHG3/miR-186-5p, induced by platinum, was involved in regulating m6A level by targeting METTL3. Our manuscript has provided clues that regulating m6A level might be a novel way to enhance the platinum efficacy.
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OBJECTIVE: Radioiodine has been increasingly used to treat hyperthyroidism for many years. Although widely regarded as an effective therapy, radioiodine treatment for hyperthyroidism has been suspected to be associated with the risk of mortality. This study aimed to quantify the mortality outcomes in patients who were treated for hyperthyroidism with radioiodine. METHODS: Systematic search and meta-analysis were performed to determine the risk of mortality in patients treated with radioiodine for hyperthyroidism. Relevant studies were searched through August 2020 and selected in accordance with the inclusion criteria. RESULTS: A total of 13 studies were identified. The summary odds ratios (ORs) showed an increased risk of all-cause mortality in patients who were treated with radioiodine for hyperthyroidism (OR = 1.20; 95% CI = 1.07-1.35). The risk of death attributed to all forms of circulatory, respiratory, and endocrine and metabolic diseases was significantly increased, with summary ORs of 1.23 (95% CI, 1.12-1.35), 1.43 (95% CI, 1.17-1.75), and 2.38 (95% CI, 1.85-3.06), respectively. The summary ORs revealed no significant association between radioiodine treatment for hyperthyroidism and the risk of cancer mortality (OR = 1.03; 95% CI, 0.98-1.09). Radioiodine treatment for hyperthyroidism was not associated with the risk of mortality from breast, respiratory system, gastrointestinal, and genitourinary cancers. CONCLUSION: Radioiodine treatment for hyperthyroidism is associated with the risk of all-cause mortality but not cancer mortality. Future research needs to address the causes of hyperthyroidism, effects of radioiodine therapy, and potential effects of confounding to identify causality.
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Hipertiroidismo , Radioisótopos de Yodo , Antitiroideos , Humanos , Hipertiroidismo/radioterapia , Radioisótopos de Yodo/efectos adversosRESUMEN
AIMS: An ongoing outbreak of 2019 novel coronavirus (CoV) disease (COVID-19), caused by severe acute respiratory syndrome (SARS) CoV-2, has been spreading in multiple countries. One of the reasons for the rapid spread is that the virus can be transmitted from infected individuals without symptoms. Revealing the pathological features of early-phase COVID-19 pneumonia is important for understanding of its pathogenesis. The aim of this study was to explore the pulmonary pathology of early-phase COVID-19 pneumonia in a patient with a benign lung lesion. METHODS AND RESULTS: We analysed the pathological changes in lung tissue from a 55-year-old female patient with early-phase SARS-CoV-2 infection. In this case, right lower lobectomy was performed for a benign pulmonary nodule. Detailed clinical, laboratory and radiological data were also examined. This patient was confirmed to have preoperative SARS-CoV-2 infection by the use of real-time reverse transcription polymerase chain reaction and RNA in-situ hybridisation on surgically removed lung tissues. Histologically, COVID-19 pneumonia was characterised by exudative inflammation. The closer to the visceral pleura, the more severe the exudation of monocytes and lymphocytes. Perivascular inflammatory infiltration, intra-alveolar multinucleated giant cells, pneumocyte hyperplasia and intracytoplasmic viral-like inclusion bodies were seen. However, fibrinous exudate and hyaline membrane formation, which were typical pulmonary features of SARS pneumonia, were not evident in this case. Immunohistochemical staining results showed an abnormal accumulation of CD4+ helper T lymphocytes and CD163+ M2 macrophages in the lung tissue. CONCLUSION: The results highlighted the pulmonary pathological changes of early-phase SARS-CoV-2 infection, and suggested a role of immune dysfunction in the pathogenesis of COVID-19 pneumonia.
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Infecciones por Coronavirus/patología , Neumonía Viral/patología , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/inmunología , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , SARS-CoV-2RESUMEN
As a new kind of RNA, circular RNA (circRNA) is a endogenous non-coding RNA with circular structure, which has the characteristics of universality, stability, conservatism and specificity. CircRNA can specifically bind to microRNAs (miRNAs) in the form of competitive endogenous RNA, thus directly or indirectly regulating the expression of related genes. In addition to the role of sponge, circRNA also regulates parental gene expression, transcriptional translation and protein modification; and it can be used as a biomarker to develop potential diagnosis and treatment methods and evaluate prognosis. Due to changes in dietary habits and genetic factors, the morbidity and mortality of esophageal cancer (EC) in the world are still high, and are prone to early metastasis. Although the diagnosis and treatment techniques have been improved in recent years, the early diagnosis of EC is not common, and the 5-year survival rate of patients is still very low. This article reviews the function and significance of circRNA and discusses the research progress of circRNA as biomarkers in EC.
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PURPOSE: The present study was conducted to determine whether reduced meal frequency (MF) could restore high-fat diet (HFD)-modified phenotypes and microbiota under the condition of fixed feed allowance. METHODS: A total of 32 barrows with initial weight of 61.6 ± 0.8 kg were assigned to two diets [control diet (CON) versus HFD] and two meal frequencies [12 equal meals/day (M12) versus 2 equal meals/day (M2)], the trial lasted 8 weeks. The lipid metabolism and inflammatory response in adipose tissue as well as the profiles of intestinal microbiota and bacterial-derived metabolites were determined. RESULTS: M2 versus M12 feeding regimen decreased perirenal fat weight and serum triglyceride and liposaccharide (LPS) concentrations in HFD-fed pigs (P < 0.05). Reduced MF down-regulated mRNA expression of lipoprotein lipase, CD36 molecule, interleukin 1 beta, tumor necrosis factor alpha, toll-like receptor 4, myeloid differentiation factor 88 (MYD88), and nuclear factor kappa beta 1 as well as protein expression of MYD88 in perirenal fat of HFD-fed pigs (P < 0.05). M2 feeding regimen increased abundance of Prevotella and decreased abundance of Bacteroides in colonic content of HFD-fed pigs (P < 0.05). No difference in short-chain fatty acids (SCFAs) profile in colonic content was observed among four groups (P > 0.05). CONCLUSION: Our results suggested that M2 versus M12 feeding regimen ameliorated HFD-induced fat deposition and inflammatory response by decreasing fatty acid uptake and deactivating LPS/TLR4 signaling pathway in adipose tissue and restoring microbiota composition in distal intestine, without affecting SCFAs profile in distal luminal content.
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Tejido Adiposo/fisiopatología , Dieta Alta en Grasa/efectos adversos , Conducta Alimentaria/fisiología , Inflamación/fisiopatología , Metabolismo de los Lípidos/fisiología , Animales , Modelos Animales de Enfermedad , Lípidos/sangre , PorcinosRESUMEN
BACKGROUND: Early-life antibiotic administration is known to affect gut microbiota and host adiposity, but the effects of antibiotic exposure on skeletal muscle properties remain unknown. The present study evaluated the changes in skeletal muscle properties including myofiber characteristics and composition, as well as intramuscular fat (IMF) content in skeletal muscle of piglets when exposed to a tylosin-containing diet. RESULTS: A total of 18 piglets (28 days of age) were randomly allocated into two groups: control basal diet (Control) and Control + 100 mg tylosin phosphate/kg of feed (Antibiotic). The trial lasted for 39 days. High-throughput amplicon sequencing revealed that no significant difference in initial gut microbiota composition was existed between Control and Antibiotic groups. Antibiotic administration increased body weight and growth rate and decreased feed to gain ratio of pigs (P < 0.05). The carcass lean and fat volumes of pigs were increased by the tylosin administration (P < 0.05). Antibiotic treatment increased myofiber density and the expression of genes related to type I and type IIb myofibers in longissimus muscle (P < 0.05). The IMF content in longissimus muscle was increased by antibiotic exposure (P < 0.05). Antibiotic administration increased expression of genes related to fatty acid uptake and de novo synthesis, and decreased expression of genes related to triglyceride hydrolysis (P < 0.05). Tylosin administration affected taxonomic distribution and beta diversity of the caecal and colonic microbiota of piglets. CONCLUSION: These results confirm that the growth performance, myofiber composition and muscle lipid metabolism are affected by antibiotic administration, which may be associated with an altered gut microbiota, suggesting that the gut microbiota could be served as a potential target for modulating skeletal muscle properties of host.
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Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Metabolismo de los Lípidos/genética , Músculo Esquelético/efectos de los fármacos , Miofibrillas/efectos de los fármacos , Porcinos , Tilosina/farmacología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Músculo Esquelético/metabolismo , Miofibrillas/química , Porcinos/genética , Porcinos/metabolismoRESUMEN
BACKGROUND: Avoiding the phagocytosis by tumor-associated macrophages (TAMs) is necessary for the growth and metastasis of solid tumors. CD47 binds to the receptor signal-regulatory protein-α (SIRP-α) on the macrophages to avoid normal phagocytosis. In this study, we evaluated the expression and prognostic significance of CD47 and CD68-labeled TAMs in breast cancer solid tumors. METHODS: Two hundred seventeen cases of breast cancer tissues and 40 cases of benign breast lesions were collected for immunohistochemical staining of CD47 and CD68. RESULTS: Both of the CD47 and CD68 expression were significantly higher in breast cancer tissues (P < 0.001), and associated with multiple clinicopathological parameters in breast cancer (P < 0.05). However, CD47 or CD68 expression alone was not an independent predictor of poor DFS in multivariate survival analysis (P > 0.05). Interestingly, combined high expression of CD47 and CD68 (CD47highCD68high) not only had a significant association with advanced TNM stage, histological grade, LNM, ER status, PR status and recurrence (P < 0.05), but also displayed a poorer 5-DFS (P = 0.011). Strikingly, CD47highCD68high served as a novel independent prognostic factor for poor DFS compared to the expression of CD47 or CD68 alone (P = 0.045). Furthermore, our study also showed for the first time that the prognostic significance of CD47highCD68high not only in breast cancer in general, but also in hormone receptor-negative breast cancer in particular. CONCLUSIONS: Combined detection of CD47 and CD68 may provide guidance for the prognosis of breast cancer, especially hormone receptor-negative breast cancer.
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OBJECTIVES: Intrauterine growth retardation (IUGR) and postnatal nutrition are risk factors for adult metabolic syndrome. However, the influences of long-term high-fat diet (HFD) intake on ectopic fat deposition in non-adipose tissues in IUGR pigs remain unclear. The present study was to determine whether HFD consumption would enhance ectopic fat deposition in IUGR pigs. METHODS: At day 28, IUGR and control pigs were fed ad libitum to either a regular diet or a HFD. Lipid store, enzymatic activities and mRNA expression of lipid metabolism-related factors in liver and semitendinosus muscle (SM) were quantified at postnatal day 178. RESULTS: Feeding a HFD to IUGR pigs but not to control pigs significantly increased daily weight gain, carcass fat mass, plasma leptin level and lipid content and lipoprotein lipase (LPL) activity and mRNA abundances of LPL and peroxisome proliferator-activated receptor gamma (PPARγ) in liver and SM, but decreased daily feed intake and mRNA expression of hormone-sensitive lipase (LIPE) and carnitine palmitoyl transferase-1 (CPT-1) in liver and SM (P < 0.05). Compared with control pigs, IUGR pigs had a lower body weight but higher plasma levels of total cholesterol (TC) and insulin (P < 0.05). HFD-fed pigs exhibited greater body weight, plasma concentrations of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), regardless of birth weight (P < 0.05). CONCLUSION: Our results suggested that IUGR increased the vulnerability of HFD-fed pigs to ectopic fat deposition via enhanced fatty acid flux toward ectopic sites and reduced lipolysis and fatty acid oxidation.
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Tejido Adiposo/fisiopatología , Dieta Alta en Grasa/efectos adversos , Retardo del Crecimiento Fetal/fisiopatología , Animales , Composición Corporal , Ácidos Grasos/metabolismo , Hígado Graso/epidemiología , Hígado Graso/metabolismo , Expresión Génica , Insulina/sangre , Leptina/sangre , Metabolismo de los Lípidos/genética , Lípidos/sangre , Lipólisis , Hígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Oxidación-Reducción , Sus scrofa/fisiología , PorcinosRESUMEN
Synaptic spine loss is one of the major preceding consequences of stroke damages, but its underlying molecular mechanisms remain unknown. Here, we report that a direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death in a mouse model with stroke. We found that DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice. Either genetic deletion of DAPK1 kinase domain (KD) in mice (DAPK1-KD(-/-)) or blocking DAPK1-Tau interaction by systematic application of a membrane permeable peptide protects spine damages and improves neurological functions against stroke insults. Thus, disruption of DAPK1-Tau interaction is a promising strategy in clinical management of stroke.
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Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Espinas Dendríticas/patología , Neuronas/patología , Accidente Cerebrovascular/patología , Proteínas tau/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Muerte Celular , Células Cultivadas , Corteza Cerebral/patología , Proteínas Quinasas Asociadas a Muerte Celular/genética , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Examen Neurológico , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Péptidos/uso terapéutico , Fosfopiruvato Hidratasa/metabolismo , Fosforilación , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/fisiopatología , Proteínas tau/genéticaRESUMEN
Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS(23)) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that the pS(23) acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus, pS(23) induces the expression of proapoptotic genes, such as Bax, whereas in the mitochondrial matrix, pS(23) triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1(DDΔ)) or application of Tat-p53DM that interrupts DAPK1-p53 interaction blocks these dual pathways of pS(23) actions in mouse cortical neurons. Thus, the DAPK1-p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults.
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Apoptosis/genética , Isquemia Encefálica/genética , Isquemia Encefálica/patología , Proteínas Quinasas Asociadas a Muerte Celular/fisiología , Necrosis/genética , Neuronas/patología , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/fisiología , Animales , Hipoxia de la Célula/fisiología , Células Cultivadas , Clonación Molecular , Peptidil-Prolil Isomerasa F , Ciclofilinas/metabolismo , Proteínas Quinasas Asociadas a Muerte Celular/genética , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Dependovirus/genética , Eliminación de Gen , Glucosa/genética , Glutatión Transferasa/metabolismo , Inmunoprecipitación , Luciferasas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína p53 Supresora de Tumor/genética , Proteína X Asociada a bcl-2/biosíntesis , Proteína X Asociada a bcl-2/genéticaRESUMEN
BACKGROUND AND PURPOSE: Death-associated protein kinase 1 (DAPK1) interacts with the tumor suppressor gene p53 via a direct binding of a death domain of DAPK1 to a DNA-binding motif (DM) of p53 (p53DM) and converges multiple cell death pathways in stroke. The goals of this study are to determine whether disruption of DAPK1-p53 interaction is therapeutically effective against stroke. METHODS: We synthesized a membrane-permeable p53DM peptide (Tat-p53DM) and tested the therapeutic effects of Tat-p53DM in a mouse model with stroke. RESULTS: We showed that Tat-p53DM blocked DAPK1-p53 interaction in brain cells in vivo. When administered 6 hours after stroke onset in adult male mice, Tat-p53DM was still therapeutically effective against brain damages and improved neurological functions. CONCLUSIONS: DAPK1-p53 interaction is a preferred target for therapeutic intervention of stroke.
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Proteínas Quinasas Asociadas a Muerte Celular/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Proteínas Recombinantes de Fusión/farmacología , Accidente Cerebrovascular/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Ratones , Péptidos/síntesis química , Péptidos/farmacología , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes de Fusión/síntesis química , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
Immunotherapy plays a key role in cancer treatment, however, responses are limited to a small number of patients. The biological basis for the success of immunotherapy is the complex interaction between tumor cells and tumor immune microenvironment (TIME). Historically, research on tumor immune constitution was limited to the analysis of one or two markers, more novel technologies are needed to interpret the complex interactions between tumor cells and TIME. In recent years, major advances have already been made in depicting TIME at a considerably elevated degree of throughput, dimensionality and resolution, allowing dozens of markers to be labeled simultaneously, and analyzing the heterogeneity of tumour-immune infiltrates in detail at the single cell level, depicting the spatial landscape of the entire microenvironment, as well as applying artificial intelligence (AI) to interpret a large amount of complex data from TIME. In this review, we summarized emerging technologies that have made contributions to the field of TIME, and provided prospects for future research.
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Inteligencia Artificial , Inmunoterapia , Humanos , Tecnología , Microambiente TumoralRESUMEN
Neuronal death following ischemia is the primary cause of death and disability in patients with ischemic stroke. N6-methyladenosine (m6A) modification plays essential role in various physiological and pathological conditions, but its role and mechanism in ischemic neuronal death remain unclear. In the present study, neuronal pyroptosis was an important event in brain injury caused by ischemic stroke, and the upregulation of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) following cerebral ischemia was a key factor in activating ischemic neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling. Moreover, we first demonstrated that the demethylase fat mass and obesity-associated protein (FTO), which was decreased following ischemia, regulated MEG3 expression in an m6A-dependent manner by affecting its stability, thereby activating neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling, and ultimately leading to ischemic brain damage. Therefore, the present study provides new insights for the mechanism of ischemic stroke, and suggests that FTO may be a potential therapeutic target for ischemic stroke.
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Adenina/análogos & derivados , Accidente Cerebrovascular Isquémico , ARN Largo no Codificante , Accidente Cerebrovascular , Humanos , Piroptosis , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Accidente Cerebrovascular Isquémico/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Accidente Cerebrovascular/genética , Isquemia , Caspasas , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genéticaRESUMEN
BACKGROUND: CIC-rearranged sarcomas (CRS) represent a new entity of undifferentiated small round cell sarcoma belonging to the Ewing-like sarcomas family. CRS are the most common type. Fusion partners for the CIC gene include DUX4, FOXO4, and the recently recognizedNUTM1. Rare cases of CIC::NUTM1 sarcoma in pediatric patients have recently been reported in brain, kidney, bone, and soft tissues. However, such cases have not been identified in the soft tissues of the limbs. CASE PRESENTATION: We reported a case of CIC::NUTM1 sarcoma located in the right upper limb of an 18-year-old man. The tumor displayed morphologic features typical of CIC::DUX4 sarcomas, with small- to medium-sized round cells, a lobular pattern, focal spindling, myxoid stroma, and patchy necrosis. The tumor diffusely expressed NUTM1, was positive for WT1cter at weak to moderate intensity, and was focally positive for CD99, while it was negative for keratins, EMA, P40, MyoD1, myogenin, NKX2.2, BCOR, and pan-TRK. Fluorescence in situ hybridization analyses revealed cleavage of the CIC and NUTM1 genes. CONCLUSION: CIC::NUTM1 sarcomas represent a novel molecular variant of CRS with a preference for the central nervous system and younger pediatric persons. Its morphology and phenotype may be mistaken for NUT carcinomas, and the behavior is more progressive than other forms of CRS. For this rare and newly discovered gene fusion variant, it is necessary to integrate molecular and immunohistochemical findings with morphologic features in the diagnosis of undifferentiated neoplasms.
Asunto(s)
Proteínas Represoras , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Adolescente , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Proteínas Represoras/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma/patología , Sarcoma/diagnóstico , Extremidad Superior/patología , Reordenamiento Génico , Proteína Homeobox Nkx-2.2 , Hibridación Fluorescente in Situ , Factores de Transcripción , Proteínas de HomeodominioRESUMEN
This article presents a hybrid recommender framework for smart medical systems by introducing two methods to improve service level evaluations and doctor recommendations for patients. The first method uses big data techniques and deep learning algorithms to develop a registration review system in medical institutions. This system outperforms conventional evaluation methods, thus achieving higher accuracy. The second method implements the term frequency and inverse document frequency (TF-IDF) algorithm to construct a model based on the patient's symptom vector space, incorporating score weighting, modified cosine similarity, and K-means clustering. Then, the alternating least squares (ALS) matrix decomposition and user collaborative filtering algorithm are applied to calculate patients' predicted scores for doctors and recommend top-performing doctors. Experimental results show significant improvements in metrics called precision and recall rates compared to conventional methods, making the proposed approach a practical solution for department triage and doctor recommendation in medical appointment platforms.
RESUMEN
Two experiments were conducted to establish the prediction equations for AME and TME of corn based on chemical composition and enzymatic hydrolysate gross energy (EHGE) in roosters. In experiment 1, eighty 32-wk-old Hy-line Brown roosters with an average body weight of 2.55 ± 0.21 kg were randomly assigned to 10 diet treatments in a completely randomized design to determine AME and TME by the force-feeding method. Each treatment had 8 replicates with 1 bird per replicate. The 10 test diets used in the experiment were formulated with corn (including 96.10%) as the sole source of energy. In experiment 2, the EHGE of 14 corn samples was measured by the computer-controlled simulated digestion system (CCSDS) with 5 replicates of each sample. The average AME and TME values of corn were 14.58 and 16.46 MJ/kg DM, respectively. The EHGE of 14 corn samples ranged from 14.66 to 15.89 (the mean was 15.24) MJ/kg DM. The best-fit equations for corn based on chemical composition were AME (MJ/kg DM) = 14.5504 + 0.1166 × ether extract (EE) + 0.5058 × Ash - 0.0957 × neutral detergent fiber (NDF) (R2 = 0.8194, residual standard deviation (RSD) = 0.0860, P < 0.01) and TME (MJ/kg DM) = 16.0625 + 0.1314 × EE + 0.4725 × Ash - 0.0872 × NDF (R2 = 0.7867, RSD = 0.0860, P < 0.01). The best-fit equations for corn based on EHGE were AME (MJ/kg DM) = 7.8883 + 0.4568 × EHGE (R2 = 0.8587, RSD = 0.0693, P < 0.01) and TME (MJ/kg DM) = 10.0099 + 0.4228 × EHGE (R2 = 0.8720, RSD = 0.0608, P < 0.01). The differences between determined and predicted values from equations established based on EHGE were lower than those observed from chemical composition equations. These results indicated that EHGE measured with CCSDS could predict the AME and TME of corn for roosters with high accuracy.