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BACKGROUND: EV71 is one of the important pathogens of Hand-foot-and-mouth disease (HFMD), which causes serious neurological symptoms. Several studies have speculated that there will be interaction between 5'UTR and 3D protein. However, whether 5'UTR interacts with the 3D protein in regulating virus replication has not been clarified. METHODS: Four 5'UTR mutation sites (nt88C/T, nt90-102-3C, nt157G/A and nt574T/A) and two 3D protein mutation sites (S37N and R142K) were mutated or co-mutated using virulent strains as templates. The replication of these mutant viruses and their effect on autophagy were determined. RESULTS: 5'UTR single-point mutant strains, except for EGFP-EV71(nt90-102-3C), triggered replication attenuation. The replication ability of them was weaker than that of the parent strain the virulent strain SDLY107 which is the fatal strain that can cause severe neurological complications. While the replication level of the co-mutant strains showed different characteristics. 5 co-mutant strains with interaction were screened: EGFP-EV71(S37N-nt88C/T), EGFP-EV71(S37N-nt574T/A), EGFP-EV71(R142K-nt574T/A), EGFP-EV71(R142K-nt88C/T), and EGFP-EV71(R142K-nt157G/A). The results showed that the high replicative strains significantly promoted the accumulation of autophagosomes in host cells and hindered the degradation of autolysosomes. The low replicative strains had a low ability to regulate the autophagy of host cells. In addition, the high replicative strains also significantly inhibited the phosphorylation of AKT and mTOR. CONCLUSIONS: EV71 5'UTR interacted with the 3D protein during virus replication. The co-mutation of S37N and nt88C/T, S37N and nt574T/ A, R142K and nt574T/A induced incomplete autophagy of host cells and promoted virus replication by inhibiting the autophagy pathway AKT-mTOR. The co-mutation of R142K and nt88C/T, and R142K and nt157G/A significantly reduced the inhibitory effect of EV71 on the AKT-mTOR pathway and reduced the replication ability of the virus.
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Regiones no Traducidas 5' , Enterovirus Humano A , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Replicación Viral , Enterovirus Humano A/genética , Enterovirus Humano A/fisiología , Enterovirus Humano A/patogenicidad , Regiones no Traducidas 5'/genética , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Autofagia , Animales , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Transducción de Señal , Chlorocebus aethiops , Mutación , Línea Celular , Células VeroRESUMEN
Various studies have demonstrated that ubiquitin D (UBD) is overexpressed in different cancer types and may serve as a potential prognostic factor. However, additional research is necessary to establish the prognostic significance and possible role of UBD in glioma. Transcriptomic expression data from The Cancer Genome Atlas database (TCGA) and Chinese Glioma Genome Atlas (CGGA) were analyzed to identify UBD expression differences in tumor and normal tissues. The relative levels of UBD in glioma and normal tissues were determined using qRT-PCR and WB. Logistic regression analysis was performed to investigate the association between UBD expression and clinicopathological characteristics of glioma patients. To evaluate the diagnostic and prognostic predictive values of UBD, we used Kaplan-Meier survival curves, Cox regression analysis, diagnostic receiver operating characteristic (ROC) curves, and nomogram model. We also conducted wound healing assays, transwell assays, EdU assays, and colony formation assays to verify the UBD function. Gene ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, as well as gene set enrichment analysis (GSEA), were employed to determine the functions of UBD. Finally, we performed the western blot assays to assess changes in EMT markers as well as p-PI3K, p-AKT, and p-mTOR expressions. Our study revealed a remarkable increase of UBD expression in glioma samples. Cox regression analysis demonstrated that high expression of UBD mRNA was an independent prognostic factor for overall survival (OS) in TCGA. ROC curve analysis showed that UBD expression levels could differentiate glioma from adjacent normal tissues accurately. Additionally, knockdown of UBD reduced the migration, invasion, and proliferation ability of glioma cells while UBD overexpression had the opposite effect. GSEA showed that the expression of UBD involved with various pathways including epithelial-mesenchymal transition (EMT), PI3K-AKT-mTOR signaling, P53 pathway, angiogenesis, inflammatory response, KRAS signaling, hypoxia, as well as TGF-ß signaling. Furthermore, our findings suggest that UBD accelerates the activation of EMT and PI3K/AKT/mTOR pathway.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood. METHODS: Here, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction. RESULTS: As previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3ß to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings. CONCLUSIONS: Overall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3ß and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. Video Abstract.
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Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Enfermedades Mitocondriales , Humanos , Ratones , Animales , Mitofagia , Dinámicas Mitocondriales/genética , Diabetes Mellitus Tipo 2/complicaciones , Caveolina 1/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neuronas/metabolismo , Disfunción Cognitiva/etiología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Objective: To investigate the application of atorvastatin (AT) combined with ezetimibe (EZ) in elderly patients with hypertension (HY) combined with type 2 diabetes mellitus (T2DM) and the significance analysis of changes in serum bilirubin levels during treatment. Methods: One hundred and twelve elderly patients with HY combined with T2DM admitted to our hospital from September 2019 to March 2022 were selected and divided into a control group (AT) and a combined group (AT + EZ) according to the random number table method, with 56 cases in each group. It revealed that blood glucose, lipid function, inflammatory factors, and serum bilirubin [(total bilirubin, direct bilirubin (DBIL), indirect bilirubin (IBIL))] were also compared in both groups. The combined group was divided into high and low expression groups according to the mean total bilirubin value, and the incidence of adverse reactions was compared between the two groups. Results: Glucose, lipid function, and inflammatory factors were lower in the combined group than in the control group (P < .05). Total bilirubin, DBIL, and IBIL were higher in the combined group than in the control group (P < .05). The total incidence of adverse reactions in the high expression group was significantly lower than that in the low expression group (12.50% vs. 28.57%, P < .05). Conclusion: AT combined with EZ can effectively improve glucose, lipids, inflammation and upregulate serum bilirubin in patients with HY combined with T2DM.
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Diabetes Mellitus Tipo 2 , Hipertensión , Humanos , Anciano , Atorvastatina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ezetimiba/uso terapéutico , Bilirrubina , Hipertensión/tratamiento farmacológico , GlucosaRESUMEN
BACKGROUND: Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. METHODS: Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. RESULTS: In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L+ platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6,877,002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1ß while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. CONCLUSIONS: The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.
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Ligando de CD40 , Sepsis , Humanos , Ratones , Animales , Ligando de CD40/metabolismo , Células CACO-2 , Ocludina/metabolismo , S-Nitrosoglutatión/metabolismo , ARN Interferente Pequeño , Factor 6 Asociado a Receptor de TNF/metabolismo , Medios de Cultivo Condicionados , Activación Plaquetaria , Sepsis/metabolismo , Neuroglía/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
BACKGROUND: Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. METHODS: Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. RESULTS: In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L+ platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6877002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1ß while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. CONCLUSIONS: The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.
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Ligando de CD40 , Sepsis , Humanos , Ratones , Animales , Ocludina/metabolismo , Ligando de CD40/metabolismo , Células CACO-2 , S-Nitrosoglutatión/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , ARN Interferente Pequeño , Medios de Cultivo Condicionados/metabolismo , Activación Plaquetaria , Sepsis/metabolismo , Neuroglía/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
There are resourceful phospholipids in the eggs of the crab, Portunus trituberculatus (Pt-PL). However, their components and bioactivities regarding obesity were unclear. Here, we investigated the composition of Pt-PL and their fatty acids. Moreover, its effects on obesity and gut microbiota were also evaluated in high fat diet (HFD)-fed mice. The results showed that Pt-PL contained 12 kinds of phospholipids, mainly including phosphatidylcholine (PC, 32.28%), phosphatidylserine (PS, 26.51%), phosphatidic acid (PA, 19.61%), phosphatidylethanolamine (PE, 8.81%), and phosphatidylinositol (PI, 7.96%). Polyunsaturated fatty acids (PUFAs) predominated in the fatty acids components of Pt-PL, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Animal experiments demonstrated that Pt-PL significantly alleviated body weight gain, adipose gain, hepatic gain, fasting blood glucose, serum insulin, lipid levels in serum and the liver, and systematic inflammation in HFD-fed mice. Furthermore, Pt-PL regulated gut microbiota, especially in a dramatic reduction in the ratio of Firmicutes to Bacteroidetes at phylum level, as well as significant amelioration in their subordinate categories. Pt-PL reduced fecal lipopolysaccharide and total bile acids, and elevated fecal short chain fatty acid (SCFA) concentrations, particularly acetate and butyrate. These findings suggest that Pt-PL possesses anti-obesity effects and can alter gut microbiota owing to the abundance of PUFAs. Therefore, Pt-PL may be developed as an effective food supplement for anti-obesity and regulation of human gut health.
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Braquiuros , Microbioma Gastrointestinal , Animales , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/etiología , Fosfolípidos/farmacologíaRESUMEN
BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) may modulate cardiac autonomic function. However, the response rate of the traditional tonic paradigm is low, and the results remain inconsistent. A recent pilot study presented a novel burst paradigm to activate the cardiac parasympathetic system, which might offer a new approach to treat cardiac autonomic function. The present study reassessed the effect of burst taVNS on modulating heart rate variability and explored the difference between burst and traditional tonic paradigms. MATERIALS AND METHODS: Forty-two young adults were recruited for this study. Each participant underwent three types of taVNS with sham (30 sec of stimulation), tonic (25 Hz, 500 µsec), and burst (five pulses at 500 Hz every 200 msec) paradigms, respectively, with simultaneous electrocardiogram recording. One-way analysis of variance, multivariate analysis of variance, and linear regression were used for analysis. Multiple testing was performed using Bonferroni correction. RESULTS: Both burst and tonic paradigms induced a significant decrease in heart rate, which continued until poststimulation, and increased cardiac parasympathetic activity. Moreover, two parasympathetic system indicators showed significant increase only in burst taVNS. The response rates during burst (35.7%) and tonic (38.1%) stimulations were both higher than that during sham stimulation (11.9%). The response to taVNS showed parameter specificity with few nonresponders to the tonic paradigm responding to the burst paradigm. The overall response rate increased from 38.1% in tonic taVNS to 54.8% in taVNS using both burst and tonic paradigms. For both burst and tonic responders, baseline cardiac parasympathetic activity was found to be significantly negatively correlated with changes during stimulation. CONCLUSION: The burst parameter could be used as an alternative strategy for regulating cardiac parasympathetic function by taVNS, which has the potential to be used as a complementary paradigm to traditional tonic taVNS for promoting clinical treatment efficacy.
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Estimulación Eléctrica Transcutánea del Nervio , Estimulación del Nervio Vago , Sistema Nervioso Autónomo , Humanos , Proyectos Piloto , Estimulación Eléctrica Transcutánea del Nervio/métodos , Nervio Vago/fisiología , Estimulación del Nervio Vago/métodos , Adulto JovenRESUMEN
PURPOSE: To investigate parental acceptance of the use of general anesthesia with mask inhalation (GAMI) in the treatment of ankyloglossia. DESIGN: Parents of children with ankyloglossia received questionnaires to analyze the related factors of their acceptance of GAMI. METHODS: From July 2017 to November 2020, 131 parents of children with ankyloglossia in our hospital were enrolled and received investigation questionnaires. A total of 129 valid questionnaires were returned. The level of acceptance was evaluated using the visual analogue scale (VAS). We described the parental acceptance in a statistical method and performed univariant and multivariate analyses to identify related factors using SPSS 20.0. FINDINGS: A total of 129 (98.5%) parents completed the questionnaires. Only one patient (0.8%) experienced short-term (4 hours) abdominal bloating after surgery with GAMI. The average VAS regarding parental acceptance of the use of GAMI in the treatment was 43.80 mm (± 29.49), with only 17.8% of parents exhibiting a high level of acceptance of the anesthesia technique, while they had a relatively high level of satisfaction after surgery. CONCLUSIONS: Parents had a low level of acceptance of using GAMI in the treatment of ankyloglossia before surgery due to various factors.
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Anquiloglosia , Anestesia General/métodos , Anestesia por Inhalación , Niño , Humanos , Padres , Encuestas y CuestionariosRESUMEN
Fucoidans from sea cucumber (SC-FUC) have been proven to alleviate insulin resistance in several species. However, there are few studies that clarify the relationship between their structure and bioactivity. The present study evaluated the influence of molecular weight (Mw), sulfation concentrations (Cs), and sulfation position on improving insulin resistance using SC-FUC. Results showed that fucoidans with lower Mw exerted stronger effects. Having a similar Mw, Acaudina molpadioides fucoidans (Am-FUC) with lower Cs and Holothuria tubulosa fucoidans with higher Cs showed similar activities. However, Isostichopus badionotus fucoidans (higher Cs) activity was superior to that of low-Mw Thelenota ananas fucoidans (Ta-LFUC, lower Cs). Eliminating the effects of Mw and Cs, the bioactivity of Am-FUC with sulfation at meta-fucose exceeded that of Ta-FUC with sulfation at ortho-position. Moreover, the effects of Pearsonothuria graeffei fucoidans with 4-O-sulfation were superior to those of Am-LFUC with 2-O-sulfation. These data indicate that low Mw, 4-O-sulfation, and sulfation at meta-fucose contributed considerably to insulin resistance alleviation by SC-FUC, which could accelerate the development of SC-FUC as a potential food supplement to alleviate insulin resistance.
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Hipoglucemiantes/farmacología , Polisacáridos/farmacología , Pepinos de Mar , Animales , Organismos Acuáticos , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Fucosa , Hipoglucemiantes/química , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Peso Molecular , Polisacáridos/química , Relación Estructura-Actividad , SulfatosRESUMEN
Portunus trituberculatus eggs contain phospholipids, whose components and bioactivity are unclear. Here, we investigated the fatty acid composition of phosphatidylserine from P. trituberculatus eggs (Pt-PS). Moreover, its effects on insulin resistance and gut microbiota were also evaluated in high-fat-diet-fed mice. Our results showed that Pt-PS accounted for 26.51% of phospholipids and contained abundant polyunsaturated fatty acids (more than 50% of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)). Animal experiments indicated that Pt-PS significantly decreased body weight and adipose weight gain, improved hyperglycemia and hyperinsulinemia, mitigated insulin resistance, and regulated circulatory cytokines. Pt-PS activated insulin receptor substrate 1 (IRS1) and increased the levels of IRS1-associated phosphatidylinositol 3-hydroxy kinase (PI3K), phosphorylated protein kinase B (Akt) protein, and plasma membrane glucose transporter 4 protein. Furthermore, Pt-PS modified the gut microbiota, inducing, especially, a dramatic decrease in the ratio of Firmicutes to Bacteroidetes at the phylum level, as well as a remarkable improvement in their subordinate categories. Pt-PS also reduced fecal lipopolysaccharide concentration and enhanced fecal acetate, propionate, and butyrate concentrations. Additionally, the effects of Pt-PS on alleviation of insulin resistance and regulation of intestinal bacteria were better than those of phosphatidylserine from soybean. These results suggest that Pt-PS mitigates insulin resistance by altering the gut microbiota. Therefore, Pt-PS may be developed as an effective food supplement for the inhibition of insulin resistance and the regulation of human gut health.
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Braquiuros , Microbioma Gastrointestinal/efectos de los fármacos , Resistencia a la Insulina , Fosfatidilserinas/farmacología , Animales , Dieta Alta en Grasa , Masculino , Ratones , Ratones Endogámicos C57BL , Óvulo/química , Fosfatidilserinas/química , Fosfatidilserinas/aislamiento & purificación , Aumento de Peso/efectos de los fármacosRESUMEN
PURPOSE: To identify a lncRNA signature to predict survival of breast cancer (BRCA) patients. METHODS: A total of 1222 BRCA case and control datasets were downloaded from the TCGA database. The weighted gene co-expression network analysis of differentially expressed mRNAs was performed to generate the modules associated with BRCA overall survival status and further construct a hub on competing endogenous RNA (ceRNA) network. LncRNA signatures for predicting survival of BRCA patients were generated using univariate survival analyses and a multivariate Cox hazard model analysis and validated and characterized for prognostic performance measured using receiver operating characteristic (ROC) curves. RESULTS: A prognostic score model of eight lncRNAs signature was identified as Prognostic score = (0.121 × EXPAC007731.1) + (0.108 × EXPAL513123.1) + (0.105 × EXPC10orf126) + (0.065 × EXPWT1-AS) + (- 0.126 × EXPADAMTS9-AS1) + (- 0.130 × EXPSRGAP3-AS2) + (0.116 × EXPTLR8-AS1) + (0.060 × EXPHOTAIR) with median score 1.088. Higher scores predicted higher risk. The lncRNAs signature was an independent prognostic factor associated with overall survival. The area under the ROC curves (AUC) of the signature was 0.979, 0.844, 0.99 and 0.997 by logistic regression, support vector machine, decision tree and random forest models, respectively, and the AUCs in predicting 1- to 10-year survival were between 0.656 and 0.748 in the test dataset from TCGA database. CONCLUSIONS: The eight-lncRNA signature could serve as an independent biomarker for prediction of overall survival of BRCA. The lncRNA-miRNA-mRNA ceRNA network is a good tool to identify lncRNAs that is correlated with overall survival of BRCA.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , ARN Largo no Codificante/genética , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Estimación de Kaplan-Meier , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Interferencia de ARN , ARN Mensajero/genética , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
Fibrosis leads to organ failure and death, which is the final stage of many chronic diseases. Triptolide (TPL) is a terpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F (TwHF). Triptolide and its derivatives (Omtriptolide, Minnelide, (5R)-5-hydroxytriptolide) have been proven to have a variety of pharmacological effects. This study comprehensively reviewed the antifibrotic mechanism of TPL and its derivatives, and discussed the application of advanced nanoparticles (NPs) drug delivery system in the treatment of fibrotic diseases by TPL. The results show that TPL can inhibit immune inflammatory response, relieve oxidative stress and endoplasmic reticulum stress (ERS), regulate collagen deposition and inhibit myofibroblast production to play an anti-fibrosis effect and reduce organ injury. A low dose of TPL has no obvious toxicity. Under pathological conditions, a toxic dose of TPL has a protective effect on organs. The emergence of TPL derivatives (especially Minnelide) and NPs drug delivery systems promotes the anti-fibrosis effect of TPL and reduces its toxicity, which may be the main direction of anti-fibrosis research in the future.
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Diterpenos , Compuestos Epoxi , Fibrosis , Fenantrenos , Diterpenos/farmacología , Diterpenos/química , Diterpenos/administración & dosificación , Fenantrenos/farmacología , Fenantrenos/química , Fenantrenos/administración & dosificación , Compuestos Epoxi/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/administración & dosificación , Humanos , Fibrosis/tratamiento farmacológico , Animales , Antifibróticos/farmacología , Antifibróticos/químicaRESUMEN
Acute kidney injury (AKI) is a critical medical condition characterized by high morbidity and mortality rates. The pathogenesis of AKI potentially involves bursts of reactive oxygen species (ROS) bursts and elevated levels of inflammatory mediators. Developing nanoparticles (NPs) that downregulate ROS and inflammatory mediators is a promising approach to treat AKI. However, such NPs would be affected by the glomerular filtration barrier (GFB). Typically, NPs are too large to penetrate the glomerular system and reach the renal tubulesâthe primary site of AKI injury. Herein, we report the development of ultrasmall carbon dots-gallic acid (CDs-GA) NPs (â¼5 nm). These NPs exhibited outstanding biocompatibility and were shown not only to efficiently eliminate ROS and alleviate oxidative stress but also to suppress the activation of the NF-κB signaling pathway, leading to a reduction in the release of inflammatory factors. Importantly, CDs-GA NPs were shown to be able to rapidly accumulate rapidly in the renal tissues without the need for intricate targeting strategies. In vivo studies demonstrated that CDs-GA NPs significantly reduced the incidence of cisplatin (CDDP)-induced AKI in mice, surpassing the efficacy of the small molecular drug, N-acetylcysteine. This research provides an innovative strategy for the treatment of AKI.
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Lesión Renal Aguda , Carbono , Cisplatino , Especies Reactivas de Oxígeno , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Animales , Carbono/química , Carbono/uso terapéutico , Ratones , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/uso terapéutico , Cisplatino/farmacología , Ácido Gálico/farmacología , Ácido Gálico/química , Ácido Gálico/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , FN-kappa B/metabolismo , Masculino , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Puntos Cuánticos/toxicidad , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Background: The number of prediction models for diabetic foot ulcer (DFU) risk is increasing, but their methodological quality and clinical applicability are uncertain. We conducted a systematic review to assess their performance. Methods: We searched PubMed, Cochrane Library, and Embase databases up to 10 February 2024 and extracted relevant information from selected prediction models. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) checklist was used to assess bias risk and applicability. All statistical analyses were conducted in Stata 14.0. Results: Initially, 13,562 studies were retrieved, leading to the inclusion of five development and five validation models from eight studies. DFU incidence ranged from 6% to 16.8%, with age and hemoglobin A1C (HbA1c) commonly used as predictive factors. All included studies had a high risk of bias, mainly due to disparities in population characteristics and methodology. In the meta-analysis, we observed area under the curve (AUC) values of 0.78 (95% CI [0.69-0.89]) for development models and 0.84 (95% CI [0.79-0.90]) for validation models. Conclusion: DFU risk prediction models show good overall accuracy, but there is a risk of bias. Adherence to the PROBAST checklist is crucial for improving their clinical applicability.
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Pie Diabético , Pie Diabético/epidemiología , Pie Diabético/diagnóstico , Humanos , Medición de Riesgo/métodos , Factores de Riesgo , Hemoglobina Glucada/análisis , Modelos EstadísticosRESUMEN
Diabetes-associated cognitive dysfunction (DACD) has ascended to become the second leading cause of mortality among diabetic patients. Phosphoserine phosphatase (PSPH), a pivotal rate-limiting enzyme in L-serine biosynthesis, has been documented to instigate the insulin signaling pathway through dephosphorylation. Concomitantly, CD38, acting as a mediator in mitochondrial transfer, is activated by the insulin pathway. Given that we have demonstrated the beneficial effects of exogenous mitochondrial supplementation on DACD, we further hypothesized whether astrocytic PSPH could contribute to improving DACD by promoting astrocytic mitochondrial transfer into neurons. In the Morris Water Maze (MWM) test, our results demonstrated that overexpression of PSPH in astrocytes alleviated DACD in db/db mice. Astrocyte specific-stimulated by PSPH lentivirus/ adenovirus promoted the spine density both in vivo and in vitro. Mechanistically, astrocytic PSPH amplified the expression of CD38 via initiation of the insulin signaling pathway, thereby promoting astrocytic mitochondria transfer into neurons. In summation, this comprehensive study delineated the pivotal role of astrocytic PSPH in alleviating DACD and expounded upon its intricate cellular mechanism involving mitochondrial transfer. These findings propose that the specific up-regulation of astrocytic PSPH holds promise as a discerning therapeutic modality for DACD.
RESUMEN
The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3/3a (C3/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.
Asunto(s)
Disfunción Cognitiva , Diabetes Mellitus Tipo 1 , Ratones , Animales , Astrocitos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Factores Protectores , Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Disfunción Cognitiva/metabolismo , Receptor Sigma-1RESUMEN
Dementia, as an advanced diabetes-associated cognitive dysfunction (DACD), has become the second leading cause of death among diabetes patients. Given that little guidance is currently available to address the DACD process, it is imperative to understand the underlying mechanisms and screen out specific therapeutic targets. The excessive endogenous fructose produced under high glucose conditions can lead to metabolic syndrome and peripheral organ damage. Although generated by the brain, the role of endogenous fructose in the exacerbation of cognitive dysfunction is still unclear. Here, we performed a comprehensive study on leptin receptor-deficient T2DM mice and their littermate m/m mice and revealed that 24-week-old db/db mice had cognitive dysfunction and excessive endogenous fructose metabolism in the hippocampus by multiomics analysis and further experimental validation. We found that the rate-limiting enzyme of fructose metabolism, ketohexokinase, is primarily localized in microglia. It is upregulated in the hippocampus of db/db mice, which enhances mitochondrial damage and reactive oxygen species production by promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression and mitochondrial translocation. Inhibiting fructose metabolism via ketohexokinase depletion reduces microglial activation, leading to the restoration of mitochondrial homeostasis, recovery of structural synaptic plasticity, improvement of CA1 pyramidal neuron electrophysiology and alleviation of cognitive dysfunction. Our findings demonstrated that enhanced endogenous fructose metabolism in microglia plays a dominant role in diabetes-associated cognitive dysfunction and could become a potential target for DACD.
Asunto(s)
Disfunción Cognitiva , Diabetes Mellitus , Humanos , Ratones , Animales , Microglía/metabolismo , Fructosa/metabolismo , Disfunción Cognitiva/etiología , Encéfalo/metabolismo , Fructoquinasas/genética , Fructoquinasas/metabolismoRESUMEN
BACKGROUND: Dementia is a serious complication in patients with diabetes-associated cognitive dysfunction (DACD). In this study, we aim to explore the protective effect of exercise on DACD in diabetic mice, and the role of NDRG2 as a potential guarder for reversing the pathological structure of neuronal synapses. METHODS: Seven weeks of standardized exercise at moderate intensity was carried out using an animal treadmill in the vehicle + Run and STZ + Run groups. Based on quantitative transcriptome and tandem mass tag (TMT) proteome sequencing, weighted gene co-expression analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to investigate the activation of complement cascades to injury neuronal synaptic plasticity. Golgi staining, Western blotting, immunofluorescence staining, and electrophysiology were used to verify the reliability of sequencing data. The role of NDRG2 was assessed by overexpressing or inhibiting the NDRG2 gene in vivo. Moreover, we estimated the cognitive function in diabetic or normal patients using DSST scores. FINDINGS: Exercise reversed the injury of neuronal synaptic plasticity and the downregulation of astrocytic NDRG2 in diabetic mice, which succeeded in attenuating DACD. The deficiency of NDRG2 aggravated the activation of complement C3 by accelerating the phosphorylation of NF-κB, ultimately leading to synaptic injury and cognitive dysfunction. Conversely, the overexpression of NDRG2 promoted astrocytic remodeling by inhibiting complement C3, thus attenuating synaptic injury and cognitive dysfunction. Meanwhile, C3aR blockade rescued dendritic spines loss and cognitive deficits in diabetic mice. Moreover, the average DSST score of diabetic patients was significantly lower than that of non-diabetic peers. Levels of complement C3 in human serum were elevated in diabetic patients compared to those in non-diabetic patients. INTERPRETATION: Our findings illustrate the effectiveness and integrative mechanism of NDRG2-induced improvement of cognition from a multi-omics perspective. Additionally, they confirm that the expression of NDRG2 is closely related to cognitive function in diabetic mice and the activation of complement cascades accelerated impairment of neuronal synaptic plasticity. NDRG2 acts as a regulator of astrocytic-neuronal interaction via NF-κB/C3/C3aR signaling to restore synaptic function in diabetic mice. FUNDING: This study was supported by the National Natural Science Foundation of China (No. 81974540, 81801899, 81971290), the Key Research and Development Program of Shaanxi (Program No. 2022ZDLSF02-09) and Fundamental Research Funds for the Central Universities (Grant No. xzy022019020).